Opioids and Depression: How Mood Changes Happen and How to Monitor Them

When someone starts taking opioids for chronic pain, they often expect relief from physical discomfort. But many don’t realize that opioids can also change how they feel emotionally - sometimes in ways that are subtle, slow, and deeply troubling. Over time, what begins as temporary pain relief can turn into a persistent low mood, loss of interest in life, or even full-blown depression. This isn’t just a coincidence. Research shows a real, measurable link between long-term opioid use and worsening depression - and the cycle can be hard to break once it starts.

How Opioids Can Make Depression Worse

Opioids work by binding to receptors in the brain that control pain, but they also affect areas tied to emotion and reward. In the short term, this can feel good. Some people report feeling calmer, less anxious, or even mildly euphoric. That’s why opioids are sometimes used off-label for mood disorders - and why some patients with depression report feeling better after starting them.

But here’s the catch: those same brain changes that bring temporary relief can backfire over time. Studies using brain imaging and genetic data show that long-term opioid use disrupts the body’s natural production of endorphins and other mood-regulating chemicals. The brain gets used to the drug’s presence and starts producing less of its own. When that happens, people feel worse when the drug wears off - not just physically, but emotionally.

A 2020 study in JAMA Psychiatry analyzed genetic data from over 300,000 people and found that those with a higher genetic risk for using prescription opioids were also more likely to develop major depressive disorder. This wasn’t just correlation - it suggested opioid use might actually cause depression in some cases. Other research shows that people taking more than 50 milligrams of morphine equivalent per day have more than three times the risk of developing depression compared to those who don’t use opioids at all.

The Vicious Cycle: Pain, Depression, and More Opioids

It’s not just that opioids cause depression. Depression can also make people more likely to use opioids - and use them longer. People with untreated depression often report higher pain sensitivity. They may feel their pain more intensely, which leads doctors to prescribe higher doses. And because depression makes it harder to cope with discomfort, patients are more likely to rely on opioids just to get through the day.

This creates a dangerous loop:

1. Depression increases pain perception.
2. Higher pain leads to higher opioid doses.
3. Long-term opioid use lowers natural mood chemicals.
4. Mood worsens, reinforcing the need for more opioids.

One study of over 10 million patients found that those with depression were twice as likely to become long-term opioid users compared to those without depression. And once someone is on opioids for more than three months, their risk of developing depression jumps significantly. The longer they’re on them, the worse it gets.

What Depression Looks Like on Opioids

Depression from opioids doesn’t always show up as crying or sadness. It often looks like numbness - a loss of joy in things you used to love. You might stop calling friends, skip meals, or feel too tired to get out of bed - even if your pain has improved. People on opioids often describe it as “going through the motions.”

Key signs to watch for:

• Loss of interest in hobbies, work, or relationships
• Feeling emotionally flat or detached
• Increased fatigue or sleep problems
• Difficulty concentrating or making decisions
• Feelings of worthlessness or guilt
• Thoughts of hopelessness or self-harm

These symptoms can be easy to miss - especially if the person is focused on physical pain. Many doctors don’t ask about mood unless the patient brings it up. But research shows that primary care providers miss about half of depression cases in patients on opioids.

How to Monitor Mood Changes Properly

Monitoring isn’t just about checking in once a year. It needs to be regular, structured, and honest. The American Pain Society and CDC both recommend screening for depression at the start of opioid therapy - and then every three months after that. But in reality, only about 40% of doctors do this consistently.

The most reliable tool is the PHQ-9 (Patient Health Questionnaire-9). It’s free, takes less than five minutes, and asks about symptoms like sleep, energy, appetite, and mood over the past two weeks. Scores of 10 or higher suggest moderate to severe depression and should trigger further evaluation.

Other useful tools include the Beck Depression Inventory (BDI) and simple daily mood tracking. Some patients find it helpful to keep a journal: “On a scale of 1 to 10, how did I feel today? Did I want to do anything? Did I talk to anyone?” These small notes can reveal patterns that a single doctor’s visit might miss.

Experts like Dr. Roger Weiss recommend monthly check-ins during the first six months of opioid therapy, especially if the dose is high or the patient has a history of mental health issues. After that, quarterly screenings are still essential.

Buprenorphine: A Rare Bright Spot

Not all opioids are the same. Buprenorphine - often used to treat opioid addiction - has shown surprising antidepressant effects in clinical trials. In one study, patients with opioid use disorder and depression saw their BDI scores drop from severe (24.7) to mild (13.4) after three months on buprenorphine. Another trial found that even low doses (1-2 mg/day) improved depression in people who hadn’t responded to standard antidepressants.

Why does this happen? Buprenorphine is a partial opioid agonist - it activates receptors just enough to stabilize mood without causing the same kind of brain rewiring as full opioids like oxycodone or hydrocodone. It’s not approved by the FDA for treating depression, but doctors can prescribe it off-label. For patients with both chronic pain and depression, it may be one of the safest long-term options.

What to Do If You’re Feeling Worse

If you’re on opioids and notice your mood dropping, don’t wait. Don’t assume it’s just “the pain getting worse.” Don’t blame yourself. This is a known side effect - not a personal failure.

Here’s what to do next:

1. Track your mood for a week using the PHQ-9 or a simple journal.
2. Make an appointment with your doctor - bring your notes.
3. Ask: “Could my opioids be making my mood worse?”
4. Request a referral to a mental health professional who understands chronic pain.
5. Don’t stop opioids cold turkey - that can be dangerous. Work with your doctor to adjust safely.

Some patients benefit from adding cognitive behavioral therapy (CBT) to their treatment plan. In the COMBINE trial, patients who received CBT alongside pain management reduced their opioid doses by 32% - and their depression improved too.

The Bigger Picture: Why This Matters

This isn’t just about individual patients. The opioid-depression connection is a major driver of the overdose crisis. People who feel hopeless, numb, or trapped are more likely to take extra pills, mix medications, or turn to street drugs. Treating depression isn’t just about feeling better - it’s about saving lives.

Researchers are now using brain scans and long-term tracking to understand why short-term opioid use lifts mood, while long-term use crushes it. Early findings suggest that after months of use, the brain’s reward system becomes less responsive - not just to opioids, but to everything. That’s when life starts to feel empty, even when the pain is gone.

There’s hope. We’re learning how to break the cycle. But it starts with recognizing the signs - and talking about them honestly.