Gabapentin enacarbil is an extended-release prodrug of gabapentin, which is widely used in the treatment of conditions such as restless legs syndrome and postherpetic neuralgia. Oxycodone, on the other hand, is a potent opioid analgesic commonly prescribed for moderate to severe pain. Both medications have legitimate medical uses, but their potential for abuse, particularly when combined, has raised significant concerns within the medical and regulatory communities.

This article explores a randomized, double-blind, active- and placebo-controlled, 6-way crossover study designed to evaluate the abuse potential of orally administered gabapentin enacarbil immediate-release capsules, both alone and in combination with oxycodone, in healthy, nondependent, recreational opioid users. The study provides valuable insights into how these drugs may interact in the context of abuse, which is crucial for understanding their risks and informing public health strategies.

Background and Rationale

Gabapentin and its derivatives have been subjects of concern due to their off-label use and potential for misuse. Although originally developed as an anticonvulsant, gabapentin has been increasingly used for pain management and other indications. Its abuse potential, particularly in combination with other substances like opioids, has led to a surge in research aimed at understanding the risks associated with its non-medical use.

Oxycodone, as an opioid, is inherently associated with a high risk of dependence and abuse. The combination of gabapentin enacarbil and oxycodone could potentially enhance the effects of either or both drugs, leading to an increased risk of abuse. This study was therefore designed to evaluate this potential interaction in a controlled environment.

Study Design

1. Study Population

The study enrolled healthy, nondependent, recreational opioid users. These participants were chosen to mimic real-world scenarios where individuals who are not dependent on opioids might use these substances recreationally. The inclusion criteria were strict to ensure the safety of participants and the validity of the results. Participants were screened for medical conditions, psychiatric disorders, and drug dependency to ensure they were suitable for the study.

2. Study Interventions

The study was structured as a 6-way crossover trial, where each participant received six different interventions in a randomized order. The interventions included:

Gabapentin enacarbil alone at a therapeutic dose.
Oxycodone alone at a therapeutic dose.
Gabapentin enacarbil combined with oxycodone at therapeutic doses.
A higher dose of gabapentin enacarbil alone.
A higher dose of oxycodone alone.
Placebo.

This design allowed for the comparison of each treatment’s effects within the same individual, reducing variability and improving the reliability of the findings.

3. Blinding and Randomization

The study was double-blind, meaning neither the participants nor the researchers knew which treatment was being administered at any given time. This blinding was crucial to eliminate bias and ensure that the observed effects were due to the drugs themselves rather than participants’ or researchers’ expectations.

Randomization was employed to determine the order in which participants received each treatment. This method further minimized the risk of bias and ensured that any differences in the results could be attributed to the interventions rather than the order in which they were administered.

Outcomes Measured

1. Primary Outcome: Abuse Potential

The primary outcome of the study was the abuse potential of gabapentin enacarbil when taken alone or in combination with oxycodone. This was measured using a variety of validated scales, including:

Drug Liking Scale: Participants rated their liking of the drug on a scale from 0 (strong disliking) to 100 (strong liking).
High Scale: Participants reported the intensity of the drug-induced high on a similar scale.
Take Drug Again Assessment: Participants indicated their likelihood of taking the drug again if given the opportunity.

These scales provided quantitative data on the subjective effects of the drugs, which are crucial indicators of abuse potential.

2. Secondary Outcomes: Pharmacokinetics and Safety

In addition to assessing abuse potential, the study also measured the pharmacokinetics of the drugs, including the absorption, distribution, metabolism, and excretion of gabapentin enacarbil and oxycodone. Blood samples were collected at various time points to analyze the concentration of the drugs and their metabolites.

Safety was another key outcome, with adverse events being monitored throughout the study. Participants underwent regular medical examinations, and any side effects or complications were recorded and analyzed.

Results

1. Abuse Potential

The study found that gabapentin enacarbil alone had a low potential for abuse, as indicated by low scores on the Drug Liking and High scales. However, when combined with oxycodone, the abuse potential increased significantly. Participants reported higher scores on the Drug Liking and High scales for the combination treatment compared to either drug alone or placebo. This suggests a synergistic effect between gabapentin enacarbil and oxycodone that enhances their appeal to recreational users.

The higher doses of gabapentin enacarbil alone also showed a slight increase in abuse potential, but not to the same extent as the combination with oxycodone. This indicates that while gabapentin enacarbil has some potential for abuse, it is more likely to be abused in combination with other substances, particularly opioids.

2. Pharmacokinetics

The pharmacokinetic analysis revealed that the combination of gabapentin enacarbil and oxycodone did not significantly alter the absorption or metabolism of either drug. The concentrations of both drugs in the blood were consistent with those expected from their individual pharmacokinetics, suggesting that the increased abuse potential is likely due to their combined pharmacodynamic effects rather than any interaction at the metabolic level.

3. Safety

The combination of gabapentin enacarbil and oxycodone was generally well-tolerated, with most adverse events being mild to moderate in severity. The most common side effects included dizziness, nausea, and somnolence, which are consistent with the known side effects of both drugs. There were no serious adverse events reported, and all participants completed the study without significant complications.

Discussion

1. Implications for Public Health

The findings of this study have important implications for public health, particularly in the context of the ongoing opioid epidemic. The increased abuse potential observed with the combination of gabapentin enacarbil and oxycodone highlights the need for caution when prescribing these drugs together. While gabapentin enacarbil is effective for its intended medical uses, its potential for misuse, particularly in combination with opioids, cannot be overlooked.

Healthcare providers should be aware of the risks associated with prescribing gabapentin enacarbil and oxycodone together, especially to patients who may be at risk for substance abuse. Patient education is also crucial to ensure that patients understand the risks of combining these medications and the importance of adhering to prescribed dosages.

2. Regulatory Considerations

The results of this study may also have implications for drug regulation and scheduling. While gabapentin is not currently classified as a controlled substance in many jurisdictions, the evidence of its potential for abuse, particularly in combination with opioids, may prompt regulatory agencies to reconsider its status. Enhanced monitoring and restrictions on the prescribing of gabapentin enacarbil, particularly in combination with opioids, may be warranted to mitigate the risk of misuse.

3. Future Research Directions

This study provides a foundation for further research into the abuse potential of gabapentin enacarbil and other gabapentin derivatives. Future studies could explore the mechanisms underlying the synergistic effects observed with the combination of gabapentin enacarbil and oxycodone, as well as the potential for abuse when combined with other substances.

Additionally, research into strategies for mitigating the abuse potential of gabapentin enacarbil, such as the development of abuse-deterrent formulations, could be valuable in reducing the risk of misuse while preserving its therapeutic benefits.

Conclusion

This randomized, double-blind, active- and placebo-controlled, 6-way crossover study provides important insights into the abuse potential of gabapentin enacarbil, both alone and in combination with oxycodone. The findings underscore the need for caution when prescribing these medications together and highlight the importance of continued research into the risks associated with their non-medical use.

While gabapentin enacarbil has proven therapeutic benefits, particularly in the treatment of restless legs syndrome and postherpetic neuralgia, its potential for misuse, especially in combination with opioids, cannot be ignored. Healthcare providers, regulators, and researchers must work together to ensure that these medications are used safely and effectively, with a clear understanding of their risks and benefits.

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