Johns Hopkins Magazine - June 1994 Issue

Health & Medicine

Research Findings and News

Preventing Pain

Treat cancer pain aggressively, federal panel advises Cancer pain is widely undertreated, reported a 26-member federal panel in March. "A lot of patients die in a lot of pain," says Ada K. Jacox, professor of nursing at the Johns Hopkins School of Nursing and co-chair of the panel, because so many people--both patients and health care professionals--believe that painkilling drugs turn patients into addicts, then lose their potency when they are needed most.

Not so, says Jacox. "It is not true that there is a ceiling on morphine." Patients do develop some tolerance, but larger doses can then be given without depressing breathing (a potential side effect of morphine), "because cancer patients adapt to it if they're on it for the long term." Even if enough opiates cannot be given to control the pain, the patient need not suffer. Clinicians can resort to more invasive techniques, such as nerve blocks.

The panel also sought to debunk a widespread misconception that pain just inevitably comes with cancer. Even in terminal patients, pain may or may not be present. And for many patients, points out Jacox, "the only pain will be when they're initially diagnosed and have pain associated with the surgery."

After a cancer patient recovers and no longer suffers pain, drugs can be safely withdrawn, the panel found. "It's true that patients will become dependent on morphine," explains Jacox, "just as diabetics become dependent on insulin." But dependence should not be confused with addiction. Jacox explains that because cancer patients do not take their drugs for the sake of a high, they almost never develop the psychological cravings of true addiction. "That doesn't happen to our cancer patients," agrees Stuart Grossman, an advisor to the panel who heads the cancer pain program at the Johns Hopkins Oncology Center.

These myths debunked, the panel issued a set of 66 guidelines that are expected to improve pain management in hospitals and clinics throughout the country. The short version, according to Jacox, is "Give as much as you need, as soon as it's needed, and then increase it."

Too often patients wait till pain is really bad to report it, or nurses wait too long to treat. Then, Jacox explains, more drug is needed, not less, even though there is more suffering. When continuous medication prevents the pain, patients heal better and sooner. "They move around better, their quality of life is better, they eat better, they can deal with their illness better. When they have to deal with the pain, it blocks everything else out."

Free copies of the report, Management of Cancer Pain, can be obtained through the National Cancer Institute's Cancer Information Service by phoning 1-800-4-CANCER. --Elise Hancock

When morphine can't be used for sickle cell

The pain of a sickle cell crisis is "excruciating," says pediatrician Myron Yaster, director of Hopkins's Pediatric Pain Service. It is comparable to that of childbirth. Yet giving morphine has been a problem, and sometimes little could be done. Now physicians at the Johns Hopkins Children's Center have found that children given a local anesthetic in the lower spine, as is commonly done to women during childbirth, reported little to no pain within minutes.

In a sickle cell crisis, twisted red blood cells intertangle and form a logjam, clogging arteries so that oxygen has trouble reaching the legs, abdomen, chest, and arms. The resulting pain is so intense it makes breathing difficult, leading to further lack of oxygen and possible heart failure. But morphine, though a very effective pain- killer, can have the side effect of depressing respiration, exacerbating the lack of oxygen.

In the Hopkins study, nine children, ages 3 to 16, reported severe pain from the chest down. Epidural catheters were inserted by an anesthesiologist after other pain-control methods, both narcotic and non-narcotic, had failed. Pain relief was immediate and continuously effective, says Yaster. "One child was moving furniture in her room shortly after reporting pain so severe she couldn't even move in bed." In addition, blood oxygenation increased from as low as 87 percent to nearly 100 percent in all patients.

And in patients for whom addiction is of special concern: In other research studies, a team of researchers from Johns Hopkins and the National Institute on Drug Abuse have found that by combining morphine with verapamil, a common medication for high blood pressure and angina, "you can get greater relief of pain, at a lower dose of morphine, with less fear of addiction," says Hopkins neuroscientist Edythe D. London.

Verapamil significantly boosted the pain-killing effects of morphine in 12 volunteers, all with a history of drug abuse. It also blunted and shortened the morphine "high." --EH

Liver cells in vitro--that work like liver cells

Until recently, the only way to study a hepatocyte, the major liver cell, was to carefully (very carefully) take one out of liver tissue, culture it carefully (very carefully), then work fast. "It won't divide," says Ann Hubbard, professor of cell biology and anatomy, but if you're very deft and very lucky, "it'll live--sort of. It tends to lose its liver- specific functions." In other words, it stops doing the things researchers want to study.

Now, however, Hubbard's lab at the School of Medicine has developed a line of cells that not only do divide and grow in culture, but that also seem to retain their ability to do the hundreds of things hepatocytes do for the body. The new cell line is called WIF-B (B for Baltimore), and already there is interest in using cultured hepatocytes for transplantation and gene therapy.

One reason it has been so difficult to culture the cells is that hepatocytes are among the most complex cells in the body. Not only does each individual cell synthesize chemicals serving 500 or so different functions, but hepatocytes only work because they are what you might call two-faced. A biologist would say the cells have "polarity."

Polarity is crucial because the whole three-pound liver is interlaced with complex networks made of thousands and thousands of pulsing arteries, veins, and bile ducts. And hepatocytes, arranging themselves like cords of raggedy- looking honeycombs, are what separate the blood from bile. Every single hepatocyte is equipped to do business with both fluids, in a specialized domain of the cell.

As blood courses through the liver, each hepatocyte's "basal domain"--the part that faces the blood--pumps in essential proteins including albumin, lipoproteins, triglycerides, and blood clotting agents. The blood carries these vital proteins out to every cell of the body.

At the same time, from another surface of the same cell--the "apical domain" (apex = head)--bile acids are pumped into a bile canaliculus (little canal), for eventual delivery to the gall bladder and small intestine. Bile is essential to digesting fat.

And the hepatocytes also interact with one another. For instance, it takes more than one hepatocyte to create the mini-canal where bile begins its voyage to the gall bladder; one apical membrane has to meet the apical membrane of a neighbor cell just so, so that one cell forms the floor of the canaliculus, the other the roof.

What Hubbard would like to know is, precisely how do the cells manage to control and route all that traffic? How do they maintain their polarity, the separate domains? "The cells are in a continual dynamic flux," she says.

Despite the convenience of manipulating cells in vitro, says Hubbard, she has a philosophy of not relying on that approach. "The danger," she says, "is that you don't know if the cells have adapted to life in culture and are not really functioning the way that they do in vivo."

So when Hubbard came to Hopkins in 1980, she began her hepatocytic work in vivo, and by about three years ago she and her team had generated and cloned a library of antibodies that can pick out and label particular hepatocytic proteins. Some of these proteins are found only on the apical membranes, others only on the basal surfaces.

Meanwhile, in France at the Curie Institute of Orsay, a somatic cell geneticist named Doris Cassio had fused cells from a rat liver with a human fibroblast. In the resulting genetic free-for-all, Cassio noticed a few pairs of cells that would form a tiny open area--something resembling a bile canaliculus (BC). Excited, she picked the cells out and cultured them further, to finally evolve a stable line of cells (WIF-12s) that formed possible BCs. But did the cells have polarity?

When the WIF-12s were tested with Hubbard's monoclonal antibodies, the answer was yes, and soon an international collaboration was in flower. Cassio visits Hopkins often, and the deft hands and eyes of technician Mike Shanks have helped improve Cassio's WIF-12s into the latest line, WIF-Bs. The WIF-Bs have more and larger BCs than do WIF-12s, and they have full polarity--well, almost. WIF-Bs in culture form only a single layer, so the cultured BCs have no place to send their bile--but they are definitely pumping bile. For experimental purposes, the cells seem to behave like hepatocytes in vivo.

Excitement is high because whole new lines of research are now open. For instance, the WIF-Bs may help researchers understand the molecular basis of bile secretion. And for gene therapy, cultured hepatocytes might help researchers attach a DNA correction to the hundreds of proteins that hepatocytes send out all over the body.

Hubbard's results have been recently published in the Journal of Cell Science and the Journal of Cell Biology. --EH

A less invasive mastectomy

Hopkins surgical oncologist William Dooley has dramatically reduced the size of incision required for a mastectomy. In conventional mastectomy, surgeons make a five- to six-inch- long elliptical incision (left). Dooley, however, cuts only an inch-and-a-half circular flap of skin around the nipple (right). In both procedures, the same amount of internal breast tissue is removed and abdominal tissue is used for reconstruction.

In addition, says Dooley, he cuts the elastic breast fibers in a way that preserves the conical shape of the breast, whereas conventional mastectomies tend to flatten the breast. He compares the difference in technique to cutting with the grain versus cutting against the grain. Dooley works alongside plastic surgeon Bernard Chang, who helped develop the new technique and has improved nipple reconstruction.

Dooley cautions that the new procedure is not for every patient. "If there were a very large tumor adherent to the skin, I wouldn't do it," he says. Preliminary studies indicate that patients who have had the smaller incisions fare as well as patients who have had the conventional procedure. --Melissa Hendricks

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