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The opioid abuse epidemic.

NEW YORK -- Chronic pain--and the opioid abuse that it has engendered --have both reached epidemic proportions.

Over 100 million people in the U.S. suffer from chronic pain, costing over $560 billion in health care spending and lost productivity a year. And with prescription opioids continuing to be the primary treatment for chronic pain, the misuse, abuse and diversion of opioids has become the foremost public health issue in the country.

"The numbers are absolutely daunting --52,000 overdose deaths in 2015"--with approximately 33,000 of those related to opioids," Health and Human Services Secretary Tom Price said last month. "The numbers in 2016 are no better, and the numbers in 2017 are even worse than 2016."

Misuse is defined as the intentional or unintentional use of a prescribed medication in a manner that is contrary to directions, regardless of whether a harmful outcome occurs. Abuse is defined as therapeutic use of a drug product or substance--even once--to achieve a desirable psychological or physiological effect. Diversion is the transfer of the legal supply chain of prescription opioids to an illicit channel of distribution or use.

Abuse can be oral, intranasal or by injection. In a study of OxyContin abusers, up to 76% of abuse happened orally, including both manipulated and intact dosage forms. A study found up to 42% of oral abusers reported manipulating the pill (chewing, crushing or dissolving it). Crush resistant tablets are significantly less likely than comparators to be swallowed whole and significantly more likely to be chewed or dissolved in the mouth.

While non-oral abuse is less common, the consequences of injecting or snorting opioids--which requires manipulation--tend to be far worse that those that result from swallowing or chewing them.

To help prevent abuse, drug manufacturers have come up with abuse-deterrent formulations (ADFs). The formulas are designed to meaningfully deter abuse, even if they do not fully prevent it. ADFs can result in significant reductions in abuse, misuse and related adverse clinical outcomes.

The Food and Drug Administration, which considers ADF development a top public health priority, has established guidance on studies that should be conducted to demonstrate that a given formulation has abuse-deterrent properties. In vitro studies should be undertaken to assess the ease by which the formulation can be manipulated or compromised, while in vivo studies can discern the impact of manipulation of the formulation on a pharmacokinetic (PK) profile.

"The FDA strongly supports a transition from the current market dominated by conventional opioids to one in which the majority of opioids have meaningful abuse-deterrent properties," the agency said in a recent statement.

Strategies to deter abuse, misuse, and diversion include making a drug's manipulation more difficult and making manipulated products less attractive or rewarding. But products must still provide an opioid when prescribed.

Current ADF strategies include physical/chemical barriers such as hard-to-crush tablets (e.g., polyethylene oxide). These include gelling agents that can resist opioid extraction using common solvents and can limit drug release following mechanical manipulation, so that it is less amenable to abuse. Particle size reduction leads to a significant increase in drug release, and milling can compromise extended-release (ER) properties when a drug is placed in water and swallowed.

Having microspheres in capsules modifies the active pharmaceutical ingredient (API) to increase its lipophilicity by forming a salt with one or more fatty acids. Homogeneous dispersal in waxes with limited solubility is another key feature of this strategy. Most importantly, each microsphere has ER and abuse-deterrent properties.

Another strategy employs an opioid antagonist that interferes with, reduces or defeats the euphoria associated with abuse. The antagonist is sequestered and released only upon product manipulation. But there is a potential for withdrawal if sequestered naltrexone is released--and a potential for decreased pain relief.

Currently available opioids with ADF labeling include OxyContin (oxycodone HC1), newly formulated in 2010; Targiniq ER (oxycodone HC1 with naloxone); Embeda (morphine with naltrexone), newly labeled in 2014; Hyslingla ER (hydrocodone); Morphabond (morphine); Xtampza ER (oxycodone); Troxyca ER (oxycodone HC1 with naltrexone; Arymo ER (morphine); Vantrela ER (hydrocodone); and Roxybond (oxycodone IR).

But even with ADFs, abuse remains a problem. And not all ADFs are designed equally. A study showed that Xtampza ER maintained its ER profile, while crushed reformulated OxyContin showed PK similarities to IR oxycodone. Xtampza provided resistance to physical manipulation compared with other ER opioids, some with ADF properties.

In contrast to some other ADFs, Xtampza negates the incentive for pulverization. It employs DETERx technology to give each capsule of the drug thousands of microspheres with an average diameter of 300 microns. Each microsphere is extended release and so small (300 microns on average) that any attempt to crush it results in very little change in it and no change in the pharmacokinetics. Multiple studies that show that whether one swallows the formulation whole, crushes it or chews it, it is pharmacokinetically the same. It's all bioequivalent. Trying to snort the microspheres after crushing them actually yields a lower plasma concentration than from swallowing them whole--which is something that no other product has shown.

With each microsphere being extended release, the capsule isn't even necessary for delivery. Each capsule's contents can be swallowed whole, put on food, sprinkled directly into the patient's mouth or administered via a G-tube or NG tube, which are unavailable options with other drugs.

Opana, which can be crushed and injected for intensified effects, was voluntarily removed from the market on July 7 by Endo International PLC at the FDA's request. A review of all available post-marketing data had demonstrated a significant shift in the route of abuse of Opana from nasal to injection following the product's reformulation. Injection abuse of reformulated Opana has been associated with a serious outbreak of HIV and hepatitis C, as well as cases of a serious blood disorder (thrombotic microangiopathy).

While Xtampza is one of nine ER opioids with recognized ADFs, there are varying levels of supporting data for the efficacy of each product's abuse deterrence. They all have different technologies, and address different abuse pathways. Xtampza is the only one with data that shows that even after manipulation it maintains its extended release properties.

"The best way to prevent drug addiction and overdose is to prevent people from abusing drugs in the first place," said President Trump. "If they don't start, they won't have a problem. If they do start, it's awfully tough to get off. So we can keep them from going on, and maybe by talking to youth and telling them, 'No good; really bad for you in every way.' But if they don't start, it will never be a problem."
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Title Annotation:Focus
Publication:Chain Drug Review
Date:Sep 25, 2017
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