A careful review of the patient’s medical history is the first essential in choosing a medication. Patients with chronic pain can often tell what has worked in the past and what has not. In one study of cancer patients using opioid analgesics, 44% required trials of two or more opioids, and 20% required three or more, before achieving satisfactory pain relief without intolerable side effects. As in selecting any drug, both adverse and beneficial effects must be evaluated in the context of the individual patient’s current physical condition.

Morphine. Of the sustained-release opioids, morphine is considered by many to be the gold standard, probably because it was the first sustained-release drug that allowed adequate dosing. The designation is more historic than clinically significant, however. In comparison to other opioids, morphine generally causes more nausea and pruritus. It also has the disadvantage of being relatively hydrophilic, which delays its transport across the blood-brain barrier. In addition, morphine has several active metabolites whose levels can vary with renal or hepatic function. The drug apparently induces its own metabolism, which makes it difficult to maintain a steady serum level.

Fentanyl. Because of these problems, fentanyl, a derivative of meperidine, was specifically designed to substitute for morphine in operative anesthesia. It is lipophilic and therefore faster acting. Of greater import, however, is that its potency is hundreds of times greater than morphine’s. Microgram amounts, administered by a transdermal patch, can provide pain relief for up to 72 hours. Because fentanyl does not traverse the gastrointestinal tract, it causes less constipation than other sustained-release opioids and does not induce liver metabolism through first-pass effects. It also does not appear to have active metabolites.

Oxycodone is sometimes thought of as a weak opioid, probably because it has been formulated in low-dose pills. Like fentanyl, however, it is more potent than morphine and is associated with fewer adverse effects. A sustained-release formulation, introduced about five years ago, has quickly become the most popular opioid for treatment of chronic noncancer pain in the United States.

Oxycodone is actually a prodrug. The active metabolite, oxymorphone, is produced in the liver by the enzymatic activity of cytochrome P450 2D6. (This is the same enzyme responsible for activating two other prodrugs, hydrocodone and codeine). Approximately 10% of the population have genetically low levels of P450 2D6 and thus require higher than usual doses of the prodrug to obtain pain relief. Less than optimal effects may also be expected in patients taking neuroleptics, quinine, or selective serotonin reuptake inhibitors such as fluoxetine that inhibit P450 2D6 activity.

There have been sporadic reports of agitation, sleeplessness, and dysphoria in patients taking high doses of oxycodone, which suggests that, in addition to µ-opioid effects, the drug also has kappa-opioid effects. It may thus have some added advantage for treatment of visceral pain, which appears to respond to kappa-receptor agonists.

Hydromorphone. The clinical trials of sustained-release hydromorphone indicate that it has analgesic effects similar to those of morphine but that it has fewer side effects. None of hydromorphone’s metabolites are pharmacologically active, which will make this drug particularly useful for patients with renal failure.

Methadone and Levorphanol. By virtue of their intrinsically long half-lives, methadone and levorphanol are also useful for treatment of chronic pain. Both have significant nonopioid effects that may contribute to their utility as pain relievers, especially for neuropathic pain. Methadone appears to be a potent N-methyl-D-aspartate (NMDA)-receptor blocker. Levorphanol also has some NMDA inhibitory effect and may, in addition, inhibit reuptake of serotonin and noradrenaline.

These drugs are generally reserved for second-line treatment, however, because they are difficult to titrate and have delayed-onset side effects. To control pain effectively, methadone must be administered at intervals (6-8 hr) shorter than its metabolic half-life (15-90 hr). As serum levels of the drug increase, so does the risk of toxicity, primarily sedation.

Many U.S. physicians are under the impression that it is illegal to prescribe methadone without a license from the federal government, but that is the case only if methadone is used in a maintenance program for treatment of drug addiction. When prescribed for pain, methadone is subject to the same regulations as other high-potency opioid medications. One practical advantage of methadone and levorphanol is that they are both relatively inexpensive.

Rescue Medication. Most patients taking long-acting opioids should be supplied with a fast-acting rescue opioid to treat pain that breaks through the regular medication schedule. Oral rescue agents may be needed as often as every two to four hours. The usual dose is the analgesic equivalent of 5% to 15% of the 24-hour baseline dose of the long-acting opioid