Janus-Faced Drugs:: The Double-Edged Synthetic Opiate Trade

Abstract

“We call opiates a double-edged sword or Janus faced,” says Angst. “They do a lot of good and potentially a lot of harm as well.” Opiate side effects include respiratory depression, sedation, constipation, itching, nausea, reduced functioning, physical dependence, and in some cases, addiction. “More recently, we have learned that opioids somewhat paradoxically can increase the sensitivity to pain,” says Angst. “These side effects are more likely to occur at higher doses.”According to Angst, 10 or 20 years ago opioids were predominantly prescribed only for patients suffering from acute pain or for palliative care for the dying because of concerns about turning patients into addicts. Angst says that most people exposed to opiates become dependent, but they do not become addicted. “Being dependent on an opioid means that if you don't get the drug you will develop signs of withdrawal,” Angst says. “Being addicted means that you have an urge to get the drug. Nicotine is actually a much more addictive substance than opioids.”“The concept [behind Pain Therapeutics] is that a receptor can be inhibitory or excitatory depending on the amount of drug available at the receptor site,” says Angst. “According to this, it makes sense to give a very small amount of opiate antagonist to block the excitatory effects, thus making the opiate only exert inhibitory effects, inhibiting pain. However, the validity of this concept is controversial and by no means yet established. Studies trying to voice this principle have mixed results. I cannot say that the principle they are trying to exploit is flawed. It is a hypothesis, and I have not seen enough scientific evidence to robustly predict that the exploited principle will work clinically. Optimizing the use of opioids is a complex undertaking. The approach pursued by Pain Therapeutics is definitely innovative but lacks broad scientific backing. It does address something important: how can we take advantage of the beneficial effects of opiates and minimize or avoid the [adverse] effects?”Opioids work so well because they mesh into the body's own pain system and receptors. “Your body has natural narcotics [endorphins]. Everybody has natural receptors in the spinal cord and brain. People have come up with substitutes. None are very good,” says Dr. Carol A. Warfield, Chief of Anesthesia, Critical Care and Pain Medicine at Beth Israel Deaconess Medical Center in Boston. “For a long time, it was thought that if you gave people opiates, they would get addicted,” Warfield says. “It was common for doctors to under-medicate patients for pain. 10 or 15 years ago, it became evident that many people don't need an increase in opiate dosage over time like we thought they would.”Currently, doctors can rotate patients between roughly three classes of opiates to avoid tolerance or dependence: the Methadone group, the Demerol group (meperidine and fentanyl), and the group that includes morphine and codeine. Doctors also use opiate adjuncts, such as nonsteroidal anti-inflammatories like ibuprofen for arthritis and anticonvulsives and antidepressants for nerve pain. Warfield says that the pain program uses a whole gamut of procedures to deal with pain, including acupuncture, hypnosis, and spinal stimulators. “We tend to use opiates as a last resort,” Warfield says.It is now prime time for Pain Therapeutics. Remoxy and Oxytrex are being presented before the FDA. However, Merck's withdrawal of Vioxx and the FDA's suspension of Bextra (both COX-2 inhibitors) for clarification of long-term side effects may cast a shadow on FDA approval for new pain drugs. But Pain Therapeutics is using well-established drugs, preapproved by the FDA, and putting them in different formulations.“This is not a get rich quick type of business,” Barbier says. “If you are not passionate about the science and the end points, don't bother. There are no shortcuts.”