Abuse Deterrence
Abuse Liability of Opioids
Over the past decade, opioid use for the treatment of non-cancer pain has increased due to an improved understanding of opioid pharmacology, evidence of efficacy and safety and the availability of extended release formulations.
Widespread use of opioids in chronic pain has led to concerns about its non-medical use through both licit and illicit channels. Non-medical users of opioid analgesics may be recreational drug users who use opioids episodically or individuals with an addiction disorder who require frequent maintenance doses. Opioids may be ingested whole, crushed and then ingested, crushed and then snorted, or injected intravenously after extraction from the tablet or capsule.
The introduction of extended release opioids and their widespread use in chronic pain has been associated with diversion into the non-medical supply chain. The popularity of extended release oxycodone among addicts and recreational drug users is in part due to the large dose of drug per tablet (a 12 hour supply). Commercially available short acting opioids are usually administered every 4 to 6 hours and they release their dose over one to two hours. New extended release formulations are designed to gradually release their much larger opioid content over a 12 or 24-hour period. The 12 or 24-hour supply of opioid in one extended release dose means that intentional or inadvertent tampering can rapidly deliver a massive opioid dose and produce a variety of serious and life threatening side effects.
Alcohol-Induced Dose Dumping
Recently, a serious new clinical problem has arisen when therapeutic doses of extended release opioids are taken with alcohol (ethanol). In this setting, the opioid analgesic is being used for legitimate medical purposes and is taken intact. Although patients with chronic pain are discouraged from using opioids with alcohol, the combined use of opioids and alcohol is widespread.
The problem was discovered with a once-a-day extended release formulation of hydromorphone (Palladone® capsules). In 2005, Palladone® was withdrawn from the market in the USA due to dose-dumping when co-ingested with alcohol. Patients consuming 240 mL of 40% ethanol had a 6-fold average increase in peak blood levels of hydromorphone. One subject experienced a 16-fold increase in peak blood level. Since then, FDA has noted that a number of extended release opioids may be similarly vulnerable to dose dumping when taken with alcohol.
In vitro studies have demonstrated that when extended release morphine (Avinza®) is mixed with solutions containing ethanol, the amount of morphine released is increased. Similarly, when evaluated with alcohol, Opana® ER (twice-daily extended release oxymorphone) demonstrates significant dose dumping. The mean oxymorphone peak plasma concentration increase was 70% and 31%, after concomitant administration of 240 mL of 40% and 20% ethanol, respectively. In individual subjects, oxymorphone peak plasma concentrations increased by up to about 260%. Similarly, the mean extent of absorption was numerically higher by 13% after co-administration of 240 mL of 40% alcohol (U.S. Prescribing Information for Opana® ER).
A significant dose-dumping effect, resulting in high peak blood levels could result when extended release opioids are taken with alcohol. This dose dumping effect can be potentially serious and life threatening. There is therefore a need for extended release opioid dosage forms that do not dose dump when taken with alcohol.
Abuse Deterrent Technologies
The manufacture, distribution, sale and prescribing of opioid analgesics is highly regulated to minimize drug diversion and drug abuse. Nonetheless, it is evident that such a legal framework alone is not adequate to control the misuse and abuse of opioid analgesics.
Several pharmaceutical strategies have been proposed to deter the abuse of extended release formulations of opioid analgesics. These strategies include formulations that contain a sequestered opioid antagonist or aversive agent which is released only upon product tampering (e.g., crushing, extraction) and formulations that deter abuse by resisting release of the opioid upon mechanical (e.g., crushing), thermal (e.g., melting) or chemical (e.g., solvent extraction) tampering.
A potential drawback with the use of a sequestered opioid antagonist into a extended release opioid agonist preparation is that if a tampered product is used by an opioid dependent subject, even small doses of the antagonist can precipitate an abstinence syndrome, resulting in drug withdrawal. Opioid withdrawal symptoms can be severe, requiring hospitalization and reinstitution of the opioid agonist. Similarly, abuse deterrent pharmaceutical compositions containing sequestered aversive substances have the potential to cause harm to subjects if injected intravenously. Such formulations are likely to release at least small amounts of the “sequestered” aversive agent under conditions of chronic normal use. Finally, abuse deterrent capsule formulations with sequestered opioid antagonists or aversive agents may be vulnerable to dose dumping when co-ingested with alcohol.
Abuse Deterrent Properties of TQ-1020 (Levorphanol ER Tablets)
Toxicity from high blood levels of extended release opioids and other abusable drugs often occurs when recreational drug users and addicts crush the contents of the tablet or capsule and ingest the drug orally, snort it or inject it intravenously, after extraction and filtration.
The abuse deterrent technology within TQ-1020 operates by resisting crushing, melting and both chemical and physical attempts to extract the opioid. TQ-1020 is difficult to tamper with and forms a viscous substance upon contact with a solvent, such that the opioid cannot be easily filtered or drawn into a syringe for intravenous drug abuse. It is also resistant to extraction with common solvents, including alcohol. A potential advantage of such an abuse deterrent system is that it may protect both medical and non-medical users of opioids from intentional or unintentional opioid toxicity, without unnecessary harm to either group from the abuse deterrent technology itself.
Abuse Deterrent Properties of TQ-1028 (Buprenorphine ER Tablets)
Unlike oxycodone, oxymorphone, fentanyl, morphine, hydromorphone and methadone, which are designated Schedule II (C-II) under the Controlled Substances Act (CSA), buprenorphine is designated Schedule III (C-III), providing clinicians with wider prescribing latitude such as telephone prescriptions and refills (which are disallowed for C-II opioids). Our once-a-day oral extended release buprenorphine dosage form is intrinsically more abuse deterrent (less abusable) than the commonly used C-II opioids, by virtue of its unique pharmacology. Among its advantages over the C-III opioids are:
- Reduced risk of physical dependence;
- Reduced reinforcing properties;
- Reduced drug liking by recreational drug users; and
- Reduced risk of respiratory depression in overdose.
According to the Food and Drug Administration (FDA), Drug Enforcement Administration (DEA) and Substance Abuse and Mental Health Services Administration (SAMHSA), buprenorphine has a lower potential for abuse relative to C-II opioids such as oxycodone, oxymorphone, morphine and hydromorphone, the opioids in OxyContin®, Opana® ER, Embeda®, and Exalgo®, respectively (http://tinyurl.com/yfmcjbn; http://tinyurl.com/2cxnzxp; http://tinyurl.com/y5hhe63).