Basic Principles of Pain Management

Robert J. Boland and Richard J. Goldberg

Pain is a private experience. There is no questionnaire, blood test, or technology that can objectively quantify the amount of pain that someone feels. Pain is a complex product with contributions from personality, memory, fantasy, and cultural traditions in the context of neurophysiologic processes. Pain serves an important signaling function in the organism and often leads to recognition of some underlying disease that can be medically or surgically treated. However, despite the available technology, pain often remains inadequately treated, at times because of underlying patient or physician attitudes and sometimes because of medical or psychosocial misunderstandings.

In this chapter, we will review current research about pain. We will briefly examine the physiology of the pain experience. Most of this chapter is then devoted to techniques of assessment and pain management.

The Physiology of Pain.

One has only to examine the physiology of pain to realize how complex the pain experience is. Any desire we might have to trivialize a person's pain (with statements such as "the pain cannot be explained by the physical findings") is nullified by even a cursory examination of current research on pain mechanisms. Such research is briefly reviewed here, and available in more detail through a number of sources (eg., Brose & Spiegel, 1987). .

Origin of the Stimulus.

Nociceptors. The pain experience begins with the nociceptors. These are afferent nerves that respond to noxious stimulation. Different nociceptors may preferentially react to a specific kind noxious stimuli, such as mechanical or temperature sensation. Different types of nociceptors may be found in different sites: for example, the most common cutaneous receptor is the polymodal C fiber, which responds to pressure, temperature and chemical stimuli, whereas skeletal muscle contains mostly chemoreceptors. All nociceptors have an initial high threshold to noxious stimuli, which decreases with repeated stimuli.

Stimulus transmission. It is tempting to stop at this point and treat pain as a simple reflex, in which the nociceptor receives a noxious response and transmits it to the brain. Much pain treatment is based on this naive assumption. It is, in reality, a long and complicated journey between the nociceptor and the brain.

Signals from the nociceptor are transmitted to the spinal cord. This is done mainly by two fibers: Ad fibers and C fibers. Ad fibers are myelinated and provide the initial pain response. C fibers are unmyelinated and probably cause the slower response felt several seconds after an injury.

Most of these fibers enter the spinal cord through the dorsal root ganglion and terminate in the dorsal horn of the spinal cord. Generally they terminate ipsilaterally, but a small number will cross to the contralateral side. The clinical significance of this is not clear, but it may explain the incomplete pain relief seen after unilateral surgical ablation of this area.

The dorsal horn is organized into areas, called laminae, and certain pain fibers will predictably go to specific laminae. In the laminae the fibers synapse with second order neurons, which take various pathways to the brain. The best understood pathways are the spinothalamic and spinoreticular pathways. These pathways are named after their points of origin and termination.

Termination of the stimulus. After processing (in the thalamus and other areas) the pain stimulus arrives in the limbic system and cortex. Different areas decide various aspects of the pain. For example, projections from the thalamus to the parietal lobe are involved with localization of pain, whereas projections to the limbic system are involved in qualitative aspects of pain. The somatosensory cortex receives input from most spinal pain tracts, and is the primary cortical region for the perception of noxious information.

Modulation of the Stimulus.

Local chemicals. No "pain transmitter" has been identified. However, many substances can modulate a nociceptor's response to noxious stimuli. The best understood is substance P, which may work indirectly through vasodilatory effects. Other chemicals that have a role in pain modulation include prostaglandin, serotonin, histamine, acetylcholine, bradykinin, slow-reacting substance of anaphylaxis (SRS-A), calcitonin-gene-related peptide (CGRP), and potassium.

Higher down-modulation. Virtually every part of the pain system can reciprocally affect other parts, and the system should be envisioned as bidirectional. The cortex, in particular, can influence all previous stages of pain transmission through a variety of means. The most obvious is through attentional processes. Most of us are familiar with stories of combat victims who performed heroic acts after injury, apparently unaware of their pain until hours later. More common are reports from chronic pain patients that their pain seems to get worse at night, presumably when there is less distraction. The meaning of pain can also influence its perception-
-for example, pain perceived as jeopardizing health (eg. cancer pain) can seem worse than pain that is not life threatening. Finally, a variety of learned phenomena, such as cultural factors, can affect one's perception and expression of pain.

Assessment of Pain

Pain is always subjective. It is the result of a variety of factors. The assessment of pain, therefore, must rely on methods that are necessarily subjective and multidimensional. Currently there is no universal "gold standard" for pain assessment, and it is not our purpose here to outline a blueprint for such an assessment. However, any approach must acknowledge the many different dimensions of the pain experience. These dimensions are discussed in this section. A broader discussion is available in a number of sources (eg., Turk & Melzack, 1992)

The Immediate Pain Experience.

When a patient complains of "pain," we must first attempt to better understand what they mean. We would like to quantify and qualify the nature of their experience. Any clinician is familiar with basic questions to ask any symptom: location and duration, for example. Often we ask the patient to apply adjectives to the pain: "burning," or "stabbing." Such an approach, though helpful, may only add to the subjectivity of the exam. We may not all agree what these adjectives actually feel like, particularly without firsthand experience of being severely burnt or stabbed. Thus, we must try to better understand the pain experience in ways that are both reliable for the individual, and generalizable to others.

Intensity. Most commonly, we wish to quantify the intensity of the pain. A variety of approaches are used. We might give the patient a list of adjectives to describe the pain, usually listed in order of increasing intensity. Alternately, we might ask the patient to give a numerical value to the pain intensity. In the latter case, we often ask patients to rate the pain from one to 10, one being no pain and 10 the most pain they can imagine. The latter approach is particularly practical in that it rapid and easy to do, and most patients can readily understand the task. This can help us track changes in intensity over time, for example, in response to treatment. However, such scales are ordinal, and the distance between intervals is not clear. We cannot assume, for example, that the difference between a "one" and "two" in pain intensity is the same as the interval between an "eight" and "nine." Patients may remember previous responses and try to be consistent in their reports. Also, patients may supply their own meaning to the numbers--they may assume, for example, that we will only raise their analgesic medication for pain reports over a "five." Still, such methods are very practical at the bedside.

Another approach is to employ visual analogue scales, in which a patient is asked to indicate the intensity of their pain with a mark on a line. The line is usually 10 to 15 cm long, and has no numbers on it except at the ends ("no pain" on one end, and "the most intense pain imaginable" on the other). This approach has the benefit of being very reliable and generalizable. When tested, it seems to be better than the other methods at reflecting reliable ratios along the line. It also is very sensitive to changes in pain intensity. The major drawback of this approach is the extra time involved in scoring the result: the clinician has to measure the mark (usually in millimeters).

The affective response to pain. Individuals can usually distinguish between the intensity of pain, and their feelings associated with the pain. An "affective response" involves many dimensions, but generally, it represents the "degree of unpleasantness." This response differs from pain intensity in that it is more influenced by the context of the pain. One can imagine that a woman in labor may experience pain that is just as intense as that of a cancer patient, but the pain may seem much less unpleasant. Not surprisingly, research studies have validated such comparisons.

We can assess the affective component of pain using the same methods as for pain intensity, including either verbal, numerical or visual analogue scales.

Location. Pain location is usually assessed graphically. Patients are shown figures of a human body, and they draw on them the locations of their pain. Different symbols can represent different qualities of pain (for example "oo" for "pins and needles" or "xx" for "burning"), or different depth locations (for example, "E" for external, and "I" for internal pain).

Composite Scales. Several scales combine several different dimensions of the pain experience. Examples include the McGill Pain Questionnaire (FIGURE 1)and the Short-Form McGill Pain Questionnaire (FIGURE 2) (Melzack & Katz, 1992).

Physical Functioning

We wish to assess how patients' pain affects their ability to do many different activities. This task is necessarily subjective, and it relies on self-report. It is important, however, as it is often the basis of any determination of financial compensation.

In evaluating physical function, we must distinguish between concepts of "impairment," "functional limitation," and "disability."

"Impairment" refers to any objective abnormality or loss. These losses and abnormalities can be anatomic (eg., loss of limb, physical deformity) physiologic (eg., decreased cardiac output, muscle weakness) or psychological (eg., changes in cognition). They can usually be objectively measured.

"Functional limitations" are any restrictions in an individual's normal functioning. They are the practical result of impairment. In evaluating for functional limitations, we attempt to quantitatively measure bodily functioning in several activities judged necessary for daily living. There is no agreement on exactly what activities these are. Most evaluations include measurements of the range of motion at major joints, strength testing in major muscle groups, and endurance for specific tasks.

"Disability" refers to the inability to do one's usual activities or duties as the result of impairment. It is task specific, and we should not speak of global "disability," but whether a person is disabled from doing a particular task. Again, there is no gold standard of assessment. The different organizations that evaluate and compensate disability (such as Social Security or Worker's Compensation) will require that specific factors are assessed. Each system emphasizes different concepts of disability. For example, Social Security relies primarily on objective measures of impairment over subjective symptoms such as pain.

Psychological Factors

No pain should ever be viewed as either "physical" or "psychological." Unfortunately, we often only look for the psychological factors contributing to pain after all biological contributors are ruled out. Psychological evaluation is important for any pain patient. It is important in predicting a patient's outcome, and it may be more accurate in this than other more "objective" measures of a patient's injury.

In performing a psychological assessment in a pain patient, we must look for any factors that may affect a person's perception of pain, and subsequent response to the pain. Our goal is to find factors that influence pain, rather that cause it. It may be helpful to make these goals clear to the patient, who may be skeptical of psychological questions. Most patients will be defensive at the implication that the pain they experience is "just in their head." They are usually quite willing, however, to consider how stresses in their life might influence their pain.

In that past, much attention was devoted to notions of particular psychological profiles that were more vulnerable to pain syndromes (the "pain-prone personality") however this has never been well validated.

A proper assessment should include both the patient and other significant persons. A typical interview will examine number of psychosocial areas. We should try to identify events that exacerbate pain. Also, we should review a patient's usual daily activities, and appraise how these activities have changed because of the pain. We wish to learn how a patient copes with their pain. Possible sources of reinforcement of the pain, whether financial, sympathetic or avoidance-related should be tactfully explored. We should ask about past significant events, which may resonate with the current situation. For example, Drossman and colleagues, interviewing women who presented to a gastrointestinal clinic for abdominal pain found that almost half of those with a functional disorder (irritable bowel syndrome, chronic abdominal pain, or nonulcer dyspepsia) had a history of physical or sexual abuse (Drossman et al, 1990). Similarly, we should look for family histories of similar pain problems. Any psychiatric illnesses, such as depression and anxiety, may affect pain, and we should ask about these. Finally, we should try to understand the patient's beliefs about the pain. Such beliefs can include beliefs about etiology, such as issues of retribution or blame. They may also include beliefs about outcome: one can imagine that patients will interpret a pain differently if they think it represents the progression of a serious disease.

Standard instruments generally fall into categories of general psychological measurements and ones that are specifically designed to measure psychological factors in pain patients. The former are more widely used and accepted, but they may not have been well validated for pain patients.

Pain behavior.

Besides the subjective pain experience, patients can exhibit predictable behaviors associated with their pain. These behaviors have the advantage of being readily observable. They are also reinforced over time--that is, they are learned behaviors. Most important, they represent potential targets for behavioral intervention.

Assessment of pain behavior is best done through observation, as patients may not even be aware of their behavior.

One can observe for verbal and nonverbal behavior associated with the pain experience. Examples of verbal behavior include complaining of pain, or using other vocalizations (eg., moaning). Nonverbal behavior can be general, involving movement (eg., pacing), position, or more specific (eg., guarding or rubbing a painful joint). Though different researchers emphasize particular behaviors as "more valid" indicators of pain, the behavioral expression of pain is probably very personal.

Physical Components of Pain

It would be very useful to have objective physical measurements that would correlate well with a patient's subjective pain experience. The existence of such measures is implied each time we hear a clinician say that "the patient is having pain beyond what can be explained by the physical findings." Unfortunately, no such statement is justifiable, as the relationship between organic pathology, physiological functioning and pain report is poorly understood. Any correlations between these objective and subjective factors are weak and difficult to predict.

Several physiological measures are used in pain evaluations. Most remain only research tools, but some have clinical value. Examples include the use electromyography in evaluations of tension headaches and temporomandibular joint syndrome. In each case, they serve as adjuncts, not substitutes, for the subjective evaluation.

Diagnostic Issues

Advocacy for Proper Diagnosis

Proper evaluation of the patient with pain includes a review of medical, diagnostic, and management issues pertinent to the pain complaint. For example, a careful review of history and physical examination in an elderly somatizing patient may lead to recognition of the need for evaluation of possible hip fracture. The history and physical examination of patients with low back pain syndromes must always be reviewed carefully with attention to the results of electromyography, nerve conduction studies, myelogram, and computerized tomography (CT) scan or magnetic resonance imaging (MRI) findings. Pain in patients with a history of malignancy should be carefully evaluated with a high index of suspicion that the pain complaint, presumed to require psychological management, is actually associated with cancer progression or cancer treatment (Foley, 1985a).

Patients with a known or presumed history of drug abuse are at special risk for having a medical basis for their pain overlooked, because the medical team often assumes that these patients' pain complaints are simply drug-seeking behaviors. Similarly, patients with chronic schizophrenia or mental retardation may not be able to communicate pain complaints in a way that leads to proper medical diagnostic evaluation, and the psychiatrist should be especially careful before taking a symptomatic treatment approach in these populations. The drug abuser who gets into a motor vehicle accident and is admitted to an orthopedic unit may have complaints of foot pain that are dismissed as drug-seeking behavior but that actually represent early symptoms of a compartment syndrome from an excessively tight cast.

Certain other groups may be prone to receiving inadequate pain management, for example, minorities, the elderly and women (Cleeland et al, 1994).

DSM and Pain Disorders

In DSM-III (American Psychiatric Association, 1980), a "Psychogenic pain disorder" had to be either incompatible with organic disease, or "grossly in excess" of what one would expect from the physical findings. It also stipulated that psychological factors were judged to be "etiologically related" to pain development. Obviously, this was difficult to use, most patients with chronic pain have some organic pathology, and it is impossible to say what pain is "in excess" of the pathology. Furthermore, psychological factors are always related to pain expression. DSM-III-R (American Psychiatric Association, 1987), therefore, dropped this last criterion, and renamed the disorder "somatoform pain disorder."

DSM-IV (American Psychiatric Association, 1994) simplified the name to "Pain Disorder" and suggested three main criteria: (1) pain is the predominant focus of clinical attention, it (2) causes substantial distress or impairment, and (3) psychological factors are judged to have a role in the pain's onset or expression (TABLE 1). The disorder is further subtyped based on whether it is associated with just psychological, or psychological and medical factors. It is also subtyped on whether it is acute or chronic.

This further revision continues to present problems for the clinician treating patients with chronic pain. It invites value judgments, as one must decide the relative importance of psychological factors. It can be argued that psychological factors are always important in the expression of pain, and it is likely that any patient with chronic pain would meet the criteria of this disorder.

Treatment of Pain

Alleviating pain is one of our most fundamental roles. At times this can complex and frustrating. Often, however, through understanding some fundamental principles of pain management, even the inexperienced clinician give some relief to the suffering patient. What follows is a brief overview of the common options for pain treatment.

Pharmacologic treatment for pain.

Most patients who seek medical attention for pain will receive medication at some point. As with all treatments, it is important to follow a clear rationale in using pain medication. The physician and patient must have mutually understood goals and a plan of what to do when relief is not adequate.

All regimens must be individualized to the patient. It is best to begin with the least potent medication, the simplest dosing regimen and the least invasive route of administration, and to work up from there.

The World Health Organization (WHO) has suggested a rational titration of pain medication, called the WHO ladder (FIGURE 3). This step-wise approach was devised for the treatment of cancer pain, but is applicable for many pain situations.

The first step in the approach is the use of non steroidal anti-inflammatory drugs (NSAID's) for mild to moderate pain. Adjuvant drugs may also be used at any step. When pain persists, a low potency opioid (eg., codeine or hydrocodone) should be added to this regimen. The NSAID should be maintained as it may provide additive analgesia. Pain that persists despite this regimen should be treated with more potent opioids (for example, morphine, hydromorphone, methadone, fentanyl or levorphanol). For pain that is moderate to severe at the outset, opioids should be the first choice.

This approach emphasizes the importance of simplicity--both in drug choice and in dose scheduling. Single agents are more easily titrated, and their side effects are more predictable. Adjuvants should be added only when indicated. Several combination preparations have been used, the most famous being "Brompton's cocktail," which is a mixture of morphine, cocaine and a phenothiazine. Despite anecdotal reports, no study has demonstrated any benefit of such mixtures over using single opioids. As they can also cause additive side effects, they should not be used.

Simple dosing, using a knowledge of a drug's pharmacokinetics, is equally important. To order a short acting agent such as morphine or meperidine to be given every four to six hours betrays an overestimation of the drug's likely length of effect. Similarly, medications for persistent pain should be treated using scheduled "around the clock" medications, to assure a constant effective blood level. "As- needed" (i.e. p.r.n.) medication can be added to the regimen, but should not be used alone, as they can result in erratic levels of medication. There are a number of other important reasons for preferring scheduled doses over prn medication: scheduled doses based on the half-life of the narcotic prevent the re-emergence of pain; the dose required to treat re-emergent pain is often larger than what is needed to prevent its recurrence on a fixed schedule; patients on a prn schedule are in a dependent position requiring them to ask for medication, which can create preoccupation with and delays in administration; and elderly and cognitively impaired patients may have difficulty in initiating appropriate requests for medication (Goldberg and Tull, 1983).

Another issue in the timing of narcotic doses pertains to special procedures. It is important to note whether the patient's pain problem is the result of an intermittent procedure such as debridement, dressing changes, or physical therapy. In such instances, the most important intervention may be to ensure that the patient receives an adequate narcotic dose prior to such an intervention.

Opioid Analgesia. Opioids remain the "gold standard" of pharmacologic treatment for the patient with pain.

Mechanism of action. In their action, narcotics mimic the effect of endogenous opioids, the most potent being b endorphin (Ferranta, 1996). All opioids, endogenous and exogenous, bind to specific opioid receptors in the brain and peripheral nervous system. Most of the opioids bind to the m receptors. The potency of opioids is related to their affinity for the receptor.

There are two classes of m receptor, m1 and m2. The first is involved in analgesia, and the second is responsible for respiratory depression. There is no opioid that can bind only with m1. Of the other receptors, the most important are d and k, which are important in spinal analgesia.

It is important to understand the different relationships a compound may have at the opioid receptor. Agonists (TABLE 2) produce their response through receptor binding. Morphine is a prototypic m agonist. Partial agonists incompletely bind the receptor, exerting less than maximal effect, even at high concentrations. Buprenorphine is an example of a partial m agonist. Opioids may also have different actions at different receptors--for example, pentazocine is a weak m receptor agonist, but a strong k agonist; therefore, it is labeled an agonist-antagonist (TABLE 3). Partial agonists and agonist-antagonists are less preferable than pure agonists for pain management, given their weaker binding affinities for the m receptor. Agonist-antagonists are especially problematic as they can precipitate withdrawal in patients dependent on opioids. A number of opioids are also commonly prescribed in combination preparations (TABLE 4).

Indications. Opioids are the most effective agents available for treating acute pain--that is, pain associated with acute injury to the body.

Treatment approach. Although pharmaceutical companies expend great energy in opioid development, it is unlikely we will see a "better" opioid in the foreseeable future. Apparent differences in potency are more often due to pharmacokinetic differences rather than pharmacodynamic. That is, all opioids can be made equipotent by adjusting their dose or route of administration. Thus, the student attempting to better understand the proper use of opioids should concentrate on understanding the pharmacology of opioids as a class, rather than the intricacies of individual drugs.

Perhaps most central to the use of opioids is the idea of minimum effective concentration (MEC). The MEC is a hypothetical plasma concentration below which a drug is ineffective. The MEC for an opioid--that is, the plasma level at which analgesia is effective--can vary greatly among different individuals. Thus, when choosing an opioid dose for a patient, we cannot know what the effective dose will be before we use the drug. The only way to find the proper dose is by titrating until the patient responds to the drug. Therefore, any table of "recommended doses" can only be a rough guideline for beginning therapy (TABLE 5-6). Similarly, tables of relative potencies among opioids are rough estimates (TABLE 7).

Side effects. Beyond deciding an appropriate dose for an individual, the titration of opioids usually involves the management of side effects. The most common opioid side effects are nausea and sedation. The most problematic side effect is respiratory depression. This is due to a reduction in brainstem responsiveness to PCO2, and to the depression of pontine and medullary centers (which are involved in the regulation of breathing). Fortunately, respiratory depression can be reversed by naloxone. When it is necessary to use naloxone, it is best administered in a dilute solution (0.4 mg in 10 ml of saline) slowly given intravenously, titrated against the patient's respiratory rate (Foley, 1985b). Patients receiving this treatment must be closely followed with frequent respiratory rate checks because naloxone has a short half-life, and patients may have to be redosed if taking longer-acting narcotics such as methadone.

Opioids can also cause alterations in mood, tolerance and alertness. They decrease gastrointestinal peristalsis and increase sphincter tone, causing constipation. This effect on sphincter tone can also increase effect biliary pressure and urinary retention. Though rare, opioids can also depress cardiac function and cause bradycardia (though meperidine can cause tachycardia via its antimuscarinic effect).

The incidence and severity of side effects seen with different opioids are probably similar at equianalgesic doses (meperidine may be an exception to this and is discussed separately). Thus, changing to a different opioid is less likely to improve side effects, and the clinician should be familiar with the symptomatic treatment of these side effects. In some cases, such as treating constipation associated with opioids, the prophylactic use of laxatives is often preferred.

Meperidine. Certain treatment strategies--including some in common use, are not recommended. Perhaps the most common problem is the continued over-reliance on meperidine for pain management. Meperidine has a very short duration of action, making it inappropriate for all but brief courses of treatment. It is low in potency, and often underdosed in patients (the common choice of 75 mg of meperidine is probably inadequate for most patients). Its metabolite, normeperidine, can be toxic and cause central nervous system irritation. It can accumulate over time and lead to dysphoria, delirium and even seizures. Structurally, meperidine is similar to atropine, and may share many of atropine's anticholinergic effects. For these reasons, meperidine is best avoided unless a patient cannot tolerate other high potency opioids.

The continued use of meperidine comes not only from force of habit, but from a belief that it has certain benefits over other opioids. Most common is the belief that it causes less sphincter spasm. Meperidine, therefore, remains the preferred opioid for patients undergoing endoscopic procedures at the pancreatic or bile duct. The evidence for such a belief, however, is weak. Thune and colleagues (1990) found the meperidine did not increase phasic contractions at the sphincter of Oddi, whereas morphine did cause a dose dependent increase. It is significant, however, that neither opioid affected the basal sphincter pressure, and the study used subanalgesic doses of both medications. Using analgesic doses, Elta and Barnett (1994) did find that meperidine increased phasic contractions at the sphincter of Oddi. Again, there was no significant change in sphincter pressure. In the latter study, only meperidine was used and we do not know how other opioids would have compared. In a recent editorial reviewing the literature on opioids and the sphincter of Oddi, Sherman and Lehman (1994) continue to advise against routine use of meperidine for these procedures.

Tolerance, Physical Dependence and Addiction. The greatest barrier to opiate use is fear of causing addiction. In understanding this, it is important to distinguish between tolerance, dependence and withdrawal. Tolerance is the decline in potency of an opioid experienced with continued use, so that higher doses are needed to achieve the same effect. This is a receptor mediated effect, and common to all opioids. Physical dependence refers to the development of withdrawal symptoms once a drug is stopped. Typical symptoms of opioid withdrawal include yawning, diaphoresis, lacrimation, coryza and tachycardia, followed by abdominal cramps, nausea and vomiting.

Tolerance and dependence are physiological phenomena, and are not the same as addiction. Addiction is a compulsion to use a drug, usually for its psychic, rather than therapeutic, effects. Thus, it implies a behavioral problem, with psychological as well as physical dependence. One can have tolerance or dependence without addiction, and the reverse is true as well.

Clearly individuals with histories of opiate addiction are at risk of continued addictive use if they are prescribed opioids. The question remains, however, whether we can cause opioid addiction by administering it to a patient without such history. In clinical investigations of the question, it appears that iatrogenic addiction is a very rare event. In a large review of over 11,000 Medicare inpatients who received narcotics, only four cases of iatrogenic narcotic addiction were documented (Porter & Jick, 1980).

Route of administration. An understanding of the different ways to deliver an opioid to a patient is as important as fluency with the different available opioids.

Oral administration. Drugs administered into the gastrointestinal tract go through the portal circulation to the liver. In the liver, opioids are extensively metabolized ("first-pass" metabolism) to inactive products. Therefore, most of the oral dose never reaches the target receptor.

The amount of active medication that is available after first-pass metabolism varies greatly for different agents, and varies among individuals. Heroin, for example is completely metabolized orally, whereas 80% of ingested methadone remains available after first-pass metabolism. Morphine's oral bioavailabity can range from 10% to 65%, making for great variability in an individual's oral dose requirement. Generally, the oral to parenteral potency ratio for morphine is 1:6 for acute use, and 1:2-3 for chronic use.

Several compounds have sustained release preparations (TABLE 8), and pharmaceutical companies have given much attention to the development of these compounds. In the United States, sustained-release preparations are available for morphine and for oxycodone. It remains a great challenge to develop agents that will maintain a stable blood level over time. Factors such as eating and physical activity may also alter a sustained release drug's kinetics. .

Sublingual administration. Opioids given sublingually are directly absorbed into the systemic circulation, thereby avoiding first-pass metabolism. This route may be particularly useful for individuals who cannot tolerate oral medication because of nausea and vomiting. Buprenorphine, a partial agonist, is available in a sublingual preparation.

Rectal administration. Like oral administration, substances absorbed rectally undergo first-pass metabolism. Suppositories can be useful for patients who cannot swallow, or are likely to vomit after oral administration of the opioid.

Intramuscular administration. Though very commonly used, intramuscular administration of opioids is often erratic, and patients may alternate between periods of toxicity and undertreatment. IM injections can be painful, particularly if they must be used continuously. This method of administration should usually be reserved for the unusual case in which no other method of administration is feasible.

Subcutaneous administration. Though used for years, we know surprisingly little about the pharmacokinetics of subcutaneous opioids. For morphine, the blood levels achieved with subcutaneous administration are probably comparable to intravenous administration. This is not as well understood for other opioids. This route of administration is becoming more compelling with the development of portable pumps that can deliver continuous infusions.

Intravenous administration. Intravenous (IV) administration remains the most rapid and effective means of delivering opioids to the systemic circulation. Most commonly, an IV dose is given at regular intervals. Proper use of this method requires understanding the pharmacokinetics of a drug, to ensure that the blood level does not go below the MEC for that drug. Several newer methods for IV administration are also available:

Continuous infusion. This method of IV administration is becoming more popular. It can be a very efficient way to provide long term pain relief. It should be remembered, however, that the blood level of the drug must always be kept above the MEC to continuously provide effective pain relief. This can be particularly difficult at the beginning of continuous therapy, as a drug requires four to five half-lives to achieve steady state concentration. Therefore, a loading dose is required before starting continuous infusion.

Patient controlled analgesia (PCA). In PCA, the patient can decide when to give himself a dose, and the timing between doses. The physician still decides the particular drug, and dosing and timing limits. The advantage of such a system is that is acknowledges the subjectivity of a patient's perception, and allows the patient freedom in making some treatment choices. It also avoids the potential struggles that can occur when a patient must ask someone for each dose. It has potential disadvantages, however, as patients can be just as likely as physicians to underdose themselves. Proper patient education in the use of the PCA--for example that they are better off treating their pain at it's onset rather than waiting until it gets very intense--is essential (Acute Pain Management Guideline Panel, 1992).

Transdermal administration. The delivery of opioids in a transdermal patch offers another method of delivering continuous analgesia. Currently, fentanyl is available in this formulation. Fentanyl is a potent, short acting opioid that can be released slowly from the patch. From skin absorption, the fentanyl enters systemic circulation. Peak serum concentration begins to level off between 1-2 days after initial administration, and remain relatively constant for three days. The various patches are labeled with the approximate dose delivered per hour. Because it offers a less cumbersome alternative to continuous IV administration, it is becoming popular among for use in ambulatory chronic pain patients.

Transnasal. Theoretically, this may be another practical method of delivering medication into the systemic circulation. However, only butorphanol--an agonist-
antagonist--is available in a nasal spray. This agent is primarily used for acute headache, and is not recommended for chronic pain (Jacox et al., 1994).

Spinal administration. Direct administration of opioids to receptor sites is possible through intrathecal, epidural and intracerebroventricular administration. Spinally administered opioids migrate to all areas of the spinal cord, therefore they can be appropriate for many types of pain. Enthusiasm for this technique is tempered, however, by the occurrence of severe delayed-onset respiratory depression, which occurs in perhaps 1/1000 patients receiving epidural morphine.

Non-Steroidal Anti-Inflammatory Drugs

Mechanism of action.

All non-steroidal anti-inflammatory drugs (NSAID's) inhibit cyclooxygenase. Cyclooxygenase is an enzyme responsible for the synthesis of prostaglandins. Prostaglandins are metabolized from arachidonic acid--this process occurs at sites of tissue damage and seems to help sensitize nociceptors to painful stimuli. Acetaminophen is usually included in this group: though not as potent an anti-inflammatory agent, it has similar analgesic potency to the NSAID's.

Indications.

NSAID's are helpful for treating many types of pain, ranging from minor aches and sprains to bony metastases.

Treatment approaches.

Unlike opioid analgesics, there is no clear relationship between serum levels of NSAID's and analgesia. Though often used alone, their mechanism of action is different from opioids, and they can act synergistically with opioids. Typical doses are recommended in Table 9; this data is derived from long-term use in rheumatologic disease.

Side effects. The most common side effect is gastric irritation. The decrease in prostaglandin caused by NSAID's decreases gastric mucus and increases gastric acidity. Acetaminophen is an exception to this.

Other side effects include salt and fluid retention, platelet inhibition and tinnitus. Acetominophen has an advantage of having little effect on platelet function. The drugs are excreted renally, and patients with renal insufficiency may be at risk for toxicity. NSAID's may decrease renal blood flow and, may cause renal failure. The latter effect is of most concern in patients who are elderly, volume depleted, taking other nephrotoxic drugs, have preexisting renal impairment, heart failure or hepatic dysfunction (Jacox et al., 1994). Acetaminophen carries the additional hazard of possible liver damage from an overdose.

Route of administration. Most NSAID's are available only orally. An exception is Ketorolac, which can be given parenterally, and may be more useful in the management of post-
operative pain.

Treatment: adjunctive medications.

Opioids and NSAID's remain the most important pharmacologic options in pain management. All other options must be considered secondary. The data and rationale for any of these agents are much weaker than that for opioids or NSAID's, and much of it is anecdotal. Many are only useful in combination with standard analgesia. However, there remains a sizable group of patients for whom opioids or NSAID's are either inadequate, intolerable or inappropriate. Thus, the search for alternative analgesics continues.

Antidepressants.

Antidepressants are the most commonly used adjunctive agents. They have become common in the treatment of certain types of pain.

Mechanism of action. A variety of mechanisms have been suggested. Monoamine neurotransmitters, such as norepinephrine and serotonin may influence the transmission of pain. This influence is thought to be a central phenomenon. However, sympathetic neurons are located near nociceptors, and may play a role in peripheral pain modulation.

It remains uncertain whether antidepressants have a primary analgesic effect, or whether they simply relieve pain-associated depression. Some studies find a strong association between simultaneous improvement of both pain and depression. Other studies show independent effects. Similarly, some studies suggest that effective analgesic doses for antidepressants are much less than those used for depression; other studies suggest that both disorders require similar doses.

Antidepressants are most frequently used for neuropathies, such as that caused by diabetes mellitus. Other studies have shown their usefulness in treating migraine headaches. Beyond that, there are isolated accounts--usually anecdotal-- of their use in almost every pain imaginable. It appears that the best antidepressants for pain treatment are those increase both norepinephrine and serotonin (eg., amitriptyline). In one comparison of several antidepressants in patients with diabetic neuropathies (Max et al, 1992), the tricyclic antidepressant amitriptyline and desipramine were superior to placebo. The serotonin reuptake inhibitor fluoxetine was less effective in pain relief than the other two, and no different than placebo. In this study, pain relief was independent of antidepressant effect.

Serotonin reuptake inhibitors, however, may have some adjunctive role in pain management. Using animal models, one study demonstrated that morphine analgesia was potentiated by fluoxetine, without a concomitant increase in respiratory depression (Haynes & Fuller, 1982). Similarly, nefazodone was shown to potentiate morphine analgesia in certain animal models of pain (Pick et al, 1991).

Anticonvulsants. Anticonvulsants are also used for neuropathic pain (Swerdlow, 1984). For example, carbamazepine is considered by some to be the first line treatment for trigeminal neuralgia ( Tomson & Bertilsson, 1984). Anticonvulsants may act by suppressing neuronal firing in the area of damaged neurons. Usually, they are started slowly, and gradually increased in dose to minimize side effects. Common side effects include dizziness, ataxia, drowsiness, blurred vision, and gastrointestinal irritation. Specific organ toxicities also can present a problem: carbamazepine can cause bone marrow suppression, and sodium valproate can cause liver toxicity, and both drugs require blood monitoring. Gabapentin and lamotrigine, though potentially useful, have not yet been extensively studied for pain treatment.

Local analgesics. Lidocaine and 2-chlorprocaine are used for peripheral neuropathies . There is some suggestion that patients who describe their neuropathic pain as "constant" are more likely to benefit from these agents, whereas those with episodic pain benefit more from anticonvulsants. These agents are generally given intravenously, however, oral use of lidocaine derivatives (eg., mexiletine and tocainide) has been reported to be useful in some patients (Dejard & Peterson, 1988).

Another locally acting agent is capsaicin, an alkaloid irritant derived from chili peppers. It is available as a cream (Zostrix) that is applied topically to painful areas. It appears to work by depleting substance P. It has been shown to be effective for a number of syndromes, including diabetic neuropathy, osteoarthritis, postherpetic neuralgia and psoriasis (Zhang & Po, 1994).

Antihistamines. Hydroxyzine is most often used among the antihistamines for pain control. The use of hydroxyzine in combination with meperidine is so common that it is surprisingly how little data exists to justify this practice. Antihistamines are probably weakly analgesic, but they are quite inconsistent in their ability to potentiate the analgesic effects of opioids (Jacox et al., 1994). Moreover, they are probably much more effective at potentiating opioid side effects, such as sedation and confusion. They may have some use in modulating the anxiety caused by pain, but are unlikely to be preferable to other available agents.

Antipsychotics. Though rarely used as single agents, antipyschotics are thought to potentiate the action of opioids. Most of the support for this is anecdotal. The phenothiazines are most often used. Haloperidol has also been used as an antiemetic, and to decrease opioid-associated confusion. Protracted use of these agents must be balanced against the risk of tardive dyskinesia.

Benzodiazepines. Benzodiazepines do not appear to have any analgesic properties. They may, however, modify the affective experience of pain. They also act as muscle relaxants, which can be useful in musculoskeletal pain.

Stimulants. Stimulants include the amphetamines, caffeine and cocaine. All act as sympathomimetics and they can potentiate the action of opiates. It is not clear whether this effect is long- or short-term. Amphetamines have been combined with opiates, and caffeine has been used to potentiate NSAID's. An advantage of stimulants is that they often act quickly, and their efficacy can often be judged after only a few days.

Cannabinoids. With the passage of Proposition 215 in California, and Proposition 200 in Arizona, we can anticipate a new vigor in the debate over the medical uses of marijuana. Cannabinoids do appear to have some analgesic effect. This effect is probably mediated by non-
opioid receptors, which may argue for an adjunctive role in pain management. The side effects associated with marijuana (dysphoria, drowsiness, hypotension and bradycardia) probably outweigh possible benefits (Jacox et al., 1994). Whether other cannabinoids (such as the orally available synthetic cannabinoid dronabinol) offer similar benefits while reducing the ill effects is a matter worthy of investigation.

Placebos. Occasionally a clinician will administer placebo pills or injections when they are skeptical of the patient's pain. We believe that any attempt to deceive a patient is always inappropriate. Furthermore, the fact that a patient responds to a placebo analgesic does not prove that the pain was "in their head." The placebo response is a very real phenomenon, and 30 to 40% of the population are placebo responders, even in the presence of severe disease (Beecher, 1955).

Procedural Treatments

Nonsurgical Procedures

Cutaneous Stimulation. This involves the application of heat, cold, or mechanical pressure to a superficial area. Heat may decrease pain through vasodilation and by decreasing joint stiffness. Cold causes vasoconstriction and local hyperesthesia, which reduces inflammation in an affected area. Mechanical pressure is typified by massage, which can relax muscular aches.

Electrical Stimulation. The rationale for electrical stimulation to modulate pain is based on the gate theory of pain. Here, and electrical charge excites large peripheral fibers and other nociceptive information is blocked in the process. Transcutaneous Electrical Nerve Stimulation (TENS) uses low-intensity stimulation of muscle and skin in a particular segmental distribution. Dorsal Column Stimulation uses a high-frequency current over the dorsal spinal cord and has been useful in deafferentation pain syndromes. Electrical stimulation is used both solely and in combination with other treatments.

Acupuncture. Theoretically, acupuncture analgesia is very similar to electrical stimulation, except that manual stimulation is used. The stimulation is produced through rotation of small needles at certain body sites. The resulting sensation (teh chi) confers not only local analgesia, but also a more generalized phenomenon. This generalized effects may result from stimulation of chemical modulators.

Exercise. In cases of acute pain, immobilization is often needed. Prolonged immobilization, however, can cause joint contractures, muscle atrophy and cardiovascular deconditioning, and it should be avoided whenever possible. Appropriate exercises depend on the specific injury or pathology, and can range from passive motion and positional change to weight bearing exercises and aerobic conditioning.

Surgical Treatment

Neural Blockade. Typically, nerve transmission to an area is blocked through injection of an agent. The injection sites can be around the peripheral nerves, the somatic plexuses and at the dorsal roots. Short acting agents (eg., lidocaine) can be used for acute pain, whereas more permanent blockade (eg., alcohol) is used for chronic pain. In the latter case, diagnostic blocks are done first, in which short acting agents can help localize the pain pathway.

Surgical lesions can also be used to permanently block a pain pathway. Side effects of this treatment mainly result from the fact that it is not possible to isolate the pain fibers. Therefore, other motor and sensory information may be lost as well.

The efficacy of treatment is unpredictable, and neuronal block is often unreliable in chronic pain situations. When weighing the above side effects against a questionable benefit, permanent neuronal block is not usually appropriate in chronic pain situations. It is also not appropriate for non-nociceptive pain, such as neuropathic pain. Neurodestructive techniques sometimes worsen neuropathic pain. Such techniques may be appropriate in cases where the life expectancy is short. Even then, it should only be considered when other approaches to pain management have been exhausted.

Psychological Treatments

Psychoeducation. Properly educating a patient about pain treatment can help make them an active participant in their own pain management. Education can lessen potential misunderstandings about pain treatment. For example, patients may fear that if they ask for too much pain medication, they may become addicted. Similarly, patients often believe that they should avoid asking for pain medication until they can no longer bear their pain. Proper education can allay their fears about addiction, and help them understand that their pain is probably better prevented early than when it reaches peak intensity.

Hypnosis. We have known for over a century that hypnosis can help treat pain. It remains, however, an underused option for pain management. Hypnosis works through a combination of effects, including relaxation, distraction and perceptual alteration. Clearly muscle relaxation and distraction (i.e., with other competing sensations) can be helpful in modulating the pain response. We are most intrigued, however, by hypnosis' ability to alter perceptions--this seems to give hypnosis an almost mystical quality. The phenomenon is hardly mystical. Most individuals can learn to alter their sensations somewhat, and this ability improves with practice. Typically, an individual will receive the suggestion that the pain sensation is another sensation, such as a sense of warmth. An advantage of hypnosis is that, with training, patients can learn to hypnotize themselves.

Behavioral treatment of pain. This treatment is derived from learning theory, in which most behavior is assumed to be learned. For pain treatment, the focus is on the behavior associated with the pain experience, or "pain behavior." The goal of treatment is to decrease the factors that are encouraging or "reinforcing" such behavior. A simple example is on hospital wards, where the staff pay more attention to patients with problems, thus reinforcing the behavior.

Furthermore, it is assumed that potential responses to situations, such as reacting with anxiety, may result in pain. In this sense pain may be a "conditioned response" to a variety of circumstances. Several behavioral techniques are used to approach these problems.

Relaxation training. A simple behavioral technique, this involves teaching patients to systematically relax each of their muscle groups. This can be useful in a variety of pain conditions, particularly where tension may play a role (eg., tension headaches). Usually patients are also taught to imagine a pleasant scene. With practice, the patient can perform this technique without assistance.

Biofeedback. In biofeedback, imperceptible physiological responses are amplified and made accessible. Once made aware of these responses, an individual can attempt to modify them. For example, a patient with tensions headaches might hear an audible electromyogram, representing the frequency of muscle contractions in selected muscle groups, and then learn to reduce such contractions.

Cognitive behavior therapy. In cognitive behavior therapy, the focus is on both pain behavior and the conscious thoughts that influence such behavior. Typically, the therapist thoroughly explores all aspects of the pain experience: thoughts and feelings preceding, accompanying and following the experience. The goal is less one of eliminating pain, and more of lessening the disability associated with the pain. Given the complexity of the pain experience and biopsychosocial interactions, it is not unusual for patients to perceive some lessening in pain intensity as well.

Unlike pharmacological treatments, psychological treatments clearly require a great deal of time and motivation. There is a significant rate of nonresponse in many studies. A good predictor of response, however, may be one's motivation to persevere with treatment.

Multidisciplinary Pain Rehabilitation.

Perhaps the best treatment for chronic pain can only be given by a multidisciplinary group. This approach is in contrast to the traditional medical system, in which different consultants act in relative isolation from each other and the primary medical doctor. A multidisciplinary rehabilitation program employs professionals from various disciplines working in tandem. Usually, the goals of treatment are multiple as well, simultaneously including decreasing pain intensity, increasing activity level, decreasing medication use, and decreasing use of medical services. Such a program is expensive, although it may be cost-effective when compared with traditional medical/surgical interventions and diagnostic procedures. Unfortunately, studies proving such cost-effectiveness are preliminary, and use small numbers of participants.

Some Specific Pain Situations

Headaches

Headaches are probably the most common pain complaint. They account for tens of millions of patient visits, and hundreds of millions of lost productivity days.

When a patient presents with headache complaints it is important to rule out important signs that might suggest a serious cause of a headache (TABLE 10}. Most headaches, however, fall into one of several categories of primary disorders. The International Headache Society has created a classification system for headaches (TABLE 11) with accompanying diagnostic criteria. This classification system includes traditional causes of headaches, such as migraine (TABLE 12) tension (TABLE 13) and cluster (TABLE 14) headaches, but adds some previously underappreciated causes of headaches, such as headaches associated with substance use or withdrawal (TABLE 15). The most common substances producing headaches are the analgesics and the ergotamines. Both of these substances can lead to rebound headaches when overused. "Overuse" is difficult to define, however, as an example, a person who is using ergotamines more than two days a week to treat headaches is probably overusing the substance. "Rebound" refers both to the phenomena of the worsening of a headache as the medication wears off as well as typical withdrawal phenomena. In either case, a self-perpetuating situation is created as patients attempt to use more of the medication to alleviate the headaches that the medication itself is causing.

Stress is traditionally assumed to be a major cause of headaches. In reality, it probably does not precipitate many severe headaches, but instead may make an individual more vulnerable to the onset of an episode. Surprisingly, it seems that it is not severe stressors, but rather normal life stressors that can predispose to such conditions as migraine headaches.

Assessment. As with all pain syndromes, the evaluation of headaches is subjective. One technique often used is the "headache diary." Here, a patient keeps a daily journal, recording the time of headache occurrences, the intensity of the headache, other sensations, and the psychosocial context of the event.

Treatment of headaches. Pharmacologic and non-pharmacologic approaches seem to be equally effective in the treatment of migraine and tension-type headaches. For cluster headaches and menstrual migraines, pharmacologic approaches are probably more effective. Clearly, for substance-related headaches, the offending substance must be withdrawn. Often, such patients can be very reluctant to believe that the one thing they feel helps, even if insufficiently, is what must be taken away. Often, withdrawal is only successful in an inpatient setting.

Sumatriptan. Sumatriptan is a selective serotonin agonist (5HT-1), which causes vasoconstriction in cerebral arteries. It is effective at relieving acute migraine headaches (with or without aura). It is not indicated for hemiplegic or basilar migraines. It is administered in a subcutaneous injection.

Though sumatriptan is an important advance in the treatment of migraines, the question arises whether it can be misused or cause dependence. Premarketing studies showed no evidence of dependency or misuse. A number of case studies reported after the drug became available suggest that some patients may indeed become dependent on or misuse sumatriptan, and may even resell the drug illegally (Gaist et al., 1994; Osborne et al, 1994; Kaube et al, 1994). The best predictor of misuse was previous misuse of other migraine treatments.

Pain, mood and anxiety

The relationship between pain and depression is complicated, and both can reciprocally affect the other. In experimental conditions, subjects who are depressed have a lower threshold for pain. In clinical situations, patients with depression may have a poorer response to analgesics. Also, pain can cause depression.

Pain and anxiety are also closely linked. In both clinical and experimental settings, the two correlate highly. The question ultimately arises about whether this represents a "mislabeling phenomenon" in which an individual cannot distinguish pain from anxiety. Some studies suggest a classical conditioning model in which pain becomes paired with anxiety. Anxiety can worsen pain, both through psychological (worsening the context of the pain) and physical mechanisms (though, for example, increased muscle tension).

The clinician often confronts a situation involving the ``chicken or the egg'' dilemma in which it can be difficult to sort out whether the pain is the cause of the anxiety/depression or vice versa. It is usually not productive to try to definitively sort out this dilemma. Instead, the consultant should identify signs and symptoms of significant anxiety/depression and explain to the patient (and staff) that anxiety/depression and pain often coexist in a feedback loop in which they reinforce each other. The clinical strategy is to intervene in both areas. Treat the physical basis for the pain as aggressively as possible, and simultaneously address the anxiety/depression.

Pain in children.

Pain syndromes have long been recognized in children, however there has been little attempt to study pain in children. Nonspecific limb and muscle aches--"growing pains" are common and usually do not reach medical attention. The most common pain complaint in children is probably that of headaches. Also common is recurrent abdominal pain (RAP). RAP is defined as three or more episodes of pain that is severe enough to affect activities, and occurring for longer than three months. The vast majority of these cases have no identifiable pathology, and are caused by problems with normal physiological functioning (eg., stool retention). They often relate to stressful life events, such as family pathology. With or without clear family pathology, treatment of childhood pain syndromes involves a psychosocial approach that must include family involvement.

Pain treatment in the opioid addicted patient.

In situations involving pain treatment in the narcotic addict, it is often helpful to keep the management of the addiction separate from the management of the pain. For example, the patient's underlying narcotic addiction can be managed with methadone. Most street addicts can be adequately managed on an oral dose of methadone between 20 and 40 mg/day (or an IM dose between 10 and 20 mg/day). With methadone used for maintenance of the underlying addiction, the pain can then be treated as a separate issue, using a different narcotic at doses 50% greater than normal.

Chronic Pain

In addressing a pain problem, the consultant should always try to decide, ``Does this presumed acute pain management problem actually represent a chronic pain syndrome?'' It is not unusual for a psychiatric consultation to be requested for a patient whose pain problem has exhausted other providers. Such situations are common with low back pain patients admitted for a myelogram that is read as questionable or negative or with chronic abdominal pain patients with multiple surgeries and ``million-dollar'' workups. Medical patients and providers are used to thinking of pain in terms of an acute paradigm (i.e., ``What can be done now?''). They often overlook the broader picture and can miss the fact that what they are dealing with is better conceptualized as a chronic pain syndrome. Instead of more diagnostic testing or battles over dose or drug, a shift in management philosophy is required.

Chronic pain may affect more that 50 million people in this country and cost many billions in lost productivity. In considering pain assessment and treatment, chronic pain remains one of the most controversial areas.

Part of this controversy relates to how we understand pain (Turk, 1996). Traditionally, we have viewed pain dichotomously: either it is somatogenic or psychogenic. If there is explainable pathology, we would consider the pain to be somatogenic. We would expect direct associations between physical pathology and reports of pain, and would treat the pain by treating its cause. If the cause could not be treated, we would treat the symptoms, and it follows that the most humane treatment would be with opioids (because it is most efficacious at treating somatogenic pain). If a physical reason for the pain cannot be found, the pain must then be psychogenic, and the treatment would then be psychological (and opioids would be contraindicated).

Unfortunately, pain is not that simple. We cannot always show clear pathology causing pain, even if we are convinced that the pain is a physical phenomenon. Some of this may represent limitations in out technology, as is presumed for migraine headaches. Even when pathology is proven, it often correlates poorly with pain reports: for example lower back pain seems to correlate poorly with the degree of degenerative disc disease.

In a report commissioned by the Social Security Administration to examine the problems of pain, the Institute of Medicine concluded that

the experience of pain is more than a simple sensory process. It is a complex perception involving higher levels of the central nervous system, emotional status, and higher order mental processes . . . it is not always possible to identify the causes of pain, how it is expressed, and its behavioral and psychological reactions and consequences (Osterweis et al, 1987).

Thus, as already discussed, pain is a subjective and biopsychosocial in nature.

No issue is more hotly contested that whether opioids should be used in the treatment of chronic pain (Turk, 1996). Opinions in the literature range from complaints that opioids are underused to statements that they are totally inappropriate for the treatment of chronic pain.

Some of this controversy may be due to patient populations: clinicians in specialty pain clinics are often more critical of opioid use than those in cancer pain centers. There is little doubt now that in the treatment of cancer pain, opioids have a role, thus much of the controversy now revolves around chronic noncancerous pain.

Beyond moral or ethical issues, we should consider whether opioids are efficacious for chronic noncancerous pain. Unfortunately, to date there is no convincing study that conclusively supports or reject the use of opioids. Most studies have methodological weaknesses. Furthermore, many studies come to different conclusions, with some showing reasonable response, and others suggesting that opioids can actually worsen pain symptoms (eg., with headache patients). We are, therefore, left without clear answers.

Several surveys have tried to learn what clinicians are doing. For example, American Pain Society surveyed their membership to try to get a sense of how clinicians were treating chronic pain (Turk, 1996). They found that, while their members devoted a large part of their practice to treating chronic noncancerous pain (65%), only a small number (13%) did not use long term opioids. The respondents tended to agree that the goal of treatment was to improve function rather than symptoms. This survey was limited by the small number of respondents (12% of their membership).

A larger survey of almost two thousand physicians throughout the US found that most did not often use long-term opioids (Turk, 1996). This practice differed by specialties (rheumatologists used the most long-term opioids, surgeons, the least, and general practitioners somewhere in the middle) and by region (Midwestern physicians were the most conservative).

Unfortunately, there are no widely accepted rules to guide us in deciding what patient would be eligible for long-term opioids. Several guidelines have been proposed, but they differ widely in many issues. Opinions vary about what other interventions should first be tried, who should evaluate the patient, and whether a history of substance abuse is a contraindication. There is growing evidence that interdisciplinary pain clinics can be very useful in improving functioning and limiting opioid use. They must, however, still prove their cost effectiveness in this cost-conscious climate.

Ultimately, as Turk suggests, our decision to use long-term opioids is a judgment call, in which we ask ourselves "how much suffering are we willing to accept to prevent what amount of abuse and negative side effects?" (Turk, 1996).

REFERENCES

Acute Pain Management Guideline Panel: Acute Pain Management Operative or Medical Procedures and Trauma. Clinical Practice Guideline. AHCPR Pub. No. 92-0032. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Department for Health and Human Services, Feb, 1992.

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American Psychiatric Association, 1994

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised. Washington, DC, American Psychiatric Association, 1987

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition. Washington, DC, American Psychiatric Association, 1980

Andrasik F, Baskin S: Headache. In R.L. Morrison & A.S. Bellack (Eds.) Medical factors and psychological disorders: A handbook for psychologists, (pp.325-349). New York: Plenum, 1987

Beecher HK: The powerful placebo. JAMA 159:1602-1606, 1955

Brose WG, Spiegel D: Neuropsychiatric aspects of pain management. In: Hales RE, Yudofsky (eds): Textbook of Neuropsychiatry. Washington DC, American Psychiatric Press, 1987.

Cleeland CS, Gonin R, Hatfielf AK, Edmonson JH, et al: Pain and its treatment in outpatients with metastatic cancer. N Engl J Med 330:592-6, 1994

Dejard A, Peterson P, Kestrup J: Mexiletine for the treatment of chronic painful diabetic neuropathy. Lancet 1:9-11, 1988

Drossman DA, Laserman J, Nachman G, et al: Sexual and physical abuse in women with functional or organic gastroenterological disorders. Ann Intern Med 113:828-833, 1990

Elta GH, Barnett JL: Meperidine need not be proscribed during sphincter of Oddi mamometry. Gastrointest Endosc 40:7-9, 1994

Ferranta FM: Principles of Opioid pharmacotherapy: practical implications of basic mechanisms. J Pain Symptom Manage 11:265-273, 1996

Foley KM: The treatment of cancer pain. N Engl J Med 313:84---95, 1985a

Foley, KM: Non-narcotic and Narcotic Analgesics: Applications. In Foley KM (ed): Management of Cancer Pain, pp 135---148. Syllabus of postgraduate course. New York: Memorial Sloan Kettering Cancer Center, 1985b

Gaist P, Sindrup S, Hallas J, Gram LF: Misuse of sumatriptan (letter). The Lancet 344:1090, 1994

Goldberg RJ, Tull RK: The Psychosocial Dimensions of Cancer. New York, Free Press, 1983

Haynes MD, Fuller RW: The effect of fluoxetine on morphine analgesia, respiratory depression, and lethality. Drug Dev Res. 2:033-042, 1982.

Headache Classification Committee of the International headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias, and facial pain. Cephalalgia, 8, (Suppl. 7), 1-96, 1988

Jacox A, Carr DB, Payne R, et al: Management of Cancer Pain. Clinical Practice Guideline No. 9. AHCPR Pub. No. 94-0592. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Department for Health and Human Services, Feb, 1994.

Kaube H, May A, Diener HC Pfaffenrather V: Sumatriptan (letter). BMJ 308:1573-4, 1994

Max MB, Lynch SA, Muir J, et al: Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326:1250-6, 1992

Melzack R, Katz J: The McGill pain questionnaire: appraisal and current status. In: Turk DC, Melzack R (eds): Handbook of Pain Assessment. NY, Guilford Press. 1992

Osborne MJ, Austin RCT, Dawson KJ, Lange L: Is there a problem with long term use of sumatriptan in acute migraine? (letter). BMJ 308:113, 1994

Osterweis M, Kleinman, A, Mechanic D: Pain and disability: clinical, behavioral, and public policy perspectives. Washington, DC: National Academy Press, 1987.

Pick CG, Paul D, Eison MS, Pasternak GW: Potentiation of opioid analgesia by the antidepressant nefazodone. European Journal of Pharmacology 211:375-381, 1992

Porter J, Jick H: Addiction rare in patients treated with narcotics. N Engl J Med 302:123, 1980

Sherman S, Lehman GA: Opioids and the sphincter of Oddi. Gastrointest Endosc 40:105-6, 1996

Swerdlow M: Anticonvulsant drugs and chronic pain. Clin Neuropharmacol 7:51-82, 1984

Thune A, Baker RA, Saccone GTP: Differing effects of pethidine and morphine on human sphincter of Oddi motility. Br J Surg 77:992-5, 1990

Tomson T, Bertilsson L: Potent therapeutic effect of carbamazepine-10,11-epoxide in trigeminal neuralgia. Arch Neurol 41:598-601, 1984

Turk DC, Melzack R (eds): Handbook of Pain Assessment. NY, Guilford Press, 1992

Turk: Clinicians Attitudes about prolonged use of opioids and the issue of patient heterogeneity. J Pain Symptom Manage 11:218-230, 1996.

WY Zhang, A Li Wan Po: The effectiveness of topically applied capsaicin. European Journal of Clinical Pharmacology 46:517-22, 1994

TABLE 1.

Diagnostic criteria for Pain Disorder

A. Pain in one or more anatomical sites is the predominant focus of the clinical presentation and is of sufficient severity to warrant clinical attention.

B. The pain causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

C. Psychological factors are judged to have an important role in the onset, severity, exacerbation, or maintenance of the pain.

D. The symptom or deficit is not intentionally produced or feigned (as in Factitious Disorder or Malingering).

E. The pain is not better accounted for by a Mood, Anxiety, or Psychotic Disorder and does not meet criteria for Dyspareunia.

Code as follows:

307.80 Pain Disorder Associated With Psychological Factors: psychological factors are judged to have the major role in the onset, severity, exacerbation, or maintenance of the pain. (If a general medical condition is present, it does not have a major role in the onset, severity, exacerbation, or maintenance of the pain.) This type of Pain Disorder is not diagnosed if criteria are also met for Somatization Disorder.

Specify if:

Acute: duration of less than 6 months

Chronic: duration of 6 months or longer

307.89 Pain Disorder Associated With Both Psychological Factors and a General Medical Condition: both psychological factors and a general medical condition are judged to have important roles in the onset, severity, exacerbation, or maintenance of the pain. The associated general medical condition or anatomical site of the pain (see below) is coded on Axis III.

Specify if:

Acute: duration of less than 6 months

Chronic: duration of 6 months or longer

Note: The following is not considered to be a mental disorder and is included here to facilitate differential diagnosis.

Pain Disorder Associated With a General Medical Condition: a general medical condition has a major role in the onset, severity, exacerbation, or maintenance of the pain. (If psychological factors are present, they are not judged to have a major role in the onset, severity, exacerbation, or maintenance of the pain.) The diagnostic code for the pain is selected based on the associated general medical condition if one has been established (see Appendix G) or on the anatomical location of the pain if the underlying general medical condition is not yet clearly established--for example, low back (724.2), sciatic (724.3), pelvic (625.9), headache (784.0), facial (784.0), chest (786.50), joint (719.4), bone (733.90), abdominal (789.0), breast (611.71), renal (788.0), ear (388.70), eye (379.91), throat (784.1), tooth (525.9), and urinary (788.0).

TABLE 2.

Narcotic Agonists

Name	Brand name	PO	IV	PR
Alfentanil	Alfenta	X
Morphine	Astramorph, Duramorph, Infumorph, Kadian, MSIR, RMS, Roxanol	X	X	X
Propoxyphene	Darvon	X
Meperidine	Demerol	X	X
Hydromorphone	Dilaudid	X	X	X
Fentanyl	Sublimaze	X
Levophanol	Levo-Dromoran	X	X
Methadone	Methadone	X
Oxymorphone	Numorphan	X	X
Levo-alpha-acetymethadol (LAAM)	Orlaam	X
Oxycodone	Roxicodone	X
Sufentanil	Sufenta	X

TABLE 3. Drugs approved as Analgesics:

Narcotic Agonist-Antagonists

Name	Brand name	PO	IV	IN
Buprenorphine	Buprenex	X
Dezocine	Dalgan	X
Nalbuphine	Nubain	X
Butorphanol	Stadol	X	X
Pentazocine	Talwin	X

TABLE 4. Narcotic Combinations

Narcotic	+ Acetominophen	+ Aspirin
Dihydrocodeine	DHC plus1
Propoxyphene	Darvocet, Wyegesic
Codeine	Tylenol with Codeine #'s 2 - 4, Fiorect1,2	Fiorinal1,2
Hydrocodone	Hydrocet, Lorcet, Lortab, Vicodin, Zydone
Oxycodone	Percocet, Tylox	Percodan
Pentazocine3	Talacen

1 also contains caffeine

2also contains butalbital

3agonist-antagonist

TABLE 5. Opioid Agonists--Usual Adult Starting Doses (for opioid-naive Individuals)

DRUG	Oral	Parenteral	Transdermal
Alfenta	8-20 mg/kg1
Morphine	30 mg q 3-4 h	10 mg q 3-4 h
Morphine controlled-release	90-120 mg q 12 h
Propoxyphene	65 mg q 4 h
Hydromorphone	6 mg q 3-4 h	1.5 mg q 3-4 h
Levo-alpha-acetymethadol2 (LAAM)	20-40 mg q 48-72 h
Levorphanol	4 mg q 6-8 h	2 mg q 6-8 h
Meperidine	not recommended	100 mg q 3 h
Methadone	20 mg q 6-8 h	10 mg q 6-8 h
Oxymorphone	1 mg q 3-4 h
Fentanyl	2-50 mg/kg1	not recommended3
Oxycodone	immediate release: 10-
30 mg q 4 h

controlled release: not recommended3
Sufentanil	1-8 mg/kg1

1Usually used only for general anesthesia. Please see the package insert for dosing guidelines.

2 Generally indicated only for the treatment of opioid dependence

3 Neither transdermal fentanyl nor oxycodone controlled-release are recommended for initial use. In each case, it is preferable to start a immediate-release opioid and then convert to a continuous release preparation.

TABLE 6. Narcotic Combinations: Usual Adult Starting Doses (opioid naive)

DRUG	DOSE (of Narcotic)
Dihydrocodeine + acetominophen	32 mg q 4 h
Propoxyphene + acetominophen	100 mg q 4 h
Codeine + aspirin or acetominophen	60 mg q 3-4 h
Hydrocodone + acetominophen	10 mg q 3-4 h
Oxycodone + aspirin or acetominophen	10 mg q 3-4 h
Pentazocine + acetominophen	25 mg q 4h

TABLE 7. Opioid Agonists--Approximate equipotent dose

DRUG	Oral	Parenteral	Transdermal
Morphine	single/intermittent dose: 60 mg q 3-4 h

repeated (around the clock) dose: 30 mg q 3-4 h	10 mg q 3-4 h
Morphine controlled-release	90-120 mg q 12 h
Codeine	180-200 mg q 3-4 h	130 mg q 3-4 h
Fentanyl	~100 mg/hr
Hydrocodone	30 mg q 3-4 h
Hydromorphone	7.5 mg q 3-4 h	1.5 mg q 3-4 h
Levorphanol	4 mg q 6-8 h	2 mg q 6-8 h
Meperidine	300 mg q 2-3 h	100 mg q 3 h
Methadone	20 mg q 6-8 h	10 mg q 6-8 h
Oxycodone	immediate release: 30 mg q 4 h

controlled release: 80 mg q 12 h
Oxymorphone	1 mg q 3-4 h
Propoxyphene	120-200 mg q 3-4 h

TABLE 8. Narcotic Agonists- Slow Release Preparations

Name	Brand name	PO	TD	PR
Morphine	MS Contin, Oramorph	X
Fentanyl	Duragesic	X
Oxycodone	Oxycontin	X

TABLE 9. Acetominophen and NSAID's--Usual Adult Starting Doses

DRUG	DOSEl
Acetaminophen	650-975 mg q 4h
Aspirin	650-975 mg q 4 h
Choline magnesium (Trilisate)	1000-1500 mg bid
Diflunisal (Dolobid)	1000 mg initial dose followed by 500 mg q 12 h
Etodolac (Lodine)	200-400 mg q 6-8 h
Fenoprofen calcium (Nalfon)	200 mg q 4-6 h
Ibuprofen (Motrin, Advil, others)	400 mg q 4-6 h
Ketoprofen (Orudis)	25-75 mg q 6-8 h
Magnesium salicylate	650 mg q 4 h
Meclofenamate sodium (Meclomen)	50 mg q 4-6 h
Mefenamic acid (Ponstel)	250 mg q 6 h
Naproxen (Naprosyn)	500 mg initial dose followed by 250 mg q 6-8 h
Naproxen sodium (Anaprox)	550 mg initial dose followed by 275 mg q 6-8 h
Salsalate (Disalcid, others)	500 mg q 4 h
Sodium salicylate	325-650 mg q 3-4 h
Ketorolac tromethamine (Toradol)	IM: 30 or 60 mg IM initial dose followed by 15 or 30 mg q 6 h Oral: 10 mg q 6-8 h

TABLE 10. "Danger Signs" in Headache Pain Patients.1

1. Headache is a new symptoms for the individual in the past 3 months, or the nature of the headache has changed markedly in the past 3 months.

2. Presence of any sensory or motor deficits preceding or accompanying headache other than the typical vidual prodromata of migraine with aura. Examples include weakness or numbness in an extremity, twitching of the hands or feet, aphasia, or slurred speech.

3. Headache is one sided and has always been on the same side of the head.

4. Headache is due to trauma, especially if it follows a period of unconsciousness (even if only momentary).

5. Headache is constant and unremitting.

6. For a patient reported tension-type headache-=like symptoms:

a. Pain intensity has been steadily increasing over a period of weeks to months with little or no relief.

b. Headache is worse in the morning and becomes less severe during the day.

Headache is accompanied by vomiting.

7. Patient has been treated for any king of cancer and now has a complaint of headache.

8. Patient or significant other reports a noticeable change in personality or behavior or a notable decrease in memory or other intellectual functioning.

9. The patient is over 60 years of age, and the headache is a relatively new complaint.

10. Pain onset is sudden and occurs during condition of exertion (such as lifting heavy objects), sexual intercourse, or "heated" interpersonal situation.

11. Patient's family has a history of cerebral aneurysm, other vascular anomalies, or polycystic kidneys.

TABLE 11. Classification of Headaches2

1. Migraine

1.1 Migraine without aura

1.2 Migraine with aura

1.5 Childhood periodic syndromes that may be precursors to or associated with migraine

2. Tension-Type Headache

2.1 Episodic tension-type headache

2.1.1 Episodic tension-type headache associated with disorder of pericranial muscles

2.1.2 Episodic tension-type headache unassociated with disorder of pericranial muscles

2.2 Chronic tension-type headache

2.2.1 Chronic tension-type headache associated with disorder of pericranial muscles

2.2.2 Chronic tension-type headache unassociated with disorder of pericranial muscles

3. Cluster headache and chronic paroxysmal hemicrania

3.1 Cluster headache

3.1.1 Cluster headache periodicity undetermined

3.1.2 Episodic cluster headache

3.1.3 Chronic cluster headache

4. Miscellaneous headaches unassociated with structural lesion

5. Headaches associated with head trauma

5.1 Acute posttraumatic headache

5.1.1 with significant head trauma and/or confirmatory signs

5.1.2 with minor head trauma and no confirmatory signs

5.2 Chronic posttraumatic headache

5.2.1 with significant head trauma and/or confirmatory signs

5.2.2 with minor head trauma and/or confirmatory signs

6. Headache associated with vascular disorder

7. Headache associated with nonvascular intracranial disorder

8. Headache associated with substances or their withdrawal

8.1 Headache induced by acute substance use or exposure

8.1.1 Nitrate/nitrite-induced headache

8.1.2 Monosodium glutamate-induced headache

8.1.3 Carbon monoxide-induced headache

8.1.4 Alcohol-induced headache

8.1.5 Other substances

8.2 Headache induced by chronic substance use or exposure

8.2.1 Ergotamine-induced headache

8.2.2 Analgesic abuse headache

8.2.3 Other substances

8.3 Headache from substance withdrawal (acute use)

8.3.1 Alcohol withdrawal headache (hangover)

8.3.2 Other substances

8.4 Headache from substance withdrawal (chronic use)

8.4.1 Ergotamine withdrawal headache

8.4.2 Caffeine withdrawal headache

8.4.3 Narcotics abstinence headache

8.4.4 Other substances

8.5 Headache associated with substances but with uncertain mechanism

8.5.1 Birth control pills or estrogens

8.5.2 Other substances

9. headache associated with noncephalic infection

10. Headache associated with metabolic disorder

11. Headache or facial pain associated with disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures

12. Cranial neuralgias, nerve trunk pain, and deafferentation pain

13. Headache nonclassifiable

TABLE 12. Headache Diagnostic Criteria: Migraine3

Migraine without aura

A. At least 5 attacks fulfilling B-D

B. Headache attacks lasting 4-72 hours (2-48 hours for children below age 15), untreated or unsuccessfully treated.

C. Headache has at least two of the following characteristics

1. unilateral location

2. pulsating quality

3. moderate or severe intensity (inhibits or prohibits daily activities)

4. aggravation by walking stairs or similar routine physical activity.

D. During headache at least on of the following

1. nausea and/or vomiting

2. photophobia and phonophobia

E. At least one of the following:

1. History, physical, and neurological examinations do not suggest 1 of the disorders listed in groups 5-11 {other table}

2. History and/or physical, and/or neurological examination do suggest such disorders, but is ruled out by appropriate investigations

3. Such disorder is present, but migraine attacks do not occur for the first time in close temporal relation to the disorder.

Migraine with aura

A. At least 2 attacks fulfilling B

B. At least 3 of the following 4 characteristics

1. One or more fully reversible aura symptoms indicating focal cerebral cortical and/or brain stem dysfunction

2. At least 1 aura symptom develops gradually over more than 4 minutes or 2 or more symptoms occur in succession

3. No aura symptom lasts more than 60 minutes. If more than 1 aura symptom is present, accepted duration is proportionally increased

4. Headache follows aura with a free interval of less than 60 minutes. It may also begin before or simultaneously with the aura.

C. Same as Migraine without aura, criteria E.

TABLE 13. Headache Diagnostic Criteria: Tension-Type Headaches4

Episodic tension-type headache

A. At least 10 previous headache episodes fulfilling criteria B-D. Number of days with such headache <180/year (<15/month).

B. Headache lasting from 30 minutes to 7 days

C. At least 2 of the following pain characteristics:

1. Pressing//tightening (nonpulsating) quality

2. Mild or moderate intensity (may inhibit, but does not prohibit activities)

3. Bilateral location

4. No aggravation by walking stairs or similar routine physical activity

D. Bother of the following

1. No nausea or vomiting (anorexia may occur)

2. Photophobia and phonophobia are absent, or one but not the other is present.

E. Same as Migraine without aural, criteria E.

Chronic tension-type headaches

As above, but:

Average headache frequency >15/month (180 days/year) for > 6 months.

Criteria C from above not needed

No more than 1 of the following: nausea, photophobia or phonophobia (and no
vomiting)

Subtypes for both episodic and chronic tension headaches:

Associated with disorder of pericranial muscles

A. Fulfills criteria for tension-type headache (episodic or chronic)

B. At least on of the following:

1. Increased tenderness of pericranial muscles demonstrated by manual palpation or pressure algometer

2. Increased EMG level of pericranial muscles at rest or during physiological tests

Unassociated with disorder of pericranial muscles

A. Fulfills criteria for tension type headache (episodic or chronic)

B. No increased tenderness of pericranial muscles. If studies, EMG of pericranial muscles shows normal levels of activity.

TABLE 14. Headache Diagnostic Criteria: Cluster Headache5

A. At least 5 attacks, fulfilling migraine criteria B-D

B. Severe unilateral orbital, supraorbital, and/or temporal pain lasting 15-180 minutes untreated

C. Headache is associated with at least 1 of the following signs which have to be present on the pain side:

1. Conjunctival injection

2. Lacrimation

3. Nasal congestion

4. Rhinorrhea

5. Forehead and facial sweating

6. Miosis

7. Ptosis

8. Eyelid edema

D. Frequency of attacks from 1 every other day to 8 per day.

E. Same as Migraine criteria E.

TABLE 15. Headache Diagnostic Criteria: Substance Related Syndromes6

Headache Induced by chronic substance use or exposure

A. Occurs after daily doses of a substance for >= 3 months

B. A certain required minimum dose should be indicated

C. headache is chronic (15 days or more a month)

D. Headache disappears within 1 month after withdrawal of the substance

Ergotamine-induced headache

A. Is preceded by daily ergotamine intake (oral >= 2 mg, rectal >= 1 mg)

B. Is diffuse, pulsating, or distinguished from migraine by absent attack pattern and/or absent associated symptoms

Analgesic abuse headache

A. One or more of the following:

1. >= 50 g aspirin a month or equivalent of other mild analgesics

2. >= 100 tablets a month of analgesics combined with barbiturates or other nonnarcotic compounds

3. One or more narcotic analgesics

Figures.

Figure 1. The McGill Pain Questionnaire

Figure 2. Short-Form McGill Pain Questionnaire

Figure 3. The WHO Pain Ladder.