Stick and Deliver
The Fentanyl Patch

by Phil Maggitti

A synthetic opioid, Fentanyl was first introduced to the medical field in the 1960s. The effects of the Fentanyl Patch, a noninvasive pain relief system, are currently being tested on cats at the Louisiana State University's School of Veterinary Medicine. The pain threshold of the laboratory-raised cats is tested with a thermal dolorimeter. After the patch is applied, researchers measure the drug's concentration in blood plasma through radio immuno assay. The patch has been found to be highly effective in treating pain in humans, and it may prove to be a more humane pain relief procedure for cats.

Delivering the Goods

After Timothy Leary had orchestrated and starred in the Internet's first death watch, a July 1996 article in the The Boston Globe reported that author William Burroughs, while visiting Leary, had developed "a particular interest in Leary's pain-relieving fentanyl patch." This skin patch -- whose technical name is the fentanyl transdermal system -- delivers a measured dose of the narcotic analgesic fentanyl, which, like other analgesics, produces insensibility to pain without producing unconsciousness.

First synthesized in Belgium in the late 1950s, fentanyl was introduced into clinical practice in the 1960s as an intravenous anesthetic called Sublimaze. Described as being 30 to 100 times more powerful than morphine, fentanyl is a synthetic opioid that is also used to provide relief to persons suffering with chronic pain. Some fentanyl users, like Leary, are afflicted with cancer; others are plagued by chronic pain from different conditions.

A Patch on the News

   Veterinarians, too, have developed an interest in the fentanyl patch. Last September 1 a headline in the Anchorage Daily News declared, "New Patch Helps Kill Pain in Pets." As newspaper headlines often are, this one was partially misleading. The fentanyl patch isn't new. It was approved in August 1990 by the Food and Drug Administration (FDA) for use with humans. Marketed by Janssen Pharmaceutica under the trade name Duragesic, the patch provides a noninvasive way to administer fentanyl, which passes through the layers of the skin into the tiny capillaries that lie underneath the skin and is, thereupon, absorbed directly into the bloodstream. From the bloodstream it goes to the brain and spinal cord, where it gets busy relieving pain.

Although the fentanyl patch has not been approved for use with animals, veterinarians are free to employ any medication they believe to be in the best interest of their patients. Thus, said the Anchorage Daily News, the patch "is becoming an increasingly effective way to control pain in any major orthopedic or soft-tissue surgery" performed on animals. In addition it can be used "for cats that are undergoing a declawing procedure" and in nonsurgical cases, such as pancreatitis or trauma, that "involve pain."

More Than Skin Deep

Coincident with the small but growing use of fentanyl by veterinarians is a new study of the effects of the patch on cats. Funded in part by the Morris Animal Foundation, this study, "Evaluation of Transdermal Fentanyl Analgesia in the Cat," is being conducted at the Louisiana State University's School of Veterinary Medicine. Ten cats will take part in the investigation, which began July 1998 and will end February 1999.

According to one member of the research team, Steven Kamerling, R.Ph., Pharm.D., "Even though the fentanyl patch is being used in clinical settings on cats and dogs, I don't think there has been any in-depth, systematic testing of its effectiveness on animals. Other people have looked at how much fentanyl gets into [an animal's] bloodstream over a period of 100 hours, but there has been no attempt I know of to correlate a level of fentanyl in the bloodstream with elevation in pain detection in the animal and with behavioral changes."

Shorn on the Bayou

The cats participating in the Louisiana State investigation are "laboratory-raised cats that were donated to us from other research projects," says Kamerling, a full professor working in veterinary physiology and pharmacology at Louisiana State. The cats are "healthy and normal and are not experiencing any pain. We begin by testing the cat's pain detection threshold with a device called a thermal dolorimeter," which projects a beam of regular light onto a one-inch square of shaved skin between the cat's shoulder blades. As the light gradually warms the skin, researchers will measure the time it takes for the cat to react to this stimulus.

"When we tried it on ourselves," says Kamerling, "our skin gradually warmed until we started to feel a little uncomfortable. Then we turned the dolorimeter off." Researchers will shine the light on a cat until it twitches its skin. "The skin twitch is a reflex that tells us the cat feels the heat from the light," says Kamerling. "We'll measure the interval between the time we turn on the light and the time the cat twitches its skin." That interval, in scientific parlance, is referred to as the Skin Twitch Reflex Latency (STRL).

After researchers have determined a cat's normal STRL, they'll apply a fentanyl patch to the cat. The semitransparent patch is composed of several layers. The backing or outer layer, the part furthest from the skin, is made of polyester film. Under that is a thin reservoir layer containing a combination of fentanyl and alcohol in a gel base. Then comes a vinyl acetate membrane that controls the rate at which fentanyl reaches the surface of the skin. The next layer of the patch is a fentanyl-containing silicone adhesive that enables the patch to adhere to the skin. The inner -- and final -- layer of the patch is a protective liner that is removed just prior to applying the patch.

Fentanyl patches are currently available in four strengths (and sizes) that release either 25, 50, 75 and 100 micrograms of fentanyl per hour. The 25-microgram patch is 10 centimeters (3.9 inches) squared and contains 2 ½ milligrams of fentanyl. The 100-microgram-per-hour patch is 40 centimeters (15.7 inches) squared and contains 10 milligrams of fentanyl. The size of the patch used on cats in the Louisiana State study will be determined by the size of the cat.

"Any animal weighing fewer than 10 kilos (22 pounds) will get the small patch," says Julia Smith, DVM, DACVA, another member of the Louisiana State team. "For a smaller animal, 5 kilos (11 pounds) or fewer," the dose will be reduced proportionately.

Anaylsis by Correlation

Having determined a cat's STRL, Louisiana State researchers will then apply a fentanyl patch to the cat. "We shave the area where the patch will be applied," says Smith, an assistant professor teaching anesthesiology for all species in the veterinary clinical sciences department at LSU "Also, because animal skin is usually more oily than human skin, we clean the area with soap and water. Sometimes we clean the skin with an alcohol wipe and let it dry completely before applying the patch. We put the patch where the animal won't be able to get to it and where the skin is not so thick that it impairs absorption." In this case, the thorax, where the patch will be covered by a bandage, but patches can also be affixed on the neck or the abdomen.

At various intervals after applying the fentanyl patch, researchers will measure fentanyl concentrations in blood plasma by means of radio immunoassay (RIA), a medical diagnostic procedure that, among other things, tests for the presence of pharmaceuticals in the blood. "We know that when RIA has been used to determine human plasma concentrations of fentanyl," says Kamerling, "around two nanograms per milliliter, a very small amount, will produce pain relief. We don't know if a similar fentanyl level in the blood of cats will produce pain relief. That's one of the reasons we're doing this study. It's not always safe or accurate to assume that what's true for humans is also true for animals or vice versa."

At the same time that levels of fentanyl in the blood are measured, researchers will use the thermal dolorimeter to remeasure a cat's STRL. Those additional measurements will be made during a period of up to 144 hours. "We hope to find that when plasma levels of fentanyl increase in the cat, its pain detection latencies go up," says Kamerling. "That will tell us the fentanyl's working. What opiates do -- and they do it in dogs, cat, horses and humans -- is prolong that latency reaction. Instead of reacting to the dolorimeter after seven seconds, you might not respond until nine or 10 seconds. That's the beauty of opiates: They raise the point at which we and our animal cousins feel discomfort. We want to know if we can correlate the level of fentanyl in the plasma with prolongation of the pain threshold latency. The basis for this study is the pharmacological tenet that the higher the concentration of a drug in the blood, the greater effect it has."

Human Testimonials

If cats are anything like people, fentanyl should help ease their misery. According to a study published in the Journal of Clinical Oncology in April 1998, 504 terminal cancer patients "in terrible pain seem to prefer a patch containing the drug fentanyl to standard morphine drugs ... patients who got fentanyl [in a skin patch] seemed to have fewer side effects than those given morphine."

In a study conducted in Houston in 1998, 50 people who had suffered from chronic low back pain for years were given fentanyl patches and asked to compare their effects to the oral pain medications the subjects had been taking. The majority of patients "felt the patch was more effective and liked it better than the oral [medications]," said Dr. Richard Simpson, associate professor of neurosurgery at Baylor College of Medicine in Houston. "Patients testing the patch reported less pain and significantly less disability."

Veterinarians appreciate the patch for an additional reason: It beats heck out of more invasive methods of medicating a sick cat. "The patch is a Godsend," says Smith, "because it delivers a drug continuously. That's a problem with the delivery of any of these drugs: They have to be given by injection, rather than orally, for best results. So the cats have to be picked up, restrained, injected. In addition, these other agents seem to have more sedative and behavioral side effects in cats than the patch does.

"We also use fentanyl in cats in its injectable form intravenously, but when you use a catheter, the cats still have to be handled, and the catheters and bandages have to be checked."

Patchwork Effects

In addition to correlating STRL and fentanyl levels in the blood, the Louisiana State researchers will observe behavior differences in cats pre-and post-fentanyl. "One of the interesting behaviors we observed on the first cat that we applied a fentanyl patch to, was the cat got more affectionate," says Kamerling. "She started purring more, which was a signal to us that the fentanyl was getting into the blood and ultimately to the brain. We also noticed that the cat was more easily roused by loud noises in the room. We didn't see that response in this particular cat prior to using the patch. Those are the kinds of things you can see with opiates, but regardless of their behaviors, all animals will experience pain relief from opiates."

Animal owners, for their part, will experience some relief from the cost of medication. Smith concludes that the patch "will end up being less expensive" that other analgesics that are administered by injection.

Less expensive, more filling. Less invasive, more humane. What else can a person ask of a medical procedure? I bet those rascals Leary and Burroughs would approve.

Pain
Morphine
Duragesic
Fentanyl analogs
4-methyl fentanyl
Fentanyl: structure
Fentanyl: synthesis
Fentanyl and ketamine
Opioids and anaesthesia
Remifentanil and alfentanil
Fentanyl: subjective effects
Fentanyl versus remifentanil
From codeine to transdermal fentanyl

Opium
Glossary
References
Opium Images
Just For Chemists