Novel Tactics: Deterring Opioid Abuse

Since the introduction of the new formulation of OxyContin, drug makers have sought innovative ways to curb the abuse of painkillers.

Pain management in a patient with substance addiction creates a challenging clinical scenario for prescribers seeking efficacious treatment while attempting to minimize abuse potential. Deaths and emergency department visits for opioid-related overdoses are significant, and drug diversion and abuse remains a valid concern for health care providers treating pain.

Additionally, there is a lack of specific guideline evidence for selecting the most optimal treatment regimen for the management of pain in those with a history of substance abuse. New drug formulations and delivery systems are in development to address this problem, and they provide appropriate pain management while minimizing medication abuse.

Chronic Pain and Prescription Drug Abuse

Chronic pain is defined as pain lasting for 12 weeks or longer or beyond the expected time of healing. This type of pain tends to be more refractory to traditional drug therapy. Up to 15% of patients with acute pain will progress to chronic pain. Risk factors include female gender, increased age, a prior history of pain, obesity, restricted mobility or minimal exercise, high psychological stress, low self-esteem, job dissatisfaction, and cigarette smoking.¹

The widespread prevalence of chronic pain has led to an increase in the use of opioid medications and, unfortunately, an increase in prescription drug abuse among Americans. This represents a challenge for physicians attempting to manage acute and chronic pain in patients with a history of drug addiction.

A small study found that individuals with a substance abuse history are more likely to administer a dose of an opioid than those with no prior abuse, even in the absence of pain.² In a study of both Medicaid and commercially insured patients in Arkansas between 2000 and 2005, chronic opioid use for noncancer pain increased more substantially in patients with a mental health or substance abuse history than in those without these conditions.³

The 2010 National Survey on Drug Use and Health estimates that up to 7% of the US population older than 12 years has abused prescription medications. Nonmedical use of prescription pain relievers, tranquilizers, stimulants, or sedatives by American adults has increased in recent years—from an estimated 12.5 million in 2002 to 14.2 million in 2010— and substance dependence involving prescription medications among Americans 12 years and older has increased from approximately 1.2 million in 2002 to nearly 1.8 million in 2010.⁴

The most commonly abused prescription medications are opioids, particularly hydrocodone and oxycodone. Most abuse is via oral administration, either by swallowing or sometimes by chewing longacting tablets to increase delivery of the drug and associated feelings of euphoria.⁵ Up to 62% of abusers crush tablets for administration via nasal insufflation (snorting), making it the second most common method of abuse.⁶

Products that Address Opioid Abuse and Diversion

Novel dosage forms and drug delivery devices have been formulated to limit the experience of euphoria if products are used for nontherapeutic purposes. These products have been designed to limit or deter abuse via^5,7:

• Physical changes to dosage forms
• Combination with an opioid antagonist (eg, naloxone, naltrexone)
• Changes to the mode of drug delivery
• Addition of an aversive ingredient

Physical Changes

Physical product changes include tablets that are unable to be crushed into a powder for nasal insufflation, are not dissolvable in liquids for intravenous (IV) administration, or retain their extended-release properties even if tampering occurs.⁷ Extended-release product formulations have historically been prime targets for drug diversion and abuse, as these agents tend to contain a large amount of drug that can be released quickly if the tablet’s integrity is breached. Newly designed extendedrelease oxycodone tablets (OxyContin), approved by the FDA in 2010, are coated with a polymer that prevents drug release via chewing or cutting, inhibits powder formation through crushing, and will turn to a jelly-like substance if dissolved.⁸

Opioid Antagonist Combinations

Agonist and antagonist combinations include buprenorphine/naloxone (Suboxone) and morphine/naltrexone (Embeda).^9,10 Studies have shown that inclusion of an antagonist in the formulation may proactively decrease the risk of tolerance and dependence and reduce euphoria, even if crushed.^11,12 These products represent optimum choices for pain management in individuals with a history of or a high risk for substance abuse, or for patients concerned about addiction with the therapeutic use of these medications.

More product formulations containing opioid agonist/antagonist combinations are currently being studied, including an oxycodone/naltrexone combination product containing beads of the individual ingredients. When swallowed, differences in drug dissolution cause the release of oxycodone only, but if chewed, crushed, or ground, the naltrexone will also be released.¹³

Drug Delivery System Changes

The use of the partial opioid agonist buprenorphine in pain treatment represents an attractive option due to its lower addiction potential, increased safety and tolerability, and Schedule III status. In 2002, the FDA approved a sublingual tablet containing buprenorphine in combination with naloxone (Suboxone), in an attempt to deter abuse of buprenorphine.⁹ Naloxone, an opioid antagonist, is inactive if the tablet is taken as directed. If abuse is attempted via IV use or insufflation, the naloxone will be activated and will reverse the euphoric effects of buprenorphine and possibly precipitate withdrawal. Despite the addition of naloxone, abuse of the combination tablet has been reported, and in 2010 a sublingual film formulation, more difficult to crush than the tablet, was approved, in part to combat abuse.¹⁴

Another system currently in development to decrease diversion of buprenorphine is an implantable drug delivery system. It is designed to provide 6 months of continuous levels of buprenorphine and can be easily inserted subcutaneously during a physician’s office visit. In Phase 3 trials, this implantable delivery system exhibited noninferiority to buprenorphine/ naloxone tablets and significant efficacy versus placebo.¹⁵

Aversive Ingredients

The addition of aversive ingredients is designed to make abuse undesirable by causing uncomfortable sensations or effects. The new formulation of immediate-release oxycodone (Oxecta) contains sodium lauryl sulfate, an irritant that will cause discomfort to the nasal passage if insufflated.¹⁶ Most aversion techniques have been focused on deterring abuse via insufflation or injection, but methods to deter the ingestion of larger than recommended doses are necessary, as this is the most common type of abuse.⁶

An immediate-release oxycodone product currently under FDA review uses niacin as an additive to discourage taking large doses of the drug.¹⁷ In greater than suggested amounts, the niacin will cause undesirable effects such as flushing and dizziness that will be negligible when the drug is administered at the proper dose. This is the first aversion technique to inhibit abuse by swallowing inappropriate amounts of medication. Results of a Phase II study involving subjects with a history of opioid abuse showed statistically significant increases in drug dislike when an oxycodone/niacin combination was administered in amounts 4 times that of the recommended dose when compared with the same dose of oxycodone alone.¹⁷

Early clinical data are divided on whether or not these techniques are efficacious in discouraging abuse and diversion. One study exhibited similar abuse rates between buprenorphine and buprenorphine/naloxone tablets.¹⁸ The Researched Abuse, Diversion and Addiction-Related Surveillance System Drug Diversion Program and Street Rx system, which tracks substance abuse across the United States, reported in 2011 that street prices have decreased for drugs that are available only in formulations designed to deter abuse.

New extended-release oxycodone products that cannot be easily crushed or dissolved saw a 20% to 30% decrease in value compared with the older product, which was discontinued in August 2010.^19,20 Buprenorphine is approximately 17% more expensive if formulated without the addition of naloxone,¹⁹ leading to the discontinuation of Subutex (buprenorphine without naloxone) by its manufacturer in 2011.²¹

The Role of the Pharmacist

The role of the pharmacist in preventing and managing opioid abuse and drug diversion is manifold. Patient education can help to confirm that opioid pain relievers are used properly. Pharmacists should encourage patients to utilize the physician-patient and pharmacist-patient relationships while managing pain symptoms and treatment. Discuss with patients the importance of following label directions. This may decrease the chance of inadvertent dependence and overuse.²²

Patients may not be aware of the addictive properties of the medications they were prescribed. Having conversations about medications with a high potential for abuse can be the first step to informing the patient about this risk. Recommend to patients that, if possible, they use 1 physician and 1 pharmacy when filling these types of prescriptions.

Pharmacists can also recommend novel formulations of prescription pain relievers that are designed to discourage abuse. These dosage forms are useful for patients who worry about the possibility of addiction due to risk factors or former drug abuse issues, or for those who may need pain medication but have a member of their household who is currently living with or at risk for developing a substance abuse problem.

According to the National Survey on Drug Use and Health, 55% of those who used pain relievers for a nonmedical use obtained them for free from a friend or relative.⁴ Reinforce the importance of keeping pain medication secure and out of reach of others, especially children and teenagers. Remind patients not to share medications with others for whom the drug was not prescribed.²³ Pharmacists can also ensure the correct person is getting the medication being dispensed by checking photo identification for new patients filling controlled substances; identity theft is an increasingly prevalent problem with opioid narcotic abuse.⁷

Prescription monitoring programs are being instituted on a state level to monitor opioid prescribing and use. These programs compile information on the prescriber and pharmacy used and the name of the product, concentration, dose, and amount dispensed, and flag patients who may be abusing the system to obtain more medication than appropriate. Pharmacists can use this information to notify physicians and other pharmacists of this suspect behavior. Preliminary evidence supports the utility of these programs in reducing abuse.²⁴

Proper disposal of medications is paramount to decreasing diversion. National Prescription Drug Take Back Days have been organized in all 50 states, and 995,185 lb of medication have been removed from circulation in the 13 months since the program’s initiation.²⁵ If Take Back Days are not convenient, the FDA suggests removing pills from their bottles and mixing them with used coffee grounds or cat litter to make them less desirable to children, pets, and individuals who may intentionally search through trash for medication.²⁶

Pharmacists should remain vigilant for signs of opioid abuse and diversion and stay informed about endeavors to dissuade these activities. The increase in the prescription of opioid analgesics has created a utility for new products that attempt to deter improper use. By educating patients on the appropriate administration, safe storage, and proper disposal of commonly abused drugs, pharmacists can effectively augment these efforts to minimize the prevalence of nonmedical use of opioids.

Table: Selection of Available or Investigational Abuse Deterrent Products

Ingredient

Product

Abuse Deterrent

Company

Availability

Oxycodone

OxyContin

Physical change

Purdue Pharma

Approved 2010

Oxycodone

Oxecta

Physical change,

aversive ingredient (sodium lauryl sulfate)

Acura Pharmaceuticals

Approved 2011

Oxycodone

Acurox

Aversive ingredient (niacin)

Acura Pharmaceuticals/ King Pharmaceuticals

Under review

Morphine

Embeda

Agonist/antagonist

King Pharmaceuticals

Approved 2009

Hydrocodone

Vycavert

Physical change,

aversive ingredient (niacin)

Acura Pharmaceuticals/ King Pharmaceuticals

In development

Buprenorphine

Suboxone (tablets)

Agonist/antagonist

Reckitt Benckiser Pharmaceuticals

Approved 2002

Buprenorphine

Suboxone (film)

Agonist/antagonist, physical change

Reckitt Benckiser Pharmaceuticals

Approved 2010

Buprenorphine

Probuphine

Subcutaneous implant

Titan Pharmaceuticals

Under review

Ms. Wade is a PharmD candidate at Ernest Mario School of Pharmacy, Rutgers University, in Piscataway, New Jersey. Drs. Bridgeman and Pathak are clinical assistant professors in the department of pharmacy practice and administration at Ernest Mario School of Pharmacy, Rutgers University, in Piscataway, New Jersey

References

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12. Stauffer J, Setnik B, Sokolowska M, et al. Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended release capsules versus morphine solution and placebo in experienced non-dependent opioid users: a randomized, double-blind, placebo-controlled, crossover study. Clin Drug Investig. 2009;29:777-790.

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14. Suboxone Sublingual Film [package insert]. Richmond, VA: Reckitt Benckiser Pharmaceuticals, Inc; August 2010.

15. Titan Pharmaceuticals announces positive top line results in confirmatory phase 3 trial of Probuphine [press release]. South San Francisco, CA: Titan Pharmaceuticals, Inc; July 11, 2011.

16. Oxecta [package insert]. Bristol, TN: King Pharmaceuticals, Inc; June 2011.

17. A phase ii, single-center, randomized, double-blind, assessment of the abuse liability of Acurox (oxycodone HCl and niacin) tablets in subjects with a history of opioid abuse. http://acurapharm.com/products/acurox-tablets/study-ap-adf-111/. Accessed December 11, 2011.

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19. RADARS System Fifth Annual Scientific Meeting: Abuse Deterrent Formulations of Prescription Drugs. Bethesda, MD: April 28, 2011. [NEED URL]

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21. Discontinuation of sale and distribution of Subutex Tablets CIII [press release]. Richmond, VA: Reckitt Benckiser Pharmaceuticals, Inc; September 16, 2011.

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23. Centers for Disease Control and Prevention. Injury prevention & control: home and recreational safety: tips to prevent poisonings. www.cdc.gov/HomeandRecreationalSafety/Poisoning/preventiontips.htm. Accessed December 5, 2011.

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