If a chronic pain patient who can't be helped is a doctor's worst nightmare, a patient's unrelieved agony is worse.

It doesn't have to be that way. For both patients and their doctors, new approaches to pain can make a world of difference.

Just look at the drug options. Humira, etanercept, and other new drugs have helped ease the pain of rheumatoid arthritis by slowing the disease's progression.

Lidocaine and similar anesthetics have long been a mainstay at dentists' offices, keeping pain from dental procedures at bay. Now physicians are finding new uses for them: A patch that releases lidocaine is a common treatment for pain from nerve damage from shingles. It may also be injected to relieve chronic pain from injured nerves.

Because they alter brain and spinal cord chemistry, several drugs designed to treat depression and epilepsy are now widely prescribed to treat pain "off-label" -- that is, for a use other than the one for which they're approved by the Food and Drug Administration. They appear to be especially helpful in treating pain from nerve injuries -- something that doctors term "neuropathic" conditions. These include nerve pain from stroke, multiple sclerosis, and phantom limb pain (in which amputees feel pain in a missing limb. Patients have to remember to tell doctors about all the medications and supplements they're taking, though, because of the potential for harmful drug combinations.

In a 2006 Scientific American article on new drugs to improve pain control, researchers Allan Basbaum and David Julius report on other exciting research on drugs that could interrupt the cascade of signals that transmit pain. Gains in understanding the cells and molecules that carry pain signals are allowing scientists to devise new targets for drugs that may be able to relieve once relentless agonies, including those poorly controlled by current medications.

Many people who suffer from hard-to-manage pain show "abnormal sensitivity to stimuli," Basbaum and Julius write. This hypersensitivity may make even the pressure of clothing against the skin unbearable. They add: "Biologists now understand that such heightened sensitivity -- or sensitization -- stems from molecular or structural changes in nerve cells...or central nervous system changes that lead to hyperactivity of pain-transmission pathways." Unfortunately, these inflammatory molecules can cause certain nerve cells to begin generating pain signals even when there's nothing in the environment to trigger them.

Or, as American Family Physician puts it: "Painful experiences can imprint themselves indelibly on the nervous system, amplifying the response to subsequent noxious stimuli and causing typically painless sensations to be experienced as pain."

No matter what specific cells or molecules are to blame, chronic pain is now known to lead to abnormal sensitivity, which aggravates and prolongs suffering. For this reason, the authors say, effective treatment is crucial.

"Patients need to realize that persistent pain should not be borne stoically," Basbaum and Julius write. "It requires aggressive treatment to prevent further sensitization" -- and further pain.

New targets include cells that almost always reside on neurons (nerve cells) called nociceptors, according to Basbaum and Julius. One of these is called a capsaicin receptor, which responds not only to capsaicin (the hot ingredient in chili pepper), but to heat and hydrogen ions that make things acidic and abound in inflamed tissue. Here's the reasoning: Substances that cut down on the activity of the capsaicin receptors may reduce inflammatory pain -- a theory borne out in tests of lab animals with tumor pain.

Interestingly, stimulating the capsaicin receptors can also relieve pain; topical creams containing capsaicin are already available to ease the itching and stinging sensations that accompany nerve pain from shingles and diabetes (though some patients find them ineffective).

Another possible target are sodium channels, which are found on nociceptors and open as they pass along messages from one nerve cell to the next. Researchers believe that if they can find drugs to block a subclass of these sodium channels relaying messages from pain-sensing neurons, they could relieve pain from injured nerve cells without harmful side effects. Unfortunately, because this subclass is so similar to others found throughout the body, scientists have so far been unable to develop selective inhibitors just for them.

Scientists are also excited by the recent discovery of a rare gene mutation that results in a complete inability to sense pain, according to the January 17, 2007 issue of the Journal of the American Medical Association (JAMA). Researchers from Pakistan, Jordan, the United Kingdom, and the United Arab Emirates studied three related families in northern Pakistan after hearing about the feats of one family member, a boy who earned money as a street performer by walking on coals and piercing his arms with knives. It turned out that from birth on, five related members of his clan, aged 6 to 14 years old, had never felt any pain (he himself died at age 14 after jumping off a roof). A DNA analysis showed that the six children shared a rare mutation in a gene called SCNA -- a finding that may lead to the creation of new and innovative painkillers.

Traditionally, the approach of opioids is more sweeping. They target molecules all over the body in nerve cells known as opioid receptors, binding to them and preventing neurotransmitters from releasing pain messages to nerves in the spinal cord.

Although morphine and other opioids are among the most effective painkillers, they have their drawbacks, as many cancer patients can attest. Since opioid receptors are found on nerve cells throughout the body, morphine and similar narcotics can usher a slew of unwanted side effects, including severe constipation and -- in cases of overdose -- respiratory failure.

For this reason, scientists are busy testing agents that can act on other targets in the spinal cord. In some cases, such drugs were designed for other purposes, but have found new use as pain fighters. The antiepileptic medications mentioned earlier are a case in point. They prevent the release of pain signals from nociceptor endings in the spinal cord. The logic for the new application of these neurostabilizing compounds comes straight out of Dr. Melzack's laboratory, based on the theory that pain can originate orbe amplified in the brain.

In a 2005 study published in the Clinical Journal of Pain, 91 people suffering from chronic pain took an anti-epileptic drug for three months and not only significantly decreased their pain levels, but also improved the quality of their sleep. Certain antidepressants, including tricyclics and serontonin-norepinephrine reuptake inhibitors (SNRIs), also appear to be a potent weapon against chronic pain, even when depression isn't a factor.

Another fairly new drug known as ziconotide (Prialt) comes from the venom of a Pacific Ocean cone snail. Approved to treat severe chronic pain in adults who aren't responding to other treatments, it reduces the activity of a different kind of calcium channel known as the N-type, which are found throughout the nervous system. The poison can block pain, but may cause dangerous side effects such as hallucinations, meningitis, serious muscle damage, confusion, and seizures. As such, it's generally reserved for patients with late-stage cancer who are not responding to other painkillers.

Scientists are also investigating ways to act on other targets in the spinal cord and interfere with the transmission of pain signals without causing harmful side effects.

Meanwhile, imperfect as it is, patients like Thomas Greenly and his physician, Dr. Rose, can testify to the benefits of the age-old anodyne, opium, and its opioid siblings. (And testify they do: Greenly is the founder of the National Foundation for the Treatment of Pain, an organization that helps patients get the legal narcotic drugs they need; Dr. Rose is a board member.) The news of the effectiveness and relative safety of these drugs is spreading as physicians become exposed to continuing education on the latest thinking in pain control and as those who are aggressive about treating pain emerge as role models, says the American Academy of Pain Management's Dr. Cole.

Meanwhile, the legal climate for physicians who prescribe pain medication seems to be improving as state medical boards back off, law enforcement officials pursue more pressing problems, and many states liberalize prescription laws, says Dr. Cole. "If a physician's intent is not criminal, there's really no problem," he says. "Doctors should stop worrying [so much] and start treating."

Of course, stepping up prescriptions is rarely the only answer for chronic pain patients. A growing number of nondrug options have become available as the medical community accepts some therapies once considered unconventional. Pain specialists now recommend a multifaceted approach that combines drugs with what used to be called alternative medicine: acupuncture, biofeedback, meditation, hypnosis and self-hypnosis, relaxation, visualization, therapeutic massage, and, in some cases, counseling. Attitudes of patients are changing as well: Nearly all of chronic pain patients in one recent survey used alternative treatments regardless of the medication they were on or the kind of pain they experienced.

Take acupuncture. The ancient Chinese technique is undoubtedly popular in this country, used by millions of Americans for pain relief over the past two decades. But it had never faced comprehensive scientific scrutiny in the West until recently. In late 1997 the National Institutes of Health convened a panel to study the effectiveness of the technique. The medical and scientific experts concluded that acupuncture appeared promising for postoperative dental pain, and that it might be a useful therapy for headache, menstrual cramps, tennis elbow, fibromyalgia, myofascial pain, osteoarthritis, and low back pain.

Relaxation techniques have also shown great promise. Stress-reduction programs based on meditation, such as the mindfulness-meditation program popularized by Jon Kabat-Zinn at the University of Massachusetts Medical School, have proved effective at relieving persistent pain, anxiety, and depression for chronic pain patients. A study led by Dr. Kabat-Zinn tracked 225 subjects who participated in a ten-week stress-reduction and relaxation program. Six months later, 72 percent of the subjects reported moderate or great improvement in their pain. And such gains were not fleeting: Three years after completing the program, nearly 60 percent of patients tracked were still meditating, and 72 percent reported continued reductions in pain.

Biofeedback has proven extremely useful for stress-related pain, especially tension and migraine headaches. Psychologically based interventions such as biofeedback and relaxation therapy significantly reduced recurrent headache pain in children and teenagers by up to 50 percent or more, according to a meta-analysis of 23 studies conducted between 1966 and 2004, according to a 2006 study from German researchers. In addition, a 2003 study of people with migraines, which compared 20 participants who underwent 12 biofeedback sessions to 20 "controls" who relaxed on their own, found that the biofeedback group showed significant reductions in pain, depression, and anxiety compared to the control group.

Biofeedback may also lessen chronic pain from backaches and phantom limb pain. Equally important, it promises to ease more intractable forms of pain. A 2005 report from the American Cancer Society notes that biofeedback may be able to reduce pain and "improve the quality of life" for cancer patients.

More than ten years ago, in fact, an NIH conference panel found "strong" evidence that relaxation techniques could reduce many types of chronic pain and that hypnosis could ease cancer pain. It also found "moderate" evidence that cognitive behavioral therapy and biofeedback could lessen many kinds of chronic pain.

In its 2005 Congressional update, the NIH reported on exciting research now underway. New federally sponsored studies include therapies ranging from the effect of spousal support on pain to guided relaxation techniques and tai chi. One study even uses virtual reality machines to see whether they can help reduce the pain of children coping with severe injuries like burns.

Southern author Reynolds Price has firsthand experience with alternative treatments. Wracked with pain following radiation treatment for spinal cancer, he writes of a feeling that someone was pushing a white-hot iron against his back: "There were times each day, for hours at a stretch, when my whole body felt caught in the threads of a giant hot screw and bolted inward to the point of screaming. At such times I'd lie on the bed, chew the corner of a dry pillowcase in dumb confusion, pray for relief or perfect my knowledge of every nick and crack in the ceiling."

Thankfully, Price found long-awaited help after beginning a new regimen of biofeedback and hypnosis as an adjunct to painkilling drugs. In A Whole New Life, a book that describes his descent into and out of pain, he recalls the end of his first hypnosis session: "Awake, I felt an immediate and almost scary kind of physical relief, as if I'd snorted a sizable line of some illegal drug more potent than any I'd known until now. I wasn't addled or dizzy in the least; but I instantly knew I was free in a way I'd never felt before in my life, surely not for a moment of the past three years."

Much of what's best in such therapies is being pursued along with pharmaceutical approaches in pain centers around the country. These facilities are hardly a new development; in fact, some experts think the decades-old industry is consolidating. Hospital and provider networks are also incorporating yoga, meditation, and other complementary therapies into their rehabilitation and recovery programs. As the specialty field of pain control continues to grow, there's a compelling rationale for physicians to call upon these resources for hard-to-treat patients.

As early as 1992, a meta-analysis of 65 studies of multidisciplinary pain centers indicated that the approach yielded improvement in pain and improved the odds of a patient returning to work. Dennis Turk, a professor of anesthesiology at the University of Washington School of Medicine in Seattle and coauthor of that paper, says other research suggests the centers help people reduce drug dosages and pain levels. In more recent research, Turk reported that combining medical and psychological treatment was more likely to provide relief than a purely medical approach. Cognitive-behavioral therapy, designed to replace negative patterns of thinking, was particularly effective.

Sometimes patients can find relief not from a new therapy or a new drug but from a whole new approach. Consider, for example, the growing body of evidence that patients whose acute pain is treated aggressively not only suffer less but recover faster. Why? Surgery, injury, and other causes of acute pain suppress immune function, says Michael Ashburn, director of the pain management center at the University of Utah Medical Center in Salt Lake City.

Interestingly, giving patients painkillers before surgery seems to lessen the subsequent pain, too. Two recent trials found that patients whose preemptive pain relief was started before the first incision felt significantly less discomfort immediately after surgery and needed less morphine during recovery.

Researchers have also found that simple stress-lowering strategies -- such as telling patients what kind of pain they can expect, using guided imagery, encouraging visits from spouses, or giving them a room with a window view -- can help shorten hospital stays, reduce complications and the need for pain medication, and speed along their recovery.

Part IV: What organ has the painkilling potential of morphine? Your mind.

-- Judith Horstmann is a freelance health reporter who has written for many health and medical publications. Jennifer Biddle is a research editor at Consumer Health Interactive. Part of this story is adapted from an article by Horstmann in Hippocrates magazine.

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First published March 1, 2007
Last updated June 26, 2008
Copyright © 2007 Consumer Health Interactive