Pain must be regarded as a disease... and the physician's first duty is action--heroic action--to fight disease.

Opioid medications were once withheld from suffering cancer patients because of fear of addiction, exaggerated concern about side effects, or, in some cases, doubt about the morality of treatment. Less than 50 years ago, some medical textbooks discussed the need for patients to experience pain and suffering at the end of life so that they would relate to the agony of Christ and prepare for redemption. Although few physicians still hold these views, many continue to imply that pain should be accepted without complaint, telling their patients that "after all, pain is not going to kill you."

There is growing evidence, however, that too much pain can cause damage and even death. When pain is controlled, medications for the underlying disease or disorder tend to work better. Opioid analgesia is one of the most prolife therapies that we have to offer patients with cancer pain, and there is no reason to think that patients with other diseases are any less deserving of relief or that their pain is any less amenable to treatment. Although there is currently no ideal analgesic for chronic pain, medications that act on µ-opioid receptors are the closest thing that we have.

Assessment of Pain

One of the main problems in assessing patients with chronic pain is that the physical examination and laboratory tests often do not provide the information necessary to gauge severity and assess outcomes. Various survey instruments and visual analogue scales that allow precise measurements of pain are available but used only rarely. Pain is generally assessed indirectly, which why it is so important to listen to--and believe--patients when they say that they are in pain.

Some physicians apparently have difficulty with that. Many of my patients with chronic pain have been refused treatment by previous caregivers who apparently believed that their pain was not real. Even after undergoing painful procedures and surgeries that failed to bring relief, some of these patients were labeled as drug-seekers when they continued to ask for help. They had to contend not only with the pain but also with feelings of frustration, isolation, and abandonment by those on whom they had most relied.

In some cases, physicians may be well informed about pain mechanisms but lack an organized approach to the individual assessment of pain. A comprehensive evaluation of patients with chronic pain syndromes can be time-consuming and often requires more data than can be obtained in a few brief clinic visits. I have found the following operational format to be particularly useful, both in gauging the severity of pain and in determining the degree of disability:

1) The patient's perception. Asking the patient to keep a pain diary that includes numerical scales can help to objectify the pain. If it is understood that the physician will review the diary carefully, the patient will not have to act out a month's worth of pain at every appointment. The diary can also be an important aid in identifying exacerbating or ameliorating factors and developing more effective strategies to cope with the pain such as behavioral changes or the preemptive use of analgesics in certain situations.

2) The patient's emotional state and somatic preoccupation. This relates to the degree to which the patient remains focused on bodily symptoms to the exclusion of other issues and often can be best assessed by interviewing a close family member.

3) Functional status at home. The first things that many patients in pain stop doing are usually non-work-related activities such as going out with family and friends, attending church, or engaging in hobbies. Some patients continue to report pain or discomfort even though their condition has improved. By keeping track of daily activities, both patient and physician have some measure of how disabling the pain actually is.

4) Functional status at work. The number of work days missed and the specific work activities curtailed because of pain are also useful indices of pain severity. Since these variables can be expected to change with analgesic treatment, they provide a way to gauge the patient's response to different therapies.

5) Use of analgesic medications. If the patient is given an adequate supply of effective short-acting rescue medications and told to take them as needed, the number consumed can be a measure of pain. It can also be a way to assess whether the patient is benefiting from other medications or nonpharmacologic treatments. The physician should make it plain that the other treatments are not designed to get the patient to stop using the pain medication but to stop needing it.

Setting Goals of Treatment

It is important that the physician and patient collaborate in developing the goals to guide treatment and the means to assess progress. In many cases, there is no realistic hope of cure, and patients must come to terms with the fact that treatment will probably continue for a long time. At first, the goals may be as simple as sleeping through the night, but as the patient's condition improves, more ambitious goals, such as returning to work or participating in recreational activities, may be attainable. In addition to reviewing the patient's diary and keeping track of the various functional indicators, the physician must take the time to discuss the patient's personal goals--what he or she has been missing because of pain and most wants to be restored.

Treating Suffering as Well as Pain

The ultimate goal in treating chronic pain is for patients to reclaim control of their lives, and, to do that, they must be relieved of suffering as well as pain. Issues such as sadness over lost opportunities, guilt for being a burden to others, and feelings of inadequacy or abandonment contribute to the suffering of many patients with chronic pain and deserve attention. Ensuring that the patient obtains good psychological care is just as important as providing analgesic medications.

Unfortunately, many patients with chronic pain see referral to a psychologist as an invalidation of the physical nature of their pain. After years of hearing their disease or disorder referred to as functional or somatoform, they may need to be convinced that it is common for chronic pain to have an impact on many aspects of their lives, including their relationships with family and friends. In referring my patients for psychological assessment, I encourage them to recognize that psychological health is a vital aspect of well-being.

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).

Clinical Opiology

Choosing the right opioid for a particular patient is usually a matter of guesswork. Even though opioids have been in use as long as any other class of medications, the base of knowledge on how to use them most effectively is surprisingly small, particularly with regard to combining them with nonopioid medications and with each other.

Much of the human research has involved patients who were not in pain or who experienced limited episodes of acute pain. As a result, we often see disparities between the guidance of the medical literature and empiric clinical practice. That tables of drug equivalence are still published attests that many clinicians think opioids are interchangeable. Imagine the reaction if someone were to publish a conversion table for antibiotics showing how to convert milligrams of ampicillin into milligrams of gentamicin!

The opioid medications currently in use act largely through the µ-opioid receptor, but nearly all of them stimulate kappa- and delta-opioid receptors and some nonopioid receptors as well. In addition to their inhibitory functions, some opioid receptors appear to have stimulatory functions that may be responsible for some adverse effects of opioids. According to recent studies, these stimulatory effects can be inhibited by miniscule doses of opioid antagonists such as naltrexone and nalmefene. As we get more sophisticated in using these medications, we may be able to combine opioid agonists and antagonists both to enhance pain relief and to attenuate dependence and other side effects. This exciting field of analgesic research has recently been reviewed by R. F. Crain and S. M. Shen.

While there is general agreement that µ-opioid receptors predominate in mediating opioid-induced analgesia, we still do not know the consequences of stimulating other opioid receptors, including how they affect different groups of patients. Kappa-opioid agonists, for example, produce greater analgesia in women than in men. Until recently, most clinical pain research was conducted in men to reduce the variability caused by hormonal fluctuations.

There are also wide metabolic variabilities within groups of pain patients that may be determined by genetics or influenced by interacting drugs. Yet we have little information to guide the selection of dosages. For patients on chronic opioid therapy, it may soon be reasonable to periodically assess serum levels of the drugs and their metabolites to guide therapy, much as we do with antiarrhythmics and other medications.

Titration Against Pain

The daily consumption of the rescue drug can be an indicator of how much the sustained-release drug is falling short of providing adequate relief. By titrating the sustained-release drug accordingly, the minimum dose needed to ameliorate the pain can usually be quickly established. Patients sometimes do well at the beginning of opioid therapy and then seem to lose ground within a few weeks. In those who have been severely limited in their activities, the recurrence of pain is not necessarily a sign of growing tolerance to the medication--the patient may be experiencing more pain because of increased activity and should be reassured that more medication is required to alleviate the pain of someone with a busy schedule than of someone lying in bed all day. Maintaining close communication with patients and families and explicitly laying out the criteria for evaluating the effects of analgesic medications can go a long way toward defusing the anxiety that often accompanies visits to the physician.

Side Effects

The most feared side effect of opioid medications is respiratory depression. This does not occur, however, when the drugs are titrated against the patient's pain, probably because the pain signals activate respiratory centers in the brain that counterbalance depressive effects (Figure 1). In the event of an overdose, the activity of various brain centers is affected in an orderly, progressive fashion, with the cortex affected before the brainstem. The patient will thus become unresponsive and obtunded before the opioid level is high enough to suppress the respiratory centers. One can be assured that a patient who is awake and complaining of pain is not in any imminent danger of respiratory depression.