Abuse Deterrent Formulations

Drug makers are waging the war against abuse and diversion at the molecular level with new formulations that resist common forms of misuse.

Drugs of choice among recreational abusers are changing. Prescription opioids, central nervous system (CNS) stimulants, and other controlled substances are the rage. Abusers—about 16 million of them—are using these drugs nonmedically, that is without a prescription of one’s own, or simply for the experience.^1,2

Abusers use a variety of methods to find prescription drugs. Of special concern for pharmacists, addicts sometimes demand the contents of the pharmacy safe with a loaded weapon. One way stakeholders are trying to deal with this problem is the use of abuse deterrent formulations (ADFs).

Recreational Abusers

Most opioid abusers prefer oral dosage forms.^3-5 Recreational abusers often progress to inhaling, smoking, or intravenous use.⁵ Opioid patches are also attractive: used fentanyl patches hypothetically contain 28% of the total fentanyl dose, but have been found to have up to 85% in the reservoir. When scavenging for a fix, abusers may steal patches from nursing home residents and cadavers or search health care institutions’ dumpsters.^6-9

The National Survey on Drug Use and Health data for 2009 found that among Americans 12 years or older who used analgesics nonmedically (primarily Schedule II drugs and excluding OTC medications) in the previous 12 months:

• 55.3% said they obtained pain relievers from a friend or relative for free
• 17.6% had fraudulently obtained prescriptions
• 9.9% purchased drugs from a friend or family member
• 5% stole them from a friend or family member

Just 5% purchased their supply from a dealer.¹⁰ And forget the “dealer” stereotype—“pill ladies” is now street slang for elderly women who augment their income by selling their prescription medication to others.

Between 1992 and 2002, controlled substance prescriptions increased roughly 3 times faster than prescriptions for noncontrolled substances and 12 times faster than population growth. The medical profession’s recent emphasis on appropriate pain management has increased public education, direct-to-consumer advertising, and the availability of new, more effective analgesics. It has also heightened abusers’ desire for prescription opioids. Illegitimate demand greatly exceeds legitimate medical need, driving abuse and diversion.¹¹

To consume the drugs, abusers will often crush or chew and then ingest, inject, or inhale the medication. Submerging certain drug formulations in alcohol releases a drug’s active ingredient. Abusers’ reasons for altering formulations vary, depending on their preferred outcome from consumption. Information about and procedures and recipes for drug/formulation tampering are readily available on the Internet.3 About 50% of abusers use multiple drugs or drink alcohol to improve their recreational experiences.^5,12

Abuse Deterrent Formulations

To address drug diversion, the federal government uses Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970 (also called the Controlled Substances Act). Its goal is to maintain a supply of narcotics, stimulants, depressants, and hallucinogens sufficient to meet legitimate needs without interruption while reducing diversion and abuse. The Department of Justice’s Drug Enforcement Administration enforces the law. The FDA contributes to enforcement by evaluating potential abuse and diversion during the drug approval process.¹³

Drug companies now try to identify “abusable” dosage forms during development and present their findings to the FDA for review during the product’s overall risk evaluation. The FDA may ask manufacturers to develop risk management strategies to address and ameliorate factors that make the drug substance “abuse-ready.” Risk management strategies may include surveillance programs, active interventions to reduce off-label use, and educational programs for prescribers and patients.^5,12-14

Manufacturers are developing ADFs that decrease the likelihood that specific formulations are abuse-ready. ADFs should mitigate abuse liability, reduce dependence potential, and decrease public health risk.¹⁵ Abuse resistant agents must be as safe and effective as innovator products.¹⁶ ADFs may accomplish this by altering absorption rate, prolonging half-life, exploiting prodrugs, or containing additional coingredients unattractive to abusers.¹⁵

In the best case, new formulations may also promote adherence or reduce adverse effects, which would benefit patients. ADFs must work well for patients and present no additional prescribing barriers for clinicians. Ultimately, all stakeholders hope that agents formulated as abuse deterrent products could move to a lower schedule, thereby reducing paperwork and monitoring.^11,17

Abuse Deterrent Products

Abuse-resistant formulations aren’t new. The first ADFs were developed in 1982, after law enforcement officials reported widespread “T’s and blues” use in the 1970s. Abusers crushed, dissolved, and injected pentazocine with tripelennamine to experience highs similar to that of heroin.

The ADF prototype, Talwin NX (Sanofi Winthrop Pharmaceuticals), combined 50 mg of pentazocine and 0.5 mg of naloxone. Naloxone is ineffective orally, but eliminates euphoria and can precipitate withdrawal if injected. The abuse rate dropped significantly, although some researchers attributed the drop to the sudden, widespread availability of cheap heroin.^18-21

Counteracting prescription drug abuse is complicated. Designing a product that yields little active drug when it is crushed so that misusers experience no euphoria upon injection will not deter abusers who prefer to pop gobs of intact product. Developing actual products is challenging, and manufacturers confront considerable barriers.⁵

Consider the primary driver for ADFs: opioid diversion. The industry’s profit margins for analgesics are small. There has been little incentive to develop new products, especially when drug companies ask, “Who will prescribe, use, pay for, and perhaps control the proposed product?” before initiating a new drug.

For analgesics, it is difficult to gain market share, and development costs often outweigh what drug companies will be able to charge.⁵ The search for ADFs continues regardless, especially as addicted and/or undertreated patients continue to sue prescribers, health care systems, and pharmaceutical companies, creating a different kind of cost pressure.¹⁴

Three Approaches Known to Deter Combination Products

Abusers tend to find combination products that include certain other drugs (eg, acetaminophen, aspirin, ibuprofen, and caffeine) with the main drug (usually an opioid) less abusable for the same reasons pharmacists dislike combination products—the nonopioid product can add toxicity risks to the product. Abusers tend to avoid some excipients in oral formulations (eg, dyes, binders, fillers, flavors).³ For example, Marinol (dronabinol) has an undesirable sesame oil matrix that complicates extracting the active drug. Agonist-antagonist combinations also deter abuse.

Physical Barriers

Abusers sometimes go to great lengths to extract a drug. If crushing is ineffective, they proceed to simple chemical manipulations, multistep extraction, or laboratory-level processes. ADFs using physical barriers circumvent common tampering methods. Extended-, sustained-, or controlled-release formulations deter abuse to differing degrees.

Very soon after Oxycontin’s approval, abusers learned that crushing effectively released up to 160 mg of oxycodone from its controlled-release tablet. Time-release matrixes such as the beaded formulations used for Adderall XR (amphetamine), Ionamin (phentermine), and sustained-release Ritalin (methylphenidate) more effectively deter abusers. In addition, coatings and matrixes developed to create extended-/controlled-release formulations coalesce (become gummy) when abusers try to extract the drug or heat it. One formulation, the Osmotic Release Oral System, currently used for the Concerta brand of methylphenidate, has been shown to resist common forms of physical and chemical tampering.^24,25

Prodrugs

The newest concept is using prodrugs—agents that are inactive or significantly less active until metabolized. This deters intravenous or intranasal use. Once administered, prodrugs are metabolized into active metabolites. NRP-290, currently in early clinical trials, is a lysine-modified opioid prodrug requiring biotransformation in the gastrointestinal tract to become active.

Conclusion

As ADFs for frequently abused medications become more available, prescribers can expect liability to change. Those who prescribe traditional, that is, abusable products may be forced to document why they are preferable to new, safer formulations.¹⁴

Ms. Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health, Bethesda, Maryland. The views expressed are those of the author and not those of any government agency.

References

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