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Oxycodone vs. Other Opioids: Distinct Epigenetic Effects & Molecular Adaptations (2023 Review)

The opioid crisis, particularly in North America, has spotlighted oxycodone as a central figure due to its significant role in addiction and overdose deaths.

A recent review analyzed the genomic and epigenetic mechanisms behind oxycodone’s effects compared to other opioids, shedding light on its unique impact on addiction pathways.


  1. Oxycodone, a semi-synthetic opioid derived from thebaine, has lower affinity for the mu opioid receptor (MOR) compared to morphine but is heavily implicated in the opioid crisis due to its widespread misuse.
  2. Preclinical studies highlight significant differences in the genomic and epigenetic responses to oxycodone versus other opioids, contributing to its unique addiction profile.
  3. Oxycodone’s pharmacokinetic properties, including rapid brain penetration and potent active metabolites, enhance its euphoric effects, increasing its abuse potential.
  4. The molecular and behavioral adaptations induced by oxycodone exposure in animal models provide critical insights into its addictive properties and the challenges in managing opioid dependence.

Source: Frontiers in Psychiatry (2023)

What is Oxycodone a.k.a. “Oxy”?

Oxycodone was first synthesized in 1916 in Germany as part of efforts to improve upon the existing opioid analgesics at the time.

It was developed from thebaine, an opium alkaloid that is also a precursor to several other opioids.

Oxycodone was introduced to the clinical market in 1939 under the name Eukodal, and it was touted for its potent analgesic properties with a focus on managing moderate to severe pain.

Over the decades, oxycodone has been formulated in various ways, including combination products with non-opioid analgesics like aspirin and acetaminophen to enhance its pain-relieving effects while attempting to limit its addictive potential.

Mechanisms of Action

Oxycodone’s mechanism of action centers on its interaction with mu opioid receptors (MOR) in the brain and nervous system, leading to analgesic effects and potential for addiction:

  • MOR Activation: Oxycodone binds to MOR, inhibiting adenylate cyclase and reducing cyclic AMP (cAMP) levels. This decreases neurotransmitter release associated with pain.
  • Potassium Channel Opening: Concurrently, it opens potassium channels, hyperpolarizing neurons, further inhibiting pain signal transmission.
  • Analgesia: The dual action of reducing neurotransmitter release and neuron hyperpolarization effectively blocks pain perception.
  • Addiction Potential: Activation of MOR also triggers dopamine release in the brain’s reward pathways, contributing to euphoria and the risk of dependence and misuse.

Medical Uses

Oxycodone is primarily used for managing moderate to severe acute or chronic pain when other treatments are insufficient. It is effective in a wide range of conditions, including:

  • Postoperative Pain: To relieve pain following surgery, oxycodone provides significant relief, helping patients recover more comfortably.
  • Cancer Pain: For patients with cancer, oxycodone helps manage persistent pain that affects quality of life.
  • Chronic Non-Cancer Pain: Conditions such as back pain and osteoarthritis, when other medications do not provide adequate relief, oxycodone may be considered.
  • Palliative Care: In end-of-life care, oxycodone can be essential for managing pain and improving the comfort of terminally ill patients.

Non-medical Use

Non-medical use of oxycodone represents a significant issue, contributing to the opioid crisis, especially in North America.

The prevalence of oxycodone misuse can be attributed to several factors.

  • High Availability: With widespread prescription, oxycodone became readily available, contributing to its misuse.
  • Perceived Safety: Initially, oxycodone was often perceived as safer or less addictive than other opioids, leading to liberal prescribing practices.
  • Addiction Potential: Oxycodone’s potent effects on the brain’s reward system make it highly addictive, leading to misuse even among individuals with legitimate prescriptions.
  • Transition to Other Opioids: Individuals who misuse oxycodone may transition to more potent opioids like heroin or fentanyl, especially if access to oxycodone is restricted or becomes too costly.

The non-medical use of oxycodone has led to a dramatic increase in addiction, overdose deaths, and social consequences, prompting healthcare providers and policymakers to implement stricter prescribing guidelines, develop abuse-deterrent formulations, and increase education on the risks of opioid misuse.

Major Findings: Oxycodone’s Genetic, Epigenetic, Molecular Effects vs. Other Opioids (2024)

Nicolas Marie & Florence Noble conducted a review to determine how oxycodone may be unique from other opioidergic drugs in terms of its epigenetic effects, long-term effects, etc. – below are the major findings.

1. Pharmacokinetic & Binding Properties

Lower Affinity for MOR: Oxycodone has a lower affinity for the mu-opioid receptor (MOR) compared to morphine, binding to MOR 5 to 40 times weaker depending on the study, and exhibits very low affinity for kappa (KOR) and delta (DOR) opioid receptors in the μM range.

Metabolites: Oxycodone is metabolized into noroxycodone by CYP3A4/5 and into oxymorphone via CYP2D6. Unlike noroxycodone, oxymorphone and noroxymorphone are active metabolites, with oxymorphone having a higher affinity and greater efficacy towards MOR than oxycodone.

Blood-Brain Barrier Penetration: Oxycodone demonstrates better penetration of the blood-brain barrier (BBB) compared to morphine, attributed to active transport mechanisms, leading to a faster onset of analgesic effects.

2. Molecular Adaptations & Gene Regulations

Gene Regulation: Chronic administration of oxycodone leads to specific patterns of gene regulation that are distinct from those induced by morphine or heroin. Oxycodone regulates numerous genes involved in drug metabolism, immune response, and the dopamine receptor signaling pathway, among others.

Comparison vs. Morphine & Heroin: Some genes regulated by oxycodone are also modulated by morphine, indicating overlap in their molecular effects. However, oxycodone’s unique impact on certain genes, notably those associated with the dopamine signaling pathway, suggests distinct neurobiological effects that could contribute to its high misuse potential.

Transcriptional Responses in Neurons: Oxycodone primarily affects transcriptional responses in neurons, whereas buprenorphine significantly regulates transcription in glial cells, indicating cell-type specific effects. Oxycodone was found to induce STAT1, a transcription factor involved in the interferon signaling pathway, highlighting a distinct pathway of action.

Specific miRNA Regulation: Oxycodone distinctively influences the expression of miRNAs, such as miR-9, which is critically involved in regulating synaptic plasticity and memory. This regulation could significantly impact the expression of dopamine D2 receptors, thereby modulating reward pathways uniquely compared to other opioids.

Unique Dopamine Receptor Effects: Oxycodone’s regulation of genes within the dopamine receptor signaling pathway sets it apart from other opioids. This specific influence suggests a direct effect on dopamine neurotransmission, altering reward and addiction mechanisms in a unique manner.

Induction of STAT1: The activation of STAT1 by oxycodone, a transcription factor involved in the interferon signaling pathway, points to oxycodone’s unique action on immune response modulation or stress responses, which are vital in addiction processes.

3. Epigenetic Regulation

Histone Modifications & DNA Methylation: Oxycodone’s impact on epigenetic landscapes, exemplified by changes in histone acetylation patterns (e.g., increased phosphorylation and acetylation of histone H3), underscores its role in long-term alterations of gene expression related to synaptic function and plasticity.

Differential Expression of PSD95: A notable increase in the expression of PSD95 in the hippocampus following oxycodone exposure underscores its unique impact on synaptic architecture. This protein is crucial for synaptic stability, and its regulation by oxycodone may contribute to the neuroadaptive changes associated with its addiction.

4. Behavioral Effects

Dopamine Release & Reward Pathways: The review highlights oxycodone’s pronounced effect on dopamine release in the nucleus accumbens, which is more prolonged than that induced by morphine. This extended dopamine release may contribute to oxycodone’s high abuse potential and its central role in the opioid crisis.

Prolonged Dopamine Release: Oxycodone induces a more extended dopamine release in the nucleus accumbens compared to morphine, which may contribute significantly to its high misuse potential. This extended effect on dopamine transmission is critical in understanding oxycodone’s addictive properties.

Distinct Behavioral Adaptations: Oxycodone’s specific molecular actions lead to unique behavioral outcomes, such as enhanced locomotor sensitization and conditioned place preference, reflecting its distinct effects on the reward system compared to other opioids.

Oxycodone: Genomic & Epigenetic Effects vs. Other Opioids (2023 Review)

The primary objective of this review was to explore the genomic and epigenetic regulatory features of oxycodone compared with other opioid agonists, focusing on their pharmacological response after repeated administration in preclinical models.


  • The review synthesized information from a broad range of sources, including historical data on the development of oxycodone, its pharmacokinetic and pharmacodynamic properties, and its molecular adaptations following chronic treatments.
  • It also employed a comparative analysis approach, examining preclinical studies that investigate the genetic and epigenetic changes induced by repeated opioid exposure.
  • It further reviewed behavioral consequences of chronic opioid treatments as observed in preclinical models, focusing on locomotor sensitization, conditioned place preference, and intravenous self-administration paradigms.


  • Pharmacokinetic & Pharmacodynamic Properties: Oxycodone exhibits distinct binding properties to opioid receptors and metabolizes differently from morphine and heroin, leading to unique pharmacological profiles.
  • Molecular Adaptations: Chronic exposure to opioids induces significant changes in gene expression, with some genes showing consistent regulation across different opioids, while others are uniquely affected by specific drugs like oxycodone.
  • Behavioral Consequences: The behavioral effects of chronic opioid exposure, including locomotor sensitization, conditioned place preference, and self-administration patterns, vary among opioids, highlighting differences in their addiction potential.
  • Epigenetic Regulation: Opioids induce various epigenetic changes, including alterations in histone modifications and DNA methylation patterns. These changes contribute to the long-term effects on gene expression associated with opioid addiction, with some differences observed between oxycodone and other opioids.


  • Variability in Preclinical Models: The findings are primarily based on preclinical studies, which may not fully replicate human physiology and behavior. The variability in experimental designs, animal models, and methods of drug administration may influence the results and their interpretation.
  • Comparison Across Studies: Direct comparisons between studies are challenging due to differences in methodologies, dosages, and treatment durations. This heterogeneity can complicate the understanding of specific effects attributable to oxycodone versus other opioids.
  • Translational Relevance: While preclinical models provide valuable insights into the molecular and behavioral effects of opioids, translating these findings to human populations requires caution. The complexity of human opioid use disorders may not be fully captured by animal studies.
  • Focus on Specific Opioids: Although the review aims to compare oxycodone with other opioids, the literature is vast and not all opioids have been studied with the same depth. This selective focus might overlook important aspects of opioid pharmacology and dependence potential.

Why Research Oxycodone’s Distinct Effects vs. Other Opioids?

Researching the differences in effects of opioids, even though they share a primary action on the mu opioid receptor (MOR), is critical for several reasons.

Understanding these distinctions helps in tailoring clinical use, managing side effects, and developing strategies to combat opioid addiction.

Clinical Use

  • Specificity for Pain Management: Different opioids have varying efficacy and potency for pain relief. By studying their differences, clinicians can choose the most appropriate opioid for the specific type and intensity of pain, enhancing patient comfort and outcomes.
  • Reduced Side Effects: Each opioid has a unique side effect profile. Research into these differences enables the selection of opioids with minimal side effects for a given patient, improving patient adherence and reducing healthcare costs associated with managing side effects.

Dependence Risk

  • Understanding Addiction Potential: Certain opioids may have a higher potential for abuse and dependence. Identifying and understanding the nuances of each opioid’s effect can inform prescribing practices, potentially reducing the incidence of opioid use disorder.
  • Tailored Treatment Plans for Addiction: Knowledge of how different opioids affect gene expression, epigenetic regulation, and behavior can lead to more effective, personalized treatments for opioid addiction, potentially improving recovery rates.

Development of Opioid Analogs

  • Innovative Drug Design: Insights into the differential effects of opioids pave the way for the development of new analgesic drugs that maximize pain-relieving properties while minimizing addictive potential and side effects.
  • Targeted Therapeutic Strategies: Understanding the molecular and cellular adaptations induced by various opioids can guide the creation of targeted therapeutic interventions, including non-opioid alternatives for pain management and addiction treatment.

Conclusion: Oxycodone vs. Other Opioids

The comprehensive review on oxycodone’s genomic and epigenetic effects compared to other opioids underscores the nuanced and complex nature of opioid pharmacology and its implications for addiction.

Despite sharing a primary mechanism of action, oxycodone exhibits unique properties that influence its binding affinities, metabolic pathways, and behavioral outcomes.

The findings highlight the importance of understanding individual opioid characteristics to optimize clinical use, minimize adverse effects, and tailor addiction treatment strategies.

The differential gene regulation and epigenetic modifications induced by oxycodone provide valuable insights into its distinct addiction profile and potential targets for intervention.

Furthermore, the behavioral adaptations observed with chronic oxycodone exposure emphasize the need for caution in its prescription and the development of comprehensive approaches to manage and prevent opioid misuse.

This review contributes significantly to the field by elucidating the specific attributes of oxycodone that contribute to its high misuse potential, offering a foundation for future research and policy-making aimed at addressing the opioid crisis.


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