Ketamine has captivated physicians and teens ever since 1970 when the FDA approved the drug as a surgical anesthesia, and young adults started getting high on it. First marketed as a veterinary anesthetic, ketamine — which is chemically related to PCP and encourages psychological and physical dependence — quickly caught on with drug abusers. By 1981 the U.S. Department of Health and Human Services recommended ketamine's reclassification as a controlled substance, but the DEA rejected the idea until 1992 when it received 775 reports of ketamine abuse, including veterinary clinic burglaries and hospital emergency room visits.

Despite an association with date rape and other hallucinatory drugs, infusions of ketamine now represent last-resort therapy for those with the intractable disease known as complex regional pain syndrome. The only drawback to treatment is patients literally may be betting their lives against this unorthodox, and potentially excessive, use of the drug.

"It's a crappy disease," said Philip Getson, clinical associate professor of neurology at Drexel University College of Medicine in Philadelphia. The syndrome ranks No. 1 in painful chronic conditions, according to the McGill Pain Index, and its symptoms include unbearable burning and sensitivity, muscle spasms, inflammation and problems with concentration and memory.

Like many pain management experts and despite the dearth of controlled studies, Getson uses ketamine off label. The most powerful of a set of anesthetics known as the NMDA (for N-methyl-D-aspartate) antagonists, ketamine blocks the sensitization process in the central nervous system, allowing pain cells to normalize.

Despite its awful symptoms, complex regional pain syndrome (also called reflex sympathetic dystrophy) remains difficult to diagnose. While the nonprofit RSDHope estimates 1.5 to 3 million with the syndrome in the United States, Getson believes that's a gross undercount, and that the true number is closer to 6 million, with women experiencing it disproportionately.

Plus, disagreement over number and type of diagnostic criteria (i.e. should statisticians factor in fibromyalgia as an indicator) can hurt recruitment for trials, said Jim Broatch, executive director of the RSD Syndrome Association. "Insurers don't want to diagnose it because it's costly to treat."

That reluctance echoes on the treatment side, as promising therapies involving ketamine have faced obstacles. "The FDA has taken a hands-off attitude [on ketamine]," says Getson, referring to the agency's trend toward less control of off-label use. Randall S. Stafford, associate professor at the Stanford Prevention Research Center in Palo Alto, Calif., believes that laxness discourages evidence-based practice — medicine's gold standard. The option of off-label use sends the wrong message to drug manufacturers: Why bother conducting hard, costly studies on pharmaceutical products already in the pipeline if later you can seek approval for secondary applications and run clinical trials that are much cheaper, simpler — and patient centered?

Enmeshed in the conflict between investigational science and sympathetic intervention is ketamine researcher Dr. Anthony Kirkpatrick, chairman of the Scientific Advisory Committee of the Tampa, Fla.-based RSD Foundation. Kirkpatrick performs three-day, low-dose outpatient procedures using ketamine. But he reserves a sort of secret weapon, the "ketamine coma cure" — a high-risk procedure in which patients placed in a medically induced coma receive a continuous five-day, 600-mg-to-900-mg infusion — for RSD victims with "catastrophic" conditions and "no alternative, no recourse."

"Many are suicidal," Kirkpatrick says, musing over the ethical implications of denying possible relief in those circumstances. Is it morally correct, for example, to randomize patients into two groups (one group receiving ketamine, the other put on temporary hold) or to administer a placebo or a different anesthesia such as propofol for the sake of science?

Ethics aside, funding is another hurdle. Since generic ketamine is freely available, pharmaceutical companies aren't interested in financing expensive studies. "The costs [of clinical trials] are so huge, I've heard of doctors leveraging their houses," Kirkpatrick said.

Off-label use is not without its risks either. Malpractice claims bankrupt physicians (from1985 to 2008, the payout for anesthesiologists was around $671 million; for neurosurgeons, $500 million, according to the 2009 Physician Insurers Association of America Risk Management Review for Combined Specialties). Although ketamine's wide safety margin provides some comfort, patients on respirators with their brains shut down (as in the ketamine coma) could conceivably not wake up. Plus, Kirkpatrick said, "horrific" hallucinations can emerge up to a week after the infusion.

Such risks help explain why the procedure is only done in Mexico by Mexican physicians — outside the sway of American regulators or attorneys.

Still, the cost benefits balance out, said Houston physician Everton Edmondson, one of a growing number of off-label ketamine practitioners in the United States. A few years ago Drexel University's Robert J. Schwartzman — probably the country's foremost RSD expert — performed 95 percent of infusions. Now, there are around 20 such mavericks, says Broatch.

Demand for the intervention — given that even a mild trauma such as an injection, an everyday fall or a simple sprain can trigger RSD — partly explains the increase in practitioners. Rapid diagnosis and treatment can curtail the progression, but for patients whose excruciating pain has spread to other sites, ketamine therapy is "close to a miracle," says Joshua Prager, director of the Center for the Rehabilitation of Pain Syndromes at UCLA, a tertiary medical practice there that treats patients with complex regional pain syndrome as well as severe back pain, neuropathic pain and cancer pain. "The pain usually stays away three months, but one patient was pain free for a year."

The lower-dose infusion success rate is around 80 percent, conclude Schwartzman and Kirkpatrick, but pain returns without "booster" treatments — two studies totaling 36 patients showed immediate cures half the time, with pain reappearing within six to nine months. A double-blind, randomized, placebo-controlled low-dose trial in The Netherlands — a four-day infusion of 60 patients — later confirmed those results. Schwartzman is currently evaluating data from another controlled low-dose trial.

Unfortunately, even less safety and efficacy evidence exists for the ketamine coma, which American-trained physician Fernando Cantu administers to carefully screened patients at San Jose Hospital in Monterrey, Mexico. A total of 10 published case studies describe nearly total pain relief with no neurocognitive deficiencies, and Schwartzman's recent report on 20 German coma patients detailed not only significant moderation of pain, but also greater mobility, quality of life and work potential. Anecdotally, the media reported two casualties one death and one paralysis — the latter resulting from pneumonia caused by methicillin resistant staphylococcus aureus, or MRSA, a staph infection that is resistant to a broad spectrum of antibiotics.

"It's research, not treatment," says Kirkpatrick, who obtains informed consent and videotapes all doctor-patient interactions. His Mexican team received authorization for the $30,000 procedure from the San Jose Hospital ethics committee and institutional review board after the FDA rejected Kirkpatrick's Investigational New Drug exemption application. If the agency had permitted secondary drug investigation, the costs of clinical trials would have been drastically reduced.

Kirkpatrick attributes the FDA's nonwaiver to the American institutional review board's failure to "manage" high-risk research. That's not their mission, counters Jon Merz, associate professor of medical ethics at the University of Pennsylvania: "They approve or disapprove [clinical trials]; their focus [is] the protection of human subjects' rights and welfare."

Another reason for Kirkpatrick's south-of-the-border outsourcing is the threat of U.S. malpractice suits. According to the 2009 Physicians Insurers Association of America Data Sharing Project, anesthesiology ranks seventh highest of 28 specialties in malpractice monies paid.

Although the jury is still out, pressure — from the public, insurance companies and physicians seeking a medical standard and common protocol — is fueling the gathering of more clinical evidence. A University of California, San Francisco-sponsored trial piggybacks IV ketamine with morphine; Edmondson's experiments with ketamine and nerve blocks will be shared in an upcoming 50-case paper; Sam Sharar, at the University of Washington Medical School in Seattle, recently tested immersive virtual reality and low-dose ketamine; and the team of Kirkpatrick and Schwartzman plans to publish the results of 200 coma patients. (The current count is at 100.)

Moreover, of the 54 percent of returning war veterans with chronic pain (according to a 2006 survey taken by the American Pain Foundation), many are diagnosed with polytrauma or causalgia (both military "code" for RSD). Easing the way for vets and civilians, more insurers are covering ketamine infusions, says Getson. "Aetna U.S. Healthcare ... [is] the only major insurer denying payment."

At day's end, however, with or without verifiable data, complex regional pain syndrome patients and their physicians have reason for cautious optimism. Says Getson, "Infusions are the wave of the future."

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