BETHESDA, MD. – Physicians can help minimize the potential for abuse of opioid pain medications by considering the agents' delivery route, bioavailability, and pharmacokinetics, said Dr. Pamela P. Palmer, director of PainCARE (Center for Advanced Research and Education) at the University of California, San Francisco, at a meeting of the National Institute on Drug Abuse.
“One thing we don't ever want to do is inhibit good pain therapies because we're afraid of abuse and diversion,” said Dr. Palmer, who is also chief medical officer of AcelRx Pharmaceuticals Inc., which is developing delivery methods to limit opioid abuse.
Dr. Palmer recommends matching opioid half-life with the indication. “You want short-acting drugs for short-acting problems and long-acting drugs for long-acting problems,” she said.
The same goes for route of delivery: Match the route with indication. For example, transdermal patches may be less than ideal for acute situations but work well in the chronic setting.
When choosing the optimal route, avoid options with poor bioavailability. Low bioavailability means that higher doses are needed to get the required effect. This excess loading contributes to the amount of drug available for abuse and diversion. For example, the bioavailability of oral oxymorphone is 10%. Ten times the intravenous dose would be required to achieve the same response orally.
Extended-release formulations with low bioavailability pose a particular risk for diversion and abuse. For example, a drug that is 10% bioavailable would require 10 times the intravenous amount to achieve the same response. To use a short-acting compound for long-acting pain with twice-daily dosing, the amount of drug needed goes up again, meaning that a lot of drug is now available for diversion and abuse.
In contrast, methadone is rarely abused for practical reasons. The drug is 100% bioavailable. The same amount of drug is available regardless of how it's administered. In addition, methadone is long lasting, based on the nature of the molecule, so an extended-release formulation isn't necessary. If you're suspicious about a patient possibly diverting or abusing opioids, “this is a great drug to start with.”
Transdermal delivery of opioids involves a delay in onset of action–about 4 hours. For this reason, Dr. Palmer thinks these drugs are not the best options for breakthrough pain. In the setting of outpatient cancer breakthrough pain, it's important to have fast-, short-acting compounds. This avoids layering on excess opioids when breakthrough pain resolves after a short time.
There are a number of new and upcoming ways to avoid the potential for abuse. One problem is that opioid drugs can be crushed or rapidly extracted with alcohol. The SABER (sucrose acetate isobutyrate extended release) technology overcomes this problem because the viscous gel locks the drug into the matrix, despite attempts to crush or melt it, or extract it with alcohol.
Another option is to add antagonists, such as naloxone and naltrexone. Naloxone has a bioavailability of 3% when taken orally, so when a patient takes a drug like Suboxone (buprenorphine and naloxone in a 4:1 ratio) sublingually, “they're not having any inhibition of the mu-opioid receptor due to the naloxone.” But if they attempted to crush and inject the drug, there would be 100% bioavailability of naloxone, and it would inhibit the action of buprenorphine, said Dr. Palmer. The drug is made by Reckitt Benckiser Pharmaceuticals Inc.
A similar drug, Oxytrex (oxycodone and naltrexone), is being developed by Pain Therapeutics Inc. and currently is in phase III trials. “What they're finding in their studies is that there may be less euphoria and less physical withdrawal related to this compound, compared with just the native oxycodone,” said Dr. Palmer.
In 2006, the FDA approved Ionsys (fentanyl iontophoretic transdermal system). This patient-activated analgesic system is indicated for the short-term management of acute postoperative pain in adult patients requiring opioid analgesia during hospitalization. The system (made by Alza Corp.) delivers a preprogrammed, 40-mcg dose of fentanyl through the skin over a 10-minute period. The drug is 100% bioavailable, said. Dr. Palmer.
AcelRx is developing a sublingual sufentanil “nanotab”–six times smaller than a nitroglycerin pill–with 90% bioavailability. Abusers “could crush this if they wanted to, but it's along the order of methadone: They're not going to get any advantage by crushing it and shooting up,” said Dr. Palmer.
Another problem is the tracking of opioids. “I can track a pair of socks through FedEx or UPS from New Jersey to California, yet when I write an OxyContin prescription, I have absolutely no idea how it's used,” said Dr. Palmer. With the technology that's available to track those socks, why isn't there a better way to track the use of prescription opioids, she queried.