Another important concept is noninvasive drug delivery. Controlled release systems offer the advantages of decreasing dosage frequency, increasing convenience, and maintaining blood levels with fewer fluctuations. Transdermal drug delivery is an example of noninvasive drug administration. A number of transdermal patches are now available for nitroglycerin, fentanyl, scopolamine, nicotine, clonidine , and other drugs. These patches decrease hepatic first pass metabolism, improve or maintain relatively stable blood drug concentrations, improve patient comfort because of the continuous noninvasive delivery of drugs, and, because of patient comfort, increase patient compliance.
Clearly, these devices are able to maintain relatively constant plasma concentrations of agents such as fentanyl. One can maintain plasma concentration and reduce the frequency with which patients with cancer pain have to take other drugs to get pain relief. The fentanyl patch comes in 4 sizes, delivering 25, 50, 75, or 100 μg/hour. Although many studies have been reported in patients in the postoperative period and in patients with cancer pain, only the use for cancer pain has been approved by the FDA.
Respiratory depression and misuse by applying >1 patch are risks associated with these techniques. Perhaps the most serious problem of the transdermal systems is the fact that they are good for chronic problems but not for acute problems. It takes 6 to 8 hours to achieve a sufficient plasma concentration with today's patches, and patients may not be willing to wait that long. Another problem is that once a patch is removed, much drug remains in the skin and thus delivery can continue for a day or more. Plasma concentrations are not easily changed, either up or down, with current patches. In addition, 20% of patients have dermatologic reactions to the patch.
In an attempt to make drug delivery faster with transdermal patches, iontophoresis is being evaluated. Iontophoresis is a technique in which an electric current helps drive a drug from a patch through the skin. The devices use direct current, 40 microamperes to 10 milliamperes. Iontophoresis is generally painless, and a number of drugs are being evaluated for this approach.
One of the important delivery systems in the near future is transmucosal drug delivery—nasal, buccal, ocular, rectal, and mucosal. These techniques provide most of the advantages of the patch. In addition, because mucosal membranes are thinner and more highly vascularized, there is the potential of giving large molecules, like peptides and proteins. Because their drug delivery is much faster, the transmucosal systems also allow the possibility of titrating drugs and thus provide enhanced flexibility.
The easiest mucosal technology is the transnasal mucosal approach. For example, dipping a cotton swab tip into sufentanil and applying it to the nasal mucosa of the ferret produces an effect within seconds. For a more potent drug, like carfentanil, the effect is more immediate and can be achieved with less drug. The reason why these systems work so well is that there is an enormous surface area, 180 cm2, and an enormous blood supply in the mucosa, almost the same blood supply as the brain receives.
A variety of drugs are being evaluated for transnasal drug delivery. Nasal sufentanil has been used in pediatric populations to ease separation from parents, decrease coughing, decrease inhalation anesthetic requirements, and provide faster and smoother recoveries. Nasal midazolam in doses of 0.2 or 0.3 mg/kg has been used to provide sedation in 5 to 10 minutes and to ease separation. Midazolam is a little bitter and sufentanil can cause rigidity if too much is administered too fast, but the plasma concentrations are not much lower than what occurs when the same dose is given intravenously. Nasal ketamine has also been tried, 1.5 to 3.0 mg/kg, and is effective. Transnasal buprenorphine, Stadol, and other opioids are also being considered.
Clearly, clinicians have an interest in the transnasal application of drugs. However, there are issues that need to be studied. How does a cold or an atmospheric condition like the humidity affect the speed of the mucosal flow and absorption? What is the ideal drug concentration? What is the ideal pH of drugs for transnasal approaches? To my knowledge, much of this work remains to be done.
Oral or buccal transmucosal delivery is another potentially important transmucosal technique. The buccal cavity is also highly vascularized and moist; the epithelium is very thin, and there is an enormous surface area for drug absorption. Many drugs are approved by the FDA for buccal or sublingual absorption. Not many of them are anesthetics, and not many of them find use in the operating room. Obviously, nitroglycerin does have a potential use in the operating room. One company is working on buprenorphine as a transbuccal patch, and there are now patches that will stick on wet surfaces and transmit their drug through the mucosa of the mouth.
We at the University of Utah have been studying oral transmucosal fentanyl citrate (OTFC or fentanyl Oralet). The drug is incorporated in a dissolvable matrix on a stick (Oralet). As patients suck on the fentanyl Oralet, fentanyl dissolves in saliva and can be absorbed through the mucosal membranes of the oropharynx. Increases in plasma fentanyl and onset of clinical effect are more rapid (5–10 minutes) after OTFC than after swallowed solutions of fentanyl. Drug bioavailability is also greater for OTFC than swallowed fentanyl. In addition, no mucosal depot of fentanyl occurs after OTFC administration. An advantage of OTFC is that drug delivery can be stopped at any time by removing the Oralet from the mouth. This can allow titration to a sedative or analgesic endpoint. Initial studies with OTFC in volunteers and children have shown this system to produce reliable sedation and anxiolysis when used as a premedication. This system offers a new route of premedication and of providing acute postoperative analgesia and chronic pain therapy in various clinical settings. At present, it appears that its greatest use will be in patients with cancer, because the drug can be titrated, particularly in patients with breakthrough or incident pain.
The side effects are classical opioid side effects: nausea, vomiting, pruritus. The potential for respiratory depression and aspiration also exists, because consuming a unit of the drug will increase secretions in the stomach. As with any opioid, employing appropriate doses and antiemetics and reducing ambulation when significant drug action is present will reduce and minimize side effects.