Decoding the Struggle: Understanding the Neurobiology of Opioid Withdrawal

By Wesley C. Sassaman, DNP, MPH, MSN-NE, MBA, FNP-C, CARN-AP

Welcome to my blog. My name is Dr. Wesley Sassaman, and as someone who has dedicated my career to helping individuals and families overcome the devastating effects of addiction, I want you to know that you are not alone. If you are a parent—especially a single mom—feeling exhausted and heartbroken as you watch your teen or young adult struggle to break free from the grip of fentanyl, this space was created for you.

I understand how overwhelming it can be to see your child endure the anguish of withdrawal, feeling like there's nowhere to turn. That’s why I’ve pouring my expertise into creating valuable resources to answer your questions, ease your fears, and guide you step by step.

On my website, wesleysassaman.com, you’ll find a wealth of information written specifically with parents in mind. From understanding the science behind withdrawal to practical advice on supporting your child, these resources are designed to empower you with knowledge and hope.

This battle is one of the toughest any parent can face, but you’re not in it alone. With the right understanding, love, and professional support, healing is possible—for your child and for your family. Thank you for trusting me to be part of your journey. Together, we can move forward toward hope and recovery.

It’s all in the Receptors.

The overwhelming discomfort your teen or young adult might experience during opioid withdrawal stems not just from physical symptoms, but deep changes in how their brain’s reward and stress systems function. A major culprit behind this distress, known as dysphoria, is how opioids interact with two types of receptors in the brain—the mu (µ) and kappa (κ) opioid receptors.

Think of the µ-opioid receptors as the ones that opioids "hijack" to create feelings of pleasure and relief. When opioids leave the body, these same receptors become overly active in certain brain regions, amplifying the emotional and physical pain of withdrawal.

On the other hand, the κ-opioid receptors are more like the messengers of discomfort, stress, and emotional lows. When withdrawal begins, these receptors become highly active, worsening the feelings of unease and distress. Together, these brain changes create a perfect storm, where withdrawal feels unbearably heavy both physically and emotionally.

How the Brain’s Regions Contribute to Withdrawal Dysphoria

One key area affected is the central amygdala (CeA), a region heavily involved in processing negative emotions. During withdrawal, neurons in this area ramp up their activity, making every sensation of withdrawal feel harsher. Studies show that if these µ-opioid receptor-containing neurons in the CeA are silenced, the aversive withdrawal symptoms dramatically lessen—proving just how central they are to feelings of dysphoria (Chaudun et al., 2024).

Even the brain’s support cells, known as astrocytes, play a role. These small but mighty cells express µ-opioid receptors and are tied to energy function within brain cells. When withdrawal occurs, a loss of these receptors in astrocytes can worsen the discomfort experienced, showing their importance in long-term brain balance during and post-withdrawal (Murlanova et al., 2023).

The Role of κ-Opioid Receptors in Emotional Distress

If µ-opioid receptors are key to the brain’s reward system, κ-opioid receptors (KORs) are tied to stress and sadness. During withdrawal, dynorphins—brain chemicals that activate KORs—flood the system, enhancing feelings of depression and unease. This system’s role is so significant that researchers have investigated how blocking KORs might ease these symptoms. While the results are mixed, some evidence suggests that short-acting KOR blockers can ease withdrawal-caused anxiety, offering hope for better interventions (Cayir et al., 2024; Akins et al., 2023).

How Brain Plasticity Shapes Emotional Pain in Withdrawal

Withdrawal symptoms go beyond fleeting chemical changes; they involve rewiring in the brain’s networks, or what scientists call neuroplasticity. Brain regions like the extended amygdala, which includes areas such as the CeA and the bed nucleus of the stria terminalis (BNST), undergo these changes, deepening the emotional pain of withdrawal.

For instance, shifts in excitatory and inhibitory signals (such as those controlled by glutamate and CRF neurons) can intensify feelings of stress and sadness during this time (Kaplan & Thompson, 2023).

Similarly, alterations in the ventral tegmental area (VTA), a region critical to the brain’s reward and pleasure system, can worsen dysphoria. During withdrawal, increased inhibitory signals in the VTA suppress the activity of dopamine neurons, further diminishing the brain’s ability to feel pleasure or reward. Interestingly, this effect appears to differ between males and females due to variations in how GABA, a key neurotransmitter, functions in the VTA for each group (Kalamarides et al., 2023).

Genetic and Gender-Specific Factors in Withdrawal Burden

Another piece to understanding your teen’s withdrawal experience lies in biology and genetics. Genetic factors, like a common variation called OPRM1A118G, can change how connected and adaptive their brain networks are during opioid use and withdrawal. The OPRM1A118G, is a single-nucleotide polymorphism (SNP) in the gene that produces mu-opioid receptors (MOPRs). MOPRs are involved in pain regulation and the effects of opioids and placebos. This genetic "wiring difference" may amplify feelings of distress, making it harder for some individuals to cope (Xie & Blendy, 2023).

Gender also plays a surprising role. Males and females differ in how their brains respond to opioid withdrawal. Females may experience changes in emotional processing differently, influenced by unique patterns of synaptic plasticity and neurotransmitter activity in areas like the VTA. These biological nuances further shape the severity and nature of withdrawal dysphoria (Kalamarides et al., 2023).

Why This Matters

The intense discomfort your teen feels during withdrawal isn’t just "in their head"—it reflects profound biological and chemical shifts happening in their brain. Understanding these mechanisms, from hyperactive reward circuits to stress-inducing κ-opioid receptors, can give you valuable insight. Knowing how these systems respond and even why your child’s genetics or gender may influence their experience can help guide your empathy and patience as you support them on their recovery path.

A Parent’s Guide to Understanding Opioid Withdrawal Challenges

Supporting a teen or young adult through opioid withdrawal can be daunting. The intense emotions, physical discomfort, and behavioral changes they experience are tied to significant but temporary changes in their brain. By learning about these processes, you can better understand what they’re going through and how to help. This section explains the challenges of withdrawal in direct terms, focusing on the brain’s role during this critical time.

What Happens in the Brain During Withdrawal?

Imagine your child’s brain like a car engine. Opioids act as a powerful fuel, revving it up unnaturally, but once taken away, the engine sputters and stalls, struggling to operate without that boost. During withdrawal, the brain tries to readjust, which causes emotional, cognitive, and physical symptoms.

Opioids affect the brain’s reward system, particularly by interacting with opioid receptors. These receptors are like the brain’s happiness buttons—they normally release feel-good chemicals, endorphins, during things like exercise or relaxation. When your child used opioids, these drugs overwhelmed the system, flooding the brain with euphoria. Over time, the brain reduced its own endorphin production in response, making it dependent on opioids for even basic feelings of balance and well-being. Once the drugs are gone, the brain struggles to function, leading to intense cravings and discomfort.

How the Brain's Key Regions Contribute

Here’s how specific brain areas come into play during withdrawal, explained in everyday terms.

1. The Orbitofrontal Cortex (OFC): The Decision Maker

The orbitofrontal cortex helps your child make decisions and weigh risks, but during withdrawal, it becomes laser-focused on finding opioids. The brain mistakenly equates opioids with survival. Cravings feel overpowering because the OFC signals "danger" when opioids aren’t present.

Analogy: It’s like an overzealous GPS that insists taking a wrong route is the only way to get to safety.

Impact on Behavior: Cravings may drive desperate behavior, such as arguing, impulsive decisions, or dishonesty, as they try to quiet this intense need (Lin et al., 2024).

2. The Amygdala and Extended Amygdala System: The Stress Alarm

The amygdala is like the brain’s smoke detector—it processes fear and stress. During withdrawal, it goes into overdrive, firing off distress signals even for small challenges. The extended amygdala keeps this alarm blaring, amplifying feelings of hopelessness, sadness, and extreme irritability (Kaplan & Thompson, 2023).

Analogy: Imagine a fire alarm going off in your home, but there’s no fire—yet the alarm won’t stop, no matter how hard you try to silence it.

Impact on Behavior: Your child may seem anxious, overly emotional, or even angry without a clear reason. This hyper-alert state is draining and makes coping with other symptoms harder (Kalamarides et al., 2023).

3. The Dorsal Hippocampus (DH): The Emotional Scrapbook

This part of the brain is responsible for linking memories and emotions. During withdrawal, it amplifies fear and anxiety tied to situations or places associated with opioid use. This is why your child may avoid places or people from their past life of addiction—it can feel emotionally overwhelming.

Analogy: Picture a scrapbook that only contains the worst moments of their life, and every page makes them relive tough memories.

Impact on Behavior: Withdrawal can cause anxious avoidance of social interactions or specific environments as their brain struggles to process these emotional triggers (Parekh et al., 2024).

4. The Ventral Tegmental Area (VTA): The Pleasure Button

The VTA is a key part of the brain’s reward system, producing dopamine, a chemical responsible for pleasure and motivation. Opioid withdrawal suppresses dopamine production, leaving your child feeling flat, joyless, and unable to enjoy normal activities.

Analogy: It’s like a vending machine that stops working—no matter how many times you press the button, nothing comes out.

Impact on Behavior: Your child might seem uninterested in activities they used to enjoy or say that "everything feels pointless." This numbness often deepens withdrawal-related depression (Zhu et al., 2023).

Common Symptoms During Withdrawal

The brain’s struggles spill over into emotional, physical, and behavioral symptoms. Here’s what you might see and what they mean.

Cravings: These result from the OFC’s relentless drive to "fix" the imbalance. Cravings can feel as urgent as needing air.
Anxiety and Fear: Overactivity in the amygdala makes fears seem larger and harder to manage.
Mood Swings and Depression: Without dopamine, the brain feels empty and can shift from anger to despair rapidly.
Physical Pain: The lack of natural endorphins causes aches, chills, and stomach issues.
Sleep Problems: Heightened brain activity and discomfort make rest elusive.

Common Concerns from Parents - "Why can’t they just push through?"

Withdrawal isn’t about willpower—it’s chemistry. Their brain isn’t weak; it’s overwhelmed. The symptoms they feel are real and biologically driven.

"What if they relapse?"

Relapse is common, but not inevitable. The brain takes time to heal, and external support can make all the difference. Triggers like stress, certain environments, or even emotions can reignite cravings. Being understanding rather than punitive helps rebuild trust and reduces shame.

How You Can Help

Here are ways to ease their path and minimize the risk of relapse.

Therapeutic Strategies

Medication-Assisted Treatment (MAT):

Drugs like methadone or buprenorphine help stabilize the brain’s opioid receptors and reduce cravings (Brenna et al., 2024).
Short-Acting KOR Antagonists:

These medications target stress-related κ-opioid receptors, which are linked to depression and anxiety during withdrawal (Akins et al., 2023).
Behavioral Therapy:

Cognitive-behavioral therapy (CBT) can help your child tackle emotional triggers and create new coping strategies (Carter, 2024).

Your Role as a Parent

Create a Calm Environment: Reduce stressors at home and provide reassurance, not criticism.
Help Avoid Triggers: Work together to identify and avoid risky environments or situations.
Encourage Structure: Routines can provide stability and prevent boredom.
Support Professional Help: Encourage participation in therapy or group counseling.

Self-Compassion for Parents

Your role is vital but exhausting. Don’t forget to care for yourself too, whether that’s talking to a counselor, joining a family support group, or simply taking breaks.

Final Thoughts

Opioid withdrawal is tough, and watching your child go through it can be heartbreaking. But understanding the brain-based origins of their struggles can help you see that what they face is not a personal flaw—it’s a biological storm. With patience, support, and the right treatment strategies, your teen or young adult can find stability again. Recovery is a process, but together, you can help them take one step at a time toward healing.

Supporting Your Child Through Opioid Withdrawal: Medications That Can Help

Medications such as gabapentin, clonidine, ibuprofen, ondansetron, trazodone, hydroxyzine, valium, and CBD are often used to manage early withdrawal symptoms in individuals with opioid use disorder (OUD). These medications can help alleviate various withdrawal symptoms, including anxiety, pain, nausea, and insomnia, which are common during the early stages of withdrawal. Each medication has a specific role and mechanism of action that contributes to its effectiveness in managing withdrawal symptoms.

Gabapentin

Gabapentin is frequently used off-label to manage withdrawal symptoms in OUD, particularly for its potential to alleviate anxiety and neuropathic pain. However, its use is controversial due to the risk of misuse and its potential to increase the abuse liability of opioids and alcohol when used concurrently (Hiranita et al., 2024; Ellis et al., 2023; Castillo et al., 2022).

Studies have shown that gabapentin can decrease the effectiveness of naloxone in reversing opioid overdose, which raises concerns about its safety in OUD treatment settings (Flynn & France, 2023).

Clonidine

Clonidine is an alpha-2 adrenergic agonist that is effective in reducing withdrawal symptoms such as anxiety, agitation, and muscle aches by decreasing sympathetic nervous system activity.
It is commonly used in detoxification protocols to manage autonomic symptoms associated with opioid withdrawal.

Ibuprofen

As a nonsteroidal anti-inflammatory drug (NSAID), ibuprofen is used to manage pain and inflammation associated with withdrawal.
It is often used in combination with other medications to provide symptomatic relief without the risk of addiction.

Ondansetron

Ondansetron is an antiemetic that helps manage nausea and vomiting, which are common symptoms during opioid withdrawal.
It works by blocking serotonin receptors in the brain and gastrointestinal tract.

Trazodone

Trazodone is an antidepressant with sedative properties, often used to manage insomnia and anxiety during withdrawal.
It can help improve sleep quality without the risk of addiction associated with benzodiazepines.

Hydroxyzine

Hydroxyzine is an antihistamine with anxiolytic properties, used to manage anxiety and agitation during withdrawal.
It is considered a safer alternative to benzodiazepines for managing anxiety in individuals with a history of substance use disorder.

Valium (Diazepam)

Valium, a benzodiazepine, is sometimes used to manage severe anxiety and muscle spasms during withdrawal.
Its use is limited due to the risk of dependence and should be carefully monitored.

CBD (Cannabidiol)

CBD has shown promise in reducing anxiety-like behavior and normalizing gene expression changes associated with opioid withdrawal in preclinical studies (Navarrete et al., 2022).
It may offer a non-psychoactive alternative for managing withdrawal symptoms, although more research is needed to confirm its efficacy and safety in humans.

While these medications can be beneficial in managing early withdrawal symptoms, it is important to consider the potential risks and interactions associated with their use. For instance, gabapentin's potential to increase the abuse liability of opioids and its interaction with naloxone highlight the need for careful monitoring and consideration of individual patient needs (Hiranita et al., 2024.) Additionally, non-pharmacological approaches, such as transcutaneous cervical vagus nerve stimulation, have shown potential in reducing withdrawal symptoms and may serve as adjunctive treatments (Gazi et al., 2022).

Conclusion and Take Away for Busy Parents

As we wrap up this exploration into the neurobiology of opioid withdrawal, I want to leave you with some key takeaways that can empower you as a parent navigating this challenging journey with your teen or young adult.

Firstly, remember that the intense discomfort your child experiences during withdrawal is not just a matter of willpower—it's deeply rooted in the brain's chemistry. Understanding the roles of mu (µ) and kappa (κ) opioid receptors can help demystify why withdrawal feels so overwhelming. This knowledge is your ally, helping you approach your child's struggles with empathy and patience.

Secondly, know that you are not alone. Many parents are walking this path, and there are resources and professionals ready to support you. Medication-assisted treatments and behavioral therapies can be effective tools in managing withdrawal symptoms and reducing the risk of relapse. Don't hesitate to reach out for professional guidance.

Lastly, take care of yourself. Your well-being is crucial in this process. Whether it's finding a support group, talking to a counselor, or simply taking a moment for yourself, self-care is not a luxury—it's a necessity.

Thank you for trusting me to be part of your journey. Together, with understanding, love, and the right support, healing is possible. For more resources and information tailored specifically for parents, please visit my website, wesleysassaman.com. Let's move forward together toward hope and recovery.

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About the Author

Dr. Wesley Sassaman is a medical professional with nearly a decade of experience in addiction and mental health. Working on the front lines of the fentanyl epidemic in Scottsdale, Arizona , Dr. Sassaman is dedicated to empowering families affected by fentanyl addiction by providing them with the knowledge and resources to navigate the difficult road to recovery. With a deep understanding of the biopsychosocial model of addiction, Dr. Sassaman combines expert insights with compassionate guidance, offering hope to those struggling with the devastating effects of street-based fentanyl addiction. Each blog post invites readers into a transformative conversation, bridging the gap between despair and hope while illuminating a path toward healing and resilience.