Abuse-Deterrent Formulations of Prescription Opioid Analgesics in the Management of Chronic Noncancer Pain

Figures & data

Table 1. Advantages and limitations of current ADF technologies.

ADF technology	Advantages	Limitations
Physical and chemical barriers	May prevent chewing, crushing, grating or grinding	Does not deter abuse of intact tablets
	May prevent accidental crushing or chewing in compliant patients
	May resist extraction by solvents
	No adverse effects in compliant patients
Agonist/antagonist combinations	Antagonist may be formulated to be clinically active only when manipulated	Inadvertent chewing or crushing may reduce analgesic effects and/or precipitate side effects or opioid withdrawal symptoms
	May curb euphoria when formulation is compromised
Aversion	Aversive agents may be combined with the opioid to create unpleasant side effects when manipulated or taken at higher doses	Potential for unpleasant adverse effects in compliant patients who take product as intended
	May prevent abuse by chewing or crushing	Adverse effects with intact tablets may prevent legitimate dose increases
	May limit abuse of intact tablets	Adverse effects may not be sufficient to deter a motivated abuser
Delivery system	The method of drug delivery can offer resistance to abuse (e.g., depot formulations or subcutaneous implants)	It may still be possible to extract the opioid from the formulation
Prodrug	A prodrug that lacks opioid activity until transformed in the GI tract may be unattractive for intravenous or intranasal routes of abuse
Combination	A combination of two or more of the above approaches

ADF: Abuse-deterrent formulation.

Data taken from [45].

Table 2. US FDA categories of studies for characterizing abuse deterrence.

Category	Study type	Goal
1	Laboratory-based in vitro manipulation and extraction studies	To assess the ease with which the potential abuse-deterrent properties of the formulation can be overcome or compromised
2	Pharmacokinetic studies	To evaluate the in vivo properties of the formulation by comparing the pharmacokinetic profiles of intact versus manipulated formulations using one or more routes of administration
3	Clinical abuse potential studies	To assess the relative abuse potential of the formulation to predict how attractive it is likely to be to abusers; usually conducted in a drug-experienced population
4	Postmarketing epidemiologic studies	To determine whether use of the potential ADF results in a significant reduction in abuse in the community compared with conventional opioid formulations

ADF: Abuse-deterrent formulation.

Data taken from [45].

Table 3. Currently available opioid analgesics with a US FDA abuse-deterrent formulation label (as of January 2016).

Drug	ADF approach	Abuse-deterrent properties
OxyContin^® (oxycodone)	Physical and chemical barriers	Difficult to crush or break; resistant to ethanol dose dumping and other chemical extraction techniques; forms a viscous gel when dissolved
Targiniq™ ER (oxycodone/naloxone)	Agonist/antagonist combination	Naloxone exhibits extremely low oral bioavailability due to significant first-pass hepatic metabolism, and therefore has very little effect if the product is taken orally as prescribed. Naloxone is absorbed if administered intranasally or intravenously, blocking the euphoric effects of oxycodone
Embeda^® (morphine/naltrexone)	Agonist/antagonist combination	Upon manipulation, naltrexone is released and blocks the euphoric effects of morphine
Hysingla^® ER (hydrocodone)	Physical and chemical barriers	Difficult to crush or break; resistant to ethanol dose dumping and other chemical extraction techniques; forms a viscous gel when dissolved
MorphaBond™ ER (morphine sulfate)	Physical and chemical barriers	Designed to present multiple barriers to abuse through widely used methods of physical and chemical manipulation, as well as various routes of administration; does not contain an opioid antagonist
Xtampza ER™ (oxycodone)	Physical and chemical barriers	Designed to protect against common methods of manipulation, such as chewing, rushing, insufflation, and extraction for intravenous injection

ADF: Abuse-deterrent formulation; ER: Extended release.

Table 4. Potential opioid analgesic abuse-deterrent formulations under review by the US FDA (as of January 2016).

Drug	ADF approach	Abuse-deterrent properties
ALO-02 (oxycodone/naltrexone)	Agonist/antagonist combination	Upon manipulation, naltrexone is released and blocks the euphoric effects of morphine
CEP-33237 (hydrocodone)	Physical and chemical barriers	Designed to deter abuse via crushed oral, nasal and intravenous administration; prevents dose dumping when co-administered with alcohol

ADF: Abuse-deterrent formulation.

US Food and Drug Administration . Abuse-deterrent opioids – evaluation and labeling guidance for industry ( 2015 ). www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm334743.pdf .

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