So far, the creative approaches industry has taken to develop tamper-resistant and abuse-deterrent opioid drugs have been largely matched by the ingenuity of those users who manage to tamper with and abuse those same formulations.
Regardless of a physical pill’s protective characteristics, which discourage easy access to an unadulterated and active narcotic, users have successfully crushed, dissolved and otherwise extracted active opioid ingredients, and continue to do so. Generic hydrocodone, an opioid more readily known by its numerous brand names – Vicodin, Lortab, etc. – was the single-most dispensed prescription in the US last year, at nearly 215 million prescriptions, according to IMS Health data.
Two recent examples of tamper-resistant or abuse deterrent opioids include Endo’s Opana ER, and Pfizer’s Oxecta; Pfizer and Endo Pharmaceuticals licensed their tamper-resistant technologies from other companies (Acura Pharmaceuticals and the Grünenthal Group, respectively). Purdue Pharmaceuticals’ notorious OxyContin, a delayed-release oxycodone, was reformulated into an ostensibly safer version approved in 2010, although FDA – in all of the above cases – has declined to include labeling that calls any of the new formulations “tamper-resistant” or “abuse-resistant.”
The current technologies work by adding antagonist or aversive agents to the opioids – both of which either suppress the euphoric high sought by drug abusers, or make the high less groovy, by adding niacin, for example, which “causes temporary unpleasant effects such as warmth, flushing, itching, sweating and/or chills if an excess number of tablets are swallowed,” according to 2010 article in CNS Drugs titled “Abuse-Deterrent and Tamper-Resistant Opioid Formulations.” In the case of Embeda, a Pfizer drug (inherited through the acquisition of King Pharmaceuticals), the aversive agent naltrexone is added; if swallowed, the pill does not release the naltrexone, but if it’s crushed, the naltrexone is released, which suppresses the morphine high. If a user of Purdue’s newly formulated OxyContin drops the pill in water in an attempt to extract the oxycodone, for example, the active narcotic turns into a viscous gel to prevent injection.
While these resistance-related measures are admirable, and may prevent abuse in some cases, the hard-core opioid fiend – with a single Google search – can easily find step-by-step directions for circumventing the delivery obstacles related to each of the new formulations. Last April, the White House issued a report titled “Epidemic: Responding to America’s Prescription Drug Abuse Crisis,” which, among other things, promised to issue a “guidance document on developing abuse deterrent drug formulations, and on post-marketing assessment of their performance” by April 2013.
Physicians and sales reps are put in a tricky position by the fact that these new formulations can’t say that they’re tamper or abuse resistance in their labels. Physicians are already exposed to relentless media reports of nonmedical opioid abuse and accidental death, but when proper education, patient selection and monitoring are part of the drug regimen, the class is highly effective in the treatment of pain. Still, physicians often find themselves in a difficult quandary with the opioid class: they can under-prescribe, and potentially have patients that use the drugs correctly, but are subjected to unnecessary pain, or they can potentially over-prescribe, and put their DEA license and freedom at risk, not to mention the lives of nonmedical abusers who either illegally buy or filch these drugs.
PharmacoFore, a Northern California start-up, is coming at the problem from a different angle. Instead of designing new protective pill technologies, the company has spent the last several years redesigning the opioid molecules themselves. No amount of chewing or crushing – or for that matter, swallowing too many pills – would lead to toxic doses of the opioids, according to Wes Sterman, president, CEO and co-founder at PharmacoFore. Typically, crushing or chewing pills before swallowing, for example, means more active drug is exposed to a larger surface area of gastrointestinal fluids all at once, which in turn means that the dosing is elevated to potentially dangerous levels. With PharmacoFore’s candidates – the first of which is hydromorphone (brand name: Dilaudid), one of the most potent members of the class – the opioids are released via enzymatic response. In other words, the drugs would turn human enzymes into drug regulators; the enzymatic response in the body can be used to not only “unlock” the opioid, but also to put a ceiling on how much active opioid is released, according to Sterman. Additionally, those baddies who try to snort or mainline the drug won’t get off, because the opioid is “completely inert in the blood,” says Sterman. “There’s nothing in the blood to carry out the enzymatic changes” needed to release the narcotic.
“What our technology allows us to do is govern the amount [of opioid] that gets delivered, independent of the amount of pills that get swallowed,” says Sterman. “If someone wants to take three, four or five pills, or an entire vial, we could still control getting them one dose of the drug.” To prove this point, the company has conducted a phase 1 clinical trial, with the product delivered in an aqueous solution, despite plans to sell the drug in tablet form. The aqueous delivery “is essentially as dissolved as it could ever get,” showing that any attempt at liquid extraction for injection, or crushing the drug for inhalation, would be pointless. Without the normal enzymatic machinery of the GI track, the narcotic cannot be liberated. “If someone wants to get high [on these new drugs], we’ve blocked every way that they can do that, unless they’re a PhD biochemist with a lab standing by,” says Sterman.
But what about efficacy? Once the enzymes in the GI tract unlock the narcotic, it moves into the blood, where it performs identically to traditionally packaged opioids; it hits the exact same receptor and is metabolized the exact same way, says Sterman. “We matched the pharmacokinetics…for extended release and immediate release” forms of hydromorphone, says Sterman. “One of the reasons we think our regulatory path will be relatively faster than it otherwise would be for a new chemical entity is that we’re looking mostly at the pharmacokinetics of delivery.”
PharmacoFore is in the early stages of development – still “several” years out from commercialization – and is looking for a partner to take the first hydromorphone candidate through the regulatory process. “We’re in discussions with several companies who are either in the field or are interested in the field,” says Sterman. PharmacoFore’s technology is applicable to the standard opioids, including morphine, oxymorphone, oxycodone, hydromorphone and hydrocodone. An additional technology is being developed to prevent respiratory depression, in the case of patients who take an opioid and a benzodiazepine, a class that includes sleep aids, muscle relaxers and anti-anxiety meds.
Given that the global opioid market for the seven major indications – fibromyalgia, neuropathic pain, cancer pain, osteoarthritis pain, rheumatoid arthritis pain, low back pain and post-operative pain – was valued at 11.2 billion in 2010 (and expected to grow), according to GBI Research, the possibility of a truly abuse-resistant opioid is promising in terms of potential sales, but more importantly, as a public health intervention.