NEW YORKBecause it is so well known that opioids are most effective for nociceptive pain, they are often ignored when patients present with neuropathic pain. But opioids are at least as effective as current agents used for neuropathic pain, Richard Payne, MD, of Memorial Sloan-Kettering Cancer Center, said at the Third Conference on Pain Management and Chemical Dependency.
Dr. Payne said that classic teaching tells us that opioids are more effective against somatic and visceral, or nociceptive pain, and less so against neuropathic pain, but a neuropathic pain mechanism does not mean that a patient cannot achieve pain relief with an opioid. The dose-response curve will be shifted to the right, merely indicating that higher doses are needed, he observed.
A recent study, Dr. Payne pointed out, showed that patients with pure neuropathic syndromes such as in diabetic neuropathy and herpetic neuralgia, experienced equally effective relief from both opioids and the typically used drugs, eg, gabapentin(Drug information on gabapentin) (Neurontin), tricyclic antidepressants, and dextromethorphan(Drug information on dextromethorphan).
He said that opioids are thought to work by mimicking the action of endogenous opioid substances like endorphins, dynorphins, and enkephalins. The drugs bind to receptors found in both the central and peripheral nervous systems.
The fact that opioids can be administered in a wide variety of doses and formulationsincluding pills, liquids, capsules, transmucosal lozenges, suppositories, and subcutaneous, intravenous, spinal, and intraventricular injectionsincreases their clinical utility, he said.
The WHO Ladder
Dosing and prescription are dictated by the three-step WHO (World Health Organization) ladder divided into the categories of mild, moderate, or severe pain. We are really reliant on the patients self-report of pain intensity and pain quality, Dr. Payne noted.
While non-opioid analgesics can reduce mild pain quite well, moderate or severe pain usually requires an opioid drug in combination with non-opioid and adjuvant analgesic drug therapy, he said.
The three-step ladder splits opioids into weak and strong drugs. The weak opioids include codeine, dihydrocodone, hydrocodone(Drug information on hydrocodone), meperidine, and oxycodone(Drug information on oxycodone) in combination with acetaminophen, aspirin(Drug information on aspirin), and/or caffeine(Drug information on caffeine). Although effective in managing mild pain, these weak opioids are toxic at high doses. As one begins to escalate the dose to deal with more severe pain, one runs into aspirin, acetaminophen, and caffeine toxicity as well, he said.
Stronger opioids include hydromor-phone, methadone(Drug information on methadone), morphine, fentanyl, and oxycodone in its sustained-release form. Because these agents can be administered at very high doses without concern for organ toxicity (and with no ceiling to their efficacy), they are appropriate for moderate or severe pain, Dr. Payne said.
He cited a clinical trial in which patients with chronic cancer pain were given oral preparations of ketoprofen, a non-opioid analgesic, at a dose of 225 mg, or intramuscular morphine at 5 or 10 mg. Analysis showed mean pain relief over time to be the same for both.
When the dose of the ketoprofen was increased threefold, the patients failed to show a proportional increase in pain relief. However, 10 mg of morphine (far from its highest doses) and further dose increases offered significant pain relief. Doses of morphine ranged from 5 mg to 35,000 mg, with the majority of patients getting doses from 5 mg to 699 mg. There is a wide variability in the response to opioids, but there is no intrinsic ceiling, Dr. Payne said.
The strong opioids are not formulated with acetaminophen, aspirin, or caffeine. Thus, side effects are limited to those commonly seen with opioid use, including constipation, nausea, sedation, respiratory depression, and mental clouding. While 100% of patients will suffer from constipation, only some will present with the other side effects, Dr. Payne said.
Constipation can be handled with aggressive and prophylactic treatment, such as laxatives and stool softeners. Nausea, which usually subsides on its own, can be eased by changing the opioid or, as a last resort, by giving an antiemetic. In cases in which optimum pain relief has been achieved but sedation is a problem, caffeine or amphetamines can be prescribed.
Because opioids are incompletely cross tolerated and cause adverse effects with varying severity in different patients, experienced physicians will change opioids as needed. The presence of nausea with one drug does not necessarily predict its presence in a second drug given to the same patient, Dr. Payne said. At least 80% of chronic pain patients switch opioid treatment once, 44% at least twice, and 20% switch three or more times.
While tolerance to opioids does occur, side effects typically start showing before the efficient management of pain diminishes, he said. For example, respiratory depression, a clinically significant adverse effect, occurs much faster than tolerance to analgesic effects.
Chronic pain and acute pain require different management techniques. For chronic pain, Dr. Payne said, transdermal fentanyl(Drug information on fentanyl) (Duragesic) has become quite popular. It is released across a rate-controlled membrane for 72 hours, offering noninvasive, continuous, passive diffusion of the drug across the skin.
However, when a chronic pain patient is faced with breakthrough pain, there is an acute need for increased analgesia. This is best dealt with through IV morphine or the new fentanyl lozenges [Actiq], which when mixed with saliva, penetrate the oral mucosa and reach therapeutic levels as fast as IV morphine, Dr. Payne said. The transdermal/lozenge approach to pain management is superior to doses of morphine administered at intervals, he noted, because the latter allows blood levels to oscillate in and out of the therapeutic window.
Addiction Fears Unfounded
Unfounded fears that opioid use will lead to tolerance or addiction continue to impede their efficient use in pain management. Tolerance and physical dependence do not equate to the behavioral syndrome we call addiction, he said.
Reduced pain relief with a specific opioid dose, tolerance to opioid side effects, and physical dependence after withdrawing prolonged treatment do occur. However, addiction is defined by use without control, despite harm to the individual, and by compulsive use. Patients take opioids to treat pain, and in the absence of pain, we can taper their use, he said.
In the absence of a pre-existing substance abuse disorder, iatrogenic addiction occurs very rarely when patients are treated with opioids for pain management. He underscored that although opioid prescriptions have increased, there has been no evidence of increased abuse.
An ideal analgesic, Dr. Payne said, would provide pain relief in the absence of anesthesia, provide profound analgesia that isnt permanent, be easy to administer, be effective against a variety of types of pain, and have no side effects. Among the analgesics that are available to physicians today, opiates fulfill most of these requirements.