The Use of Opioids
for the Treatment of Chronic Pain:
A consensus statement from American Academy of Pain Medicine and American Pain Society
http://www.ampainsoc.org/advocacy/opioids.htm

Dr Brookoffs article
http://www.hosppract.com/issues/2000/09/brook.htm
Chronic Pain: 2. The Case for Opioids

DANIEL BROOKOFF
University of Tennessee
Methodist Hospitals of Memphis


Initiation of Opioid Therapy
In the United States, up to 90% of the prescriptions written for opioids are for noncancer pain. The efficacy and safety of these drugs in treating chronic pain syndromes has been demonstrated many times over. Most patients with chronic pain of moderate or greater severity who have not gotten good relief with disease-specific treatments or nonopioid analgesics should at least have a trial of an opioid medication, no matter what the cause of the pain. One of the most important ground rules for such a trial, as well as for subsequent treatment, is that a single physician must take full responsibility for establishing the protocol and writing all prescriptions.

Opiate-naive patients are usually started with a short half-life drug (e.g., hydrocodone, hydromorphone, oxycodone, codeine, or morphine). Because of their rapid clearance, these drugs must be taken every three to four hours. For severe pain, the usual starting dose is 10 to 15 mg of hydrocodone or oxycodone, 2 to 4 mg of hydromorphone, 30 to 60 mg of codeine, or 15 to 30 mg of morphine.

The common strategy in treating chronic pain with opioid analgesics is to rely on "as-needed" intermittent dosing, but that does not usually provide sufficient coverage. As a result, the patient is subjected to periods of anxiety and pain that are not only unnecessary but also contribute to the patient's distrust of the physician's instructions.


Posttrial Therapy: Sustained-Release Opioids
For patients with continuous pain who respond well to opioids, long-acting sustained-release agents are indicated. They can be started once a good response to a short half-life opioid has been obtained and any side effects have been managed. The initial daily dose should be roughly equivalent to the average daily amount of short-acting opioid that provided relief.

Oxycodone is available in an eight- to 12-hr formulation, morphine in both eight- to 12- and 24-hr formulations, and fentanyl in a 72-hr controlled-release skin patch. Hydromorphone formulations allowing once-a-day dosing are expected to be on the market by next year, and several other sustained-release opioids are in various stages of testing.

These drugs have many important advantages over their short half-life counterparts. Because serum levels remain steady, miniwithdrawals or rebound reactions do not occur, as they sometimes do with long-term use of short-acting opioids. Sleep patterns are also more normal; with careful titration, the intermittent sedation that occurs with high-peaking, short-acting drugs is largely avoided.

Furthermore, because dosing is more convenient, compliance increases. By reducing the number of daily pills and eliminating fluctuations in serum levels, sustained-release opioids may help patients to shift their focus away from somatic concerns. Several studies have shown that patients using sustained-release opioids for pain are more satisfied with outcomes and have a measurably higher quality of life.

These drugs also provide less reinforcement of inappropriate use. Because they are more difficult to convert into injectable forms, they have a lower potential for diversion and a lower street price than short-acting opioids. The vast majority of prescription opioid abuse or drug diversion cases investigated by the Drug Enforcement Administration, state medical boards, and other regulatory or law enforcement agencies involve short-acting opioids--sustained-release opioids are rarely a problem. A recent study by D.E. Joranson and colleagues showed that with increased use of sustained-release opioids, medical emergencies related to abuse of prescription opioids have decreased.


Drug Selection
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 (Table 1).