Chronic pain and substance use disorders share a common neurobiological root: reduced dopamine signaling in the brain's reward pathway — creating a vulnerability where self-medication with opioids or cannabis can escalate into addiction.
Read this if you use cannabis or opioids for chronic pain and want to understand the biological reasons why these substances can feel essential — and why that feeling can become a problem.
What the researchers found
Over 50 million Americans live with chronic pain, and many don't receive adequate treatment. This review tackles a question with enormous public health implications: why are chronic pain patients more likely to develop opioid and cannabis use disorders?
The answer centers on dopamine — the brain's reward and motivation chemical. Chronic pain suppresses dopamine signaling in the mesolimbic pathway (the brain's reward circuit), creating a state called hypodopaminergia. This reduced dopamine state does two things: it makes pain feel worse (because dopamine normally helps modulate pain perception) and it makes anything that boosts dopamine — including opioids and cannabis — feel especially rewarding.
Both opioids and cannabis temporarily restore dopamine signaling, relieving not just pain but the negative emotional state that accompanies chronic pain: the depression, anxiety, irritability, and loss of motivation. This dual relief — physical and emotional — is what drives self-medication and makes these substances so compelling for pain patients.
But the relief creates a trap. Repeated opioid or cannabis use further dysregulates dopamine signaling, deepening the hypodopaminergic state and increasing the drive to use. The brain adapts to the drug-boosted dopamine, and withdrawal makes the dopamine deficit even worse. This creates a cycle where the self-medication that initially provided relief gradually becomes part of the problem.
The review details the specific neurobiological mechanisms: how opioids modulate dopamine through mu-receptor activation in the ventral tegmental area, how cannabis modulates it through CB1 receptor effects on GABA and glutamate interneurons, and how chronic pain itself alters these circuits at a cellular level.
Why it matters
Understanding why chronic pain leads to substance misuse isn't just academic — it should change how we treat both conditions. If the common root is hypodopaminergic signaling, then treating chronic pain more effectively might prevent substance misuse, and understanding the shared neurobiology might lead to treatments that address both conditions simultaneously rather than treating them as separate problems.
The numbers in context
Over 50 million Americans have chronic pain. High comorbidity between chronic pain and substance use disorders is well-documented. The mesolimbic dopamine pathway is central to both conditions. Opioids act through mu-receptors in the VTA; cannabis acts through CB1 receptors on GABA/glutamate interneurons. Chronic pain creates measurable hypodopaminergic transmission.
How the study worked
Narrative review synthesizing clinical evidence and neurobiological research on the link between chronic pain and opioid/cannabis use disorders. Covered: epidemiological data on comorbidity, dopaminergic mechanisms in pain and addiction, opioid and cannabinoid effects on mesolimbic dopamine signaling, and the neuroadaptations that link pain to substance misuse.
Who was studied
Review of literature on chronic pain and substance use disorders, focusing on opioids and cannabis.
What this study cannot tell us
Narrative review, not systematic. While the dopaminergic hypothesis is compelling, chronic pain and addiction involve many neurotransmitter systems beyond dopamine (norepinephrine, serotonin, endogenous opioids, endocannabinoids). The causal direction isn't fully established — chronic pain may cause substance use disorders, substance use may worsen pain (opioid-induced hyperalgesia), or shared vulnerabilities may predispose to both. Most neurobiological evidence comes from animal models that don't fully capture the human experience of pain and addiction.
How to read the evidence
Narrative review synthesizing clinical and preclinical evidence. The dopaminergic hypothesis is well-supported by both animal and human data, but the complete picture of pain-addiction comorbidity involves mechanisms beyond dopamine.
When this study was published
Published in 2024. The neuroscience of pain-addiction overlap is an active and rapidly evolving field.
The bigger picture
This review provides the neuroscience backbone connecting several clusters in the RethinkTHC database. The dopamine-endocannabinoid interaction studies (RTHC-00072, RTHC-00073, RTHC-00075) described the basic science of how cannabinoids modulate dopamine. The tolerance and withdrawal studies (RTHC-00100, RTHC-00037) documented the brain adaptations that occur with chronic cannabis use. This review ties those mechanisms directly to chronic pain, explaining why the same biological system that cannabis acts on is dysregulated in pain patients — and why that creates both therapeutic opportunity and addiction risk.
Replication
Not stated in abstract.
Funding
Not reported in abstract.
Conflicts of interest
Not reported in abstract.
Questions still open
- Could dopamine-targeted treatments (like low-dose dopamine agonists) treat both chronic pain and associated substance misuse simultaneously? Would treating chronic pain more effectively with non-addictive approaches prevent the development of opioid and cannabis use disorders? Can we identify which chronic pain patients are at highest risk for developing substance use problems based on dopamine signaling markers?
Read the original research
Unveiling the link between chronic pain and misuse of opioids and cannabis.
Journal of neural transmission (Vienna, Austria : 1996), 131(5), 563-580
The Journal of Neural Transmission is a reputable journal focusing on neuroscience and neurobiology.
Citation
Dagher, Merel; Alayoubi, Myra; Sigal, Gabriella H; Cahill, Catherine M. (2024). Unveiling the link between chronic pain and misuse of opioids and cannabis.. Journal of neural transmission (Vienna, Austria : 1996), 131(5), 563-580. https://doi.org/10.1007/s00702-024-02765-3
Explore the wider topic
- 30 Days Without Weed: What I Learned
- 6 Months Without Weed: What Nobody Tells You
- 90 Days Weed Free: The Real Long-Term Benefits
- CBD Oil Quality Guide: How to Avoid Snake Oil
- Anxiety After Quitting Weed: When to Consider Medication
- Benefits of Quitting Weed: What Changes After 30, 60, 90 Days
- Quitting Weed and Boredom: The Hardest Part
- The Boredom Problem: Why Nothing Feels Fun After Quitting Weed
- Cannabis for Chemotherapy Nausea: What the Evidence Actually Shows
- Cannabis for Chronic Pain: What the Research Actually Supports
- Cannabis and Epilepsy: The Epidiolex Story and What It Means
- Does CBD Actually Work for Anxiety? What the Evidence Shows
- Does CBD Help with Weed Withdrawal? What Studies Show
- CBD vs THC: The Differences That Actually Matter
- Creativity After Quitting Weed: What Actually Happens
- Finding New Hobbies After Quitting Weed
- The Stoner Identity Crisis: Who Am I Without Weed?
- Leaving Stoner Culture Behind: Rebuilding Your Identity After Weed
- The Proven Medical Benefits of Cannabis: What Research Supports
- Money Saved Quitting Weed: The Real Numbers
- One Year Without Weed: Reflections on What Actually Changed
- Quitting Weed Before Surgery
- Quitting Weed and Creativity: Will I Lose My Spark?
- Does Quitting Weed Change Your Face?
- Weed and Medications: What Changes When You Quit
- Quitting Weed During Pregnancy: What You Need to Know
- Quitting Weed While Pregnant: What You Need to Know
- Quitting Weed and Weight Changes: Why Some People Lose and Others Gain
- Cannabis and Older Adults: Risks Seniors Should Know
- Cannabis and Breastfeeding: THC in Breast Milk
- Weed Withdrawal Journal: Free Printable Tracker
- Cannabis Recovery Communities Compared: Finding Your People
- Cannabis Effects and Experience: The Science Behind Your High
- Why Am I More Creative When I'm High? THC and Divergent Thinking
- THC and Weightlifting: Does Cannabis Affect Muscle Growth or Recovery
- THC and Discipline: Does Daily Use Erode Willpower
- THC and Creative Work: Artists, Musicians, and Writers on Cannabis
- Cannabis and Fibromyalgia: Evidence, Dosing, and What Patients Report
- Cannabis and Carpal Tunnel: Can THC Help Nerve Pain
- Cannabis and Migraines: Prevention, Treatment, and What Studies Show
- Cannabis and Parkinson's Disease: Tremor, Sleep, and Quality of Life
- Cannabis Recovery Devotional: 30 Days of Scripture and Science
- Celebrate Recovery vs Marijuana Anonymous: Faith-Based Comparison