A better understanding of how euphoria predicts abuse liability may help drug manufacturers to improve safety. 

It has long been theorized that the desirability of a drug of abuse is related to the speed with which it reaches maximum concentration in the plasma of the user. Basic science and clinical observation suggest that a shortened time to maximum plasma concentration (Tmax) and a heightened maximum plasma concentration (Cmax) would increase the euphoric effects conferred by a drug. This is why an opioid abuser crushes sustained-release formulations of oxycodone. It allows for immediate absorption of a full dose of active pharmaceutical ingredient rather than the 12-hour analgesia intended by the drug’s manufacturer. The abuser has shortened the Tmax and possibly, increased the Cmax, resulting in a euphoric high.


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Figure 1. Abuse quotient = Cmax/Tmax. As Cmax INCREASES and as Tmax DECREASES, the ratio becomes relatively larger, signaling potentially increased attractiveness of a drug of abuse. Crushing OxyContin is a classic example of a manipulation intended to produce this effect.

IR: Immediate release
AR-LAO: abuse-resistant, long-acting opioid. This product is an oxycodone gelatin capsule in development by Pain Therapeutics, Inc., and designed to resist common methods of drug abuse such as crushing or dissolving in liquids.

What has not been clearly demonstrated is how the two pharmacokinetic (PK) aspects of Tmax and Cmax relate to each another in contributing to abuse liability: the pharmacodynamic (PD) effects. This article presents the preliminary results from a pilot study on oxycodone abuse. This is the first to attempt to discover how manipulating PK parameters increases or diminishes the abuse liability—or PD effects—of oral oxycodone. The study explored this relationship by administering various, clinically-relevant strengths of oxycodone to opioid-experienced recreational abusers and measuring the PD effects of drug liking and euphoria at various time points. The study set out to determine which parameter—Tmax or Cmax—contributed more to the rewarding effects of commonly abused opioids, and what effect manipulating these parameters had on abuse potential.
Prescription opioid abuse
The ultimate goal is to understand what drives opioid abuse (using oxycodone as the surrogate for all opioids) in order to prevent it. This issue matters more than ever, because prescription opioid abuse is a growing national health emergency.
In 2007, 5.2 million Americans over age 12 were current non-medical users of pain relievers, second only to marijuana.1 Since 1997, the percentage of people in addiction treatment programs claiming prescription drugs as their primary drug of abuse has risen from 1% to 5%.2 Particularly alarming are the high rates of non-medical use of prescription pain relievers among adolescents. The Monitoring the Future report shows that in 2007, 11% of high school seniors misused Vicodin (hydrocodone/acetaminophen), and 4.7% misused OxyContin (oxycodone).3


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Table 1. All subjects underwent a naloxone challenge and screening for the ability to discriminate between oxycodone and placebo. Qualifying subjects proceeded to the double-blind abuse liability phase.


The need for real-world abuse prevention
Because patients in pain have a right to adequate analgesia, the challenge from a public health perspective is how to prevent the abuse of opioids while still treating the pain of those in need. To meet the abuse and diversion threat, the US Food and Drug Administration (FDA) has demanded a risk evaluation and management strategy (REMS) for some opioids, even though exact standards for human abuse liability testing remain unavailable.4 Despite the information vacuum, drug developers are answering the call for heightened safety by testing several opioid products that incorporate technologies to reduce the likelihood of dose manipulation or that otherwise prevent the rapid release of a high concentration of drug.
The FDA has indicated it will require any drug claiming to mitigate opioid abuse to actually demonstrate that drug abuse has been reduced in affected populations post-approval. To be effective, any reforms in the area of abuse liability should focus not only on pre-launch studies but must follow the drug from pre-clinical trials through to post-marketing surveillance.5 The value of human abuse liability studies lies in how well they can help predict the likelihood of abuse and the extent of diversion attached to a drug before it is exposed to the population at large.6

In consideration of the need for real-world applicability, this study proceeded on the construct that the speed of absorption and the blood level concentration of the opioid would determine the degree of euphoria the user experienced. The study also explored the effect of dose on reward experience. The hope is that a better understanding of how euphoria predicts abuse liability will help drug manufacturers to improve their products’ safety.

The abuse quotient and study particulars


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Figure 2. Tmax and Cmax vs. Pharmacodynamic (PD) effects of Liking (Drug effects questionnaire 4) and Euphoria (Drug effects questionnaire 5)

This research project introduces a new concept known as the abuse quotient (AQ). The AQ consists of the two PK parameters expressed as a ratio: AQ = Cmax/Tmax. Using this construct, the abuse potential of a drug increases as the value of the AQ increases, either by heightening Cmax or shortening Tmax. A simulation of this effect is shown in Figure 1.7

The subjects  were male, opioid-experienced, non-dependent, recreational abusers from 18 to 50 years of age. All had experienced a high on at least five occasions in the past 12 months and once in the past 90 days. Subjects who abused multiple drugs had to prefer opioids and demonstrate their ability to differentiate between an opioid and placebo.
The randomized, crossover, double-blind study involved two cohorts defined in Table 1.

The PD effects of abuse liability were measured by the subjects’ answers to Question  4 (“Do you like the drug?”) and Question  5 (“How high are you now?”) from the Drug Effects Questionnaire (DEQ), a self-administered assessment.8 The answers are, by necessity, subjective; therefore, the crossover study design was vital to minimizing inter-subject variability.
The questions were asked and the PK endpoints of Tmax and Cmax measured via plasma samples at 0.25, 0.50, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, and 12 hours after dosing. In this way, investigators were able to observe the relationship of the questions to the Tmax and Cmax.

Results and more questions


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Figure 3. Abuse Quotient vs. Drug Liking. "Do you like the drug?"

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Figure 4. Abuse Quotient vs. Euphoria. "How high are you?"

CR: Controlled release
IR: Immediate release
AUE: Area under the effect, i.e., the total area under the curve when euphoria or liking scores are plotted against time
DEQ: Drug effects questionnaire  
The results did not provide investigators with precise answers for which parameter—Tmax or Cmax— is more important to achieving drug euphoria (represented as Emax) and liking (Figure 2). What became apparent is that both Tmax and Cmax are always important as modeled by the AQ ratio (Figures 3 and 4).

Figure 3 shows excellent correlation of the AQ to liking (DEQ 4) from 15 to 60 minutes and very good correlation up to 90 minutes using the area under the curve (AUC) of DEQ 4 for each time point.

Figure 4 shows excellent correlation of AQ to euphoria (DEQ 5) up to 60 minutes but a lesser correlation from 0 to 90 minutes using the AUC of DEQ 5 for each time point.

Thus neither Tmax nor Cmax alone is sufficient to determine the degree of likeability or the magnitude of a high. However, the strong correlation with the ratio of Cmax / Tmax supports the construct that the AQ may be a reasonable assessment for the potential of abuse.

Interestingly, increasing the Cmax (dose) during 0 to 90 minutes did not produce a proportional increase in euphoria. It appears, then, that the dosage matters more upfront than at later time periods. Perhaps once euphoria is achieved, a sort of plateau is reached whereby additional drug produces effects, but those effects are not proportional.

The AQ is currently being studied as it applies to oxycodone, but it may be useful for evaluating the abuse liability of other opioids or of any other drug that releases dopamine into the limbic system, thereby initiating rewarding effects. Further research is needed to determine if this construct will hold true over time and with other drug classes.

This study suggests that if liking and euphoria drive opioid abuse, an AQ value may help determine the abuse potential of opioid formulations. Whether an AQ assessment of oxycodone or any other opioid can accurately predict abuse in a real-world setting remains to be seen.                     

Technical writing support provided by Beth Dove of Lifetree Clinical Research and Pain Clinic.

About the Author
Dr. Webster is board certified in anesthesiology and pain medicine and is also certified in addiction medicine. He is the co-founder of LifeSource, a non-profit foundation established to educate and conduct research on pain-related, scientific and social issues.

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