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Opioid analgesics

R&D pipeline: Several tamper-resistant formulations are being developed to prevent the possibility of abuse and addiction

Opioid analgesicsThe use of medically-prescribed opioid analgesics is fraught with controversy, mostly related to the potential for abuse and addiction. Issues include patient non-compliance and the reluctance of physicians to prescribe for fear of patients developing addiction, and for fear of non-medical abuse. The importance and severity of concern related to these issues was highlighted recently by the 'polar' decisions from the US Food and Drug Administration (FDA) in June, regarding the approval of two separate 'abuse-resistant' formulations of oxycodone.

On June 20, 2011, Pfizer and Acura Pharmaceuticals announced the FDA's approval of Oxecta, the first immediate-release, abuse-resistant formulation of oxycodone. However, almost immediately after, on June 27, Pfizer and development partner Pain Therapeutics, failed to gain approval and received a Complete Response Letter from the FDA following the resubmission of the new drug application (NDA) for Remoxy, an extended-release formulation of the opioid.

The development of abuse- or tamper-resistant formulations of opioid analgesics in the US came after a government initiative entitled 'The Risk Evaluation and Mitigation plan' that was outlined in 2007. This initiative was in response to published figures relating to the misuse of extended-release and long-acting opioids in an estimated 33 million Americans, and the four-fold increase in deaths caused by overdoses of medically-prescribed opioids during the period 1999 to 2007.

The need for chronic use of opioid analgesics is not denied; indeed, their use is endorsed by the World Health Organisation for moderate and severe pain. What must be denied, however, is easy access to opioids for the satisfaction of addiction purposes.

This initiative was in response to published figures relating to the misuse of extended-release and long-acting opioids in an estimated 33 million Americans

Typically, opioids are abused to obtain the euphoric effect provided by ingestion of doses higher than required for pain management; commonly this entails crushing tablets or capsules to snort or inject the contents, particularly of extended-release formulations. In an attempt to prevent this, the development of novel abuse-deterrent formulations has adopted two approaches.

One includes strategies that hinder the extraction and/or chemical manipulation of the opioid and thus prevent the subsequent use of the chemical via intranasal or intravenous routes. The other uses pharmacological tactics either to render the opioid inactive if the tablets/capsules are tampered with, or the additional pharmacological substances included in the formulation cause transient, unpleasant symptoms if tablets/capsules are administered inappropriately or taken in excess.

niacin-free oral formulation
Oxecta, the newly-approved, immediate-release oxycodone is a niacin-free oral formulation under development by Pfizer and Acura Pharmaceuticals. It uses Acura's Aversion technology, which is designed to render it difficult or painful to abuse via IV or intranasal administration. The initial development of this immediate-release tamper-resistant formulation, formally known as Acurox, was under collaboration with Acura and King Pharmaceuticals. The latter company was acquired by Pfizer in March 2011.

Acura and King Pharmaceuticals were also developing a formulation containing sub-therapeutic levels of niacin, which has an irritant effect when the product is misused. In April 2010, however, the FDA's Anaesthetic and Life Support Drugs and Drug Safety and Risk Management Committees voted that they did not have enough evidence to support the approval of the NDA for oxycodone/niacin tablets.

Remoxy employs DURECT Corporation's ORADUR sustained-release oral gel-cap technology, which renders the contents into a viscous, adhesive matrix when tampered with. Clinical trials have indicated that, in comparisons with standard extended-release formulations, Remoxy has a reduced potential for abuse and, when taken as directed, 'drug liking' is also significantly lower.

As part of the research programme initiated by King Pharmaceuticals (now Pfizer) and Pain Therapeutics, Remoxy is just one of three candidate drugs that have progressed into clinical development. The other two are PTI-721 and PTI-202, both of which are in phase I development in the US. All three are based on DURECT's ORADUR technology.

Not completely unexpected
The recent negative response by the FDA for Remoxy may have been disappointing for Pfizer, which assumed the development and commercialisation rights and obligations after it acquired King Pharmaceuticals. It may not have been completely unexpected, however, since this was the second Complete Response Letter received regarding this product; the first was issued in December 2008. Pfizer says that it is working to address the issues described in the letter and is planning further discussions with the FDA.

The question is, has the design lived up to its expectations? Post-marketing adverse events data during the first year after its launch would suggest it has

OxyContin could be considered as Purdue Pharma's 'phoenix'. It is a reformulation of controlled-release oxycodone that has less potential for abuse. It was approved by the FDA in April 2010. Prior to this, Purdue Pharma was the focus of more than 300 oxycodone lawsuits in the US, relating to the addictive potential of the drug resulting from a possible fault in the extended-release mechanism of the original formulation that was launched in 1996. Nevertheless, the confidence that the reformulated OxyContin has remedied these problems appears to have been confirmed by its approval, and the fact that phase III studies are underway in the US for the management of pain in children and adolescents.

Most of the abuse-deterrent strategies employed are aimed at preventing parenteral administration; however, there is nothing to stop multiple tablets or capsules being taken orally in a conscious attempt to overdose on the drug. Pfizer's Embeda combines morphine and naltrexone in a single extended-release capsule. This design was intended to negate the euphoric 'high' in cases of tampering (e.g. chewing and crushing) and by slowly releasing the drug in cases of excess oral intake of the whole capsules.

The question is, has the design lived up to its expectations? Post-marketing adverse events data during the first year after its launch would suggest it has.
A review of the 182 individual spontaneous adverse drug reactions reported for Embeda over this first year revealed 11 cases of overdose resulting from tampering or ingesting the manipulated contents of the capsules. In all cases the expected euphoria was replaced by disappointing withdrawal stigmata instead.

Available data from clinical trials suggests that this 'gold-standard' opioid is effective for the management of chronic pain in patients with osteoarthritis. This, combined with the post-marketing data, suggest that Embeda is providing much-needed pain relief in this patient population without exposure to the risk of abuse. Equivalent safety data for the abuse-deterrent oxycodone products are not yet available.

The US appears to be hosting the majority of the current clinical activity surrounding these novel, abuse-deterrent, opioid products that are intended for the management of moderate to severe pain. In Europe, Egalet is developing an extended-release morphine formulation, which exploits its own proprietary matrix technology that enables abuse deterrent features and prevents alcohol dose-dumping. It is currently under phase II investigation in patients with cancer pain.

Only time will tell whether these ingenious formulation designs are valuable assets with regard to providing essential pain relief to those who need it, without developing or nurturing the need to provide a 'quick fix' for an addiction, iatrogenic or otherwise.

Wendy McNeelyThe Author
R&D Pipeline was written by Wendy McNeely of Adis International (Wolters Kluwer Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight, Reactions Pharmacovigilance Insight and inThought.
For further information on Adis services, please contact Kuljeet Sohanpal on +44 (0)207 981 0714 or Email:

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23rd August 2011


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