CHAPTER 2. PAIN THERAPY USING DRUGS

2.01 Drug Therapy of Pain; Introduction

2.02 The Ladder Approach

2.03 Non-Narcotics

A. Aspirin and Acetaminophen

B. Newer NSAIDs

2.04 Narcotics: In General

2.05 Routes of Administration

A. Intravenous Injections

B. Subcutaneous Infusion under the Skin

C. Intramuscular Injections

D. Oral Administration

E. Buccal Mucosal Administration

F. Rectal Administration

G. Transdermal Administration

H. Nasal Administration

I. Administration into the Central Nervous System

2.06 Opioids in the Ladder Approach

2.07 Opioid Narcotics; Method of Action

2.08 Different Opioid Narcotics

2.09 Different "Potent" Opioid Narcotics

A. Morphine

B. Hydromorphone (Dilaudid)

C. Methadone (Dolophine)

D. Fentanyl (Duragesic or TDS-Fentanyl)

E. Levorphanol (Levo-Dromoran)

F. Meperidine (Demerol)

2.10 Patient-Controlled Analgesia (PCA)

2.11 General Principles of Narcotic Use

2.12 Dose and Choice of Narcotics

2.13 Side Effects of Narcotic Administration

2.14 Treatment of Narcotic Side Effects

A. Constipation

B. Nausea and Vomiting

C. Sedation

D. Mental Clouding

E. Respiratory Depression (decreased breathing)

F. Subacute Overdose

2.15 Influence of Concurrent Medical Conditions on Pharmacotherapy

2.16 Narcotic Tolerance and Addiction

2.17 Adjuvant Drug Therapies

A. Corticosteroids

B. Anticonvulsants

C. Antidepressants

D. Other Drugs

2.18 Reversible Medication Failures

2.19 Inadequate Pain Therapy/Health Care Providers

A. Educational Failures

B. Inadequate Pain Assessment

2.20 Inadequate Pain Therapy/Social Problems/Patients

A. Under-Reporting of Pain by Patients

B. Inappropriate Administration of Pain Medication

2.21 Inadequate Pain Therapy/Social Problems/Cultural and Religious

A. Misunderstanding of Religious Principles

B. Problems of Communication

2.22 Inadequate Pain Therapy/Social Problems/Cost-Containment

2.23 Inadequate Pain Therapy/Social Problems/Poor Communications

2.24 Inadequate Pain Therapy/Legal Problems

A. Threatened Recriminations

B. Practical Difficulties

2.25 Summary

APPENDIX

Table 1 NSAIDs

Table 2 Opioid Narcotics, Comparison of Methods of Administration

Table 3 Table of Dose Equivalents for Opioid Analgesics

Table 4 Table of Adjuvant Drugs for Treatment of Pain

2.01 Drug Therapy of Pain; Introduction

Thirty years ago medicine sought desperately to develop new technologies to impart drug free relief of pain in the terminally ill considering surgical alternatives to be preferable to drug therapy. Although this search was highly successful and many of the methods developed remain clinically useful in specific situations, recent advances in the use of morphine and related narcotics (also commonly referred to as "opioids") have proven much more significant in our ability to control pain in the terminally ill. Based on these advances, drug therapy and not mechanical intervention has become the accepted cornerstone of pain therapy as it has proven to be effective, inexpensive, rapid in onset, and of relatively low risk. This does not mean the other modalities available to manage cancer pain are outdated, but that they tend to be limited to use when drug therapy is either unsuccessful or overly intrusive on the patientís quality of life. The following are among the major factors which have made drug therapy so much more effective.

1. Acceptance of the need to individualize drug therapy (analgesia) for the patient suffering with pain in a step-wise fashion, commonly referred to as "laddering." The simplest drugs and dosage schedules involving the least invasion of the patientís life style are used first, beginning typically with acetaminophen (Tylenol), followed by a group of drugs referred to as "NSAIDs," standing for "non-steroidal anti-inflammatory drugs." When pain persists or increases, a low-potency opioid (narcotic) is added, most commonly, codeine or one of its derivatives. When moderate or severe pain persists, treatment involves the use of increasingly potent opioids, most commonly, morphine, in increasing dosages.

2. Realization that the past practice of giving pain medication only when needed, ("PRN"), should be replaced with plans calling for routine dosing of pain medications "around-the-clock" with additional doses, if needed, being added "PRN." This method has been found to be far superior to only giving medication PRN and actually has been found to result in lower total dosage of narcotic used.

3. Acceptance of the "drug tolerance" and "physical dependence" associated with long-term use of opioids as an unavoidable, but relatively unimportant side-effects of usage, to be clearly distinguished from the problems of addiction. [See discussion below.]

4. The development of new, more convenient methods of drug delivery employing oral preparations, which have proven to be superior to injections because they are more convenient, less costly and provide smoother blood levels which improve the effectiveness of pain relief. When patients cannot take medications orally, narcotics can be given by skin patches which have also been proven to be very effective and well-tolerated in the treatment of severe pain. In rare instances, use of narcotics in rectal suppositories has also been found to be effective. These innovations in drug delivery have essentially replaced the time-honored practice of giving narcotics by injection, which has only been shown to be painful, inconvenient, and unreliable because of the variations of absorption of narcotics from the site of injection.

5. The development of what can be considered to be additional rungs on the ladder when conventional narcotic therapy fails to obtain or maintain good pain relief without unacceptable side-effects. These added rungs consist of non-narcotic drugs which have been found to be additive in effect with the narcotic pain relievers. Among these drugs, the most commonly employed are drugs generally classified either as anti-depressants, tranquilizers, and a group of drugs medically designated to be "neuroleptics" which are specifically designed to alter the transmission of impulses in the brain, spinal cord, and/or peripheral nerves.

6. Progressive discontinuation of meperidine (Demerol) and pentazocine (Talwin), commonly used narcotics in the past, in favor of more appropriate narcotic choices for the treatment of chronic pain.

7. The development of patient controlled analgesia (PCA), an approach which allows self-administer of narcotics by the patient when it if felt to be required, an approach which surprisingly often reduces the amount of total dosage required.

8. The development of pain evaluation methods which make it easier for physicians to determine the effectiveness of drug therapy and to separate out the various "pains" suffered by the patient in a more organized manner.

9. The development of approaches specifically using written pain management plans, the avoidance of placebos, and the need for continuous monitoring of the effects of drug therapy. The best protection patients and their families have from inadequate therapy is being informed about pain management and speaking up clearly. In this way, they come to know what to expect, when to request additional therapy, and what sets the limits for effective pain management.

10. A change in the approach to narcotic side effects when the drug has been found to be effective in pain control. In this new approach, instead of discontinuing the "successful" narcotic, efforts are made to enable its continued use through manipulation of dosage schedules or the addition of specific therapy to control the side-effect(s). In some cases this involves anticipatory measures, most typically, starting stool softeners at the same time narcotics are started even before constipation occurs.

11. Closely related to #10 is advanced knowledge of how to switch narcotics of similar strength back and forth in an effort to maximize effectiveness of pain control while minimizing side-effects. One way this can be done is by taking advantage of the partial non-transferability of tolerance. This refers to the fact that although the patient will develop tolerance to all narcotics requiring increasing dosage with time, development of tolerance for one narcotic may not be completely transferrable to another narcotic. Therefore, a lower comparable dose of a new narcotic may be as effective in treating pain as a higher relative dose of the narcotic that has been in prior on-going use with less resultant side-effects.

12. Another possible method of taking advantage of the tolerance phenomena is related to the fact that pain relief and the production of side-effects are both subject to the development and loss of tolerance but not necessarily at the same rate. This means that a previously discontinued drug may later be found to be effective for pain relief in the patient at a dosage which does not cause side-effects. This happens if loss of tolerance for pain relief occurs faster than loss of tolerance for the side-effect.

13. Realization that the most feared and discussed complication of narcotics, depressed breathing, is actually uncommon with the modern "laddered" approach to pain therapy calling for slow increases in narcotic dosages. Also, the fact that even if breathing is depressed, it can be quickly reversed with special drugs used to stop the narcotic effects. (naloxone/Narcan)

This chapter addresses the use of drugs in the treatment of pain more extensively. Other aspects of pain management are addressed more fully in later chapters.

2.02 The Ladder Approach

The ladder approach to pain therapy was pioneered by the World Health Organization in 1990. Under this plan, pain is managed according to its severity. Mild pain is initially treated with acetaminophen (tylenol) or aspirin with additional use of NSAIDs [see discussion below] as needed. Even though moderate symptoms are likely to require the use of mild (codeine, hydrocodone-Hycodan) or strong (morphine, fentanyl-Duragesic) narcotics, they are initially treated with the same drugs as mild pain which are then continued if and when the narcotics are added. When severe pain exists from the onset, the ladder approach recognizes that more rapid relief is required and treatment is usually initiated with long-acting strong opioid narcotics. Once pain relief is achieved, the milder medications may be added and the dosage of narcotic reduced. If relief is not achieved quickly, additional drugs which have been found to add to the effectiveness of the narcotic pain killers is added until relief is obtained. Severe pain almost always necessitates the use of long-acting strong opioid narcotics, often in association with additional drugs which have been found to add to the effectiveness of the narcotic pain killers.

The five essential principles of management according to the WHO ladder include:

1. Medications should be taken by mouth when possible.

2. Medications should to taken by the clock. Research shows patients generally require less analgesics when opioids are taken according to a set schedule.

3. Medications are escalated according to the rating of pain from mild, moderate to severe.

4. Medications are tailored to individual needs. The goal is always the most effective pain management with the fewest side-effects.

5. Pain is monitored and re-assessed regularly.

The ladder approach to pain accepts and encourages the use of additional non-pharmacologic methods of pain control including both physical and psychological means. The addition of heat, cold and massage can effectively relieve muscle spasm and tension. Physical therapy and range-of-motion exercises may help prevent muscle atrophy and other problems related to disuse of body parts. Acupuncture and transcutaneous electric nerve stimulation (TENS) can be very effective in the treatment of nerve and muscle pain. Additionally, techniques such as imagery, hypnosis, biofeedback, and relaxed breathing increase feelings of self-control and may promote healing. Psychosocial and pastoral support assist with both pain and suffering. [Many of these approaches are further discussed in subsequent chapters]

2.03 Non-Narcotics

A. Aspirin and Acetaminophen

Most of the non-narcotic pain relievers commonly used for initial pain therapy in terminal illness are from a group of drugs referred to as "NSAIDs." [Usually pronounced as two words, "N-SAIDS"] NSAIDs in general work by blocking the production or activity of chemicals called prostaglandins, which are produced in multiple organs of the body. Although the term NSAID is relatively new, we now know in hindsight that NSAIDS include many older drugs, such as aspirin and acetaminophen (Tylenol), as well as the whole series of related drugs released over the last thirty-five plus years beginning with Butazolidine, Indocin and Motrin.

In general, NSAIDs are considered to be useful in a wide variety of conditions involving mild to moderate pain both related and unrelated to cancer and other terminal illnesses. They are particularly useful because they have few side effects within approved dose ranges, but are limited in their effectiveness by having what is referred to as a "ceiling effect." This means that increasing the dosage beyond a certain level, the "ceiling" dose, does not increase their effectiveness, although it does increase the side-effects.

Aspirin has traditionally been the first drug used in the treatment of mild pain, but has largely been replaced in recent years by acetaminophen because it does not have aspirinís tendency to cause bleeding both by irritating the stomach lining and by interfering with the coming together (aggregation) of blood platelets as required in the process of blood clotting. In spite of this potential problem, however, aspirin should not be forgotten because it is still relatively safe compared to other analgesics and is often found to be more effective than acetaminophen in relieving pain. [Note: many physicians believe that it is the effectiveness of Tylenol advertisements and not the superiority of the drug which has led to the recent diminished use of aspirin for pain.]

B. Newer NSAIDs

Somewhat more effective than aspirin and acetaminophen in general are the newer NSAIDs, including Motrin, Nalfon, Feldene, Toradol, Anaprox, Naprosyn, Orudis, Meclomen, and Ponstel among many others, but they, too, share aspirinís effect on the stomach lining and on platelet aggregation and therefore constitute a risk for bleeding. Although NSAIDs have ceiling effects which limits the usefulness of dosing any one drug over recommended levels, changing to a different NSAID may still be effective when the approved dosage of one provides inadequate relief. NSAIDs are frequently used as initial therapy in mild pain even before aspirin or acetaminophen because they are effective, frequently available over the counter, relatively inexpensive, and have been found to be effective in combination with opioids which are commonly required later when pain gets worse.

Use of NSAIDs and narcotics together are often additive in effect, each being better when used in combination. This is in part because the NSAIDs work primarily in the local areas of inflammation while the narcotics work in the brain and spinal cord. In addition, that part of the action of the NSAIDs which does occur in the brain involves areas of the brain different from those affected by narcotics. As a result, concurrent use of an NSAID with an opioid is likely to produce better pain relief with lower dosages of both drugs than would be required if either were used alone.

Unlike opioid analgesics, NSAIDs do not produce tolerance, physical, or psychological dependence. Like aspirin and acetaminophen, the newer NSAIDs also lower body temperature.

The major side effects of the NSAIDs, besides the inhibition of platelet aggregation noted above, is on the G.I. tract, occasionally producing gastric distress, heartburn, nausea, vomiting, loss of appetite, diarrhea, constipation, flatulence, bloating, epigastric or abdominal pain or discomfort, and, more rarely, causing bleeding, ulceration, or perforation of the stomach. NSAIDs may also cause dysfunction of the liver or kidney, but this is usually the result of long-term use greater than typically involved in terminal care.

Although this list of potential side-effects is long, the number of patients who are unable to tolerate any NSAID is small, and the incidence of the more serious side-effects like bleeding, liver or kidney failure is quite low unless there is preexisting disease of these organs. If long-term care is anticipated, routine checks of organ function by blood testing should be done on occasions. Because the damage to the liver and kidney caused by NSAIDs is gradual, such testing should avoid any significant risk of significant injury.

Most NSAIDs are available as oral tablets or capsules, and several are available as oral liquids. They are rarely used as rectal suppositories and only one, ketorolac, (Toradol) can be given by injection.

[For more information about these agents, see the table in the Appendix of this chapter]

2.04 Narcotics: In General

Pain which persists after the maximum dose of non-narcotics has been given or moderate to severe at the outset is normally treated with narcotics. Initial trial usually involves such drugs as codeine or hydrocodone (Hycodan) -- often referred to as mild opioids -- but if these fail or when they become ineffective over time, the more potent opioids, such as morphine (MS-Contin among many brand names), Hydromorphone (Dilaudid), methadone (Dolophine), fentanyl (Duragesic), or levorphanol (Levo-Dromoran), are prescribed as well.

Typically, initial dosing is fairly low, but rapidly increased to obtain control of pain as required. Usually dosages which are initially found to be effective need to be increased with time, experience showing that hesitating to make required increases only leaving the patient in unrequited pain without reducing the amount of drug that will actually be required in the end. Rarely, side effects of the narcotics will preclude obtaining adequate relief either from the beginning or as time progresses.

Most patients who require potent opioids for relief of pain will require simultaneous treatment with two different forms: a long-acting (basal) form administered around-the-clock and a short acting form, administered as needed (commonly referred to as "PRN").

Since most cancer pain is constant and unremitting, an around-the-clock schedule for the administration of a base level of narcotics is preferable to PRN administration, which is based on the presence of perceived pain. This strategy, most commonly using oral morphine, oral methadone (Dolophine), or fentanyl (Duragesic) skin patches, avoids the "roller coaster" type of pain relief which is produced when drug is withheld until pain is felt and the patient then has to wait for the drug to be given and to take effect. In addition, prolonged use of PRN drugs often leads to a pattern of patient anticipation and memory of pain which produces a form of suffering even when drug therapy has been found to be effective.

Superimposed on the above "base" regimen, potent short-acting opioids such as immediate release morphine, hydromorphone (Dilaudid), or oxycodone (Percodan, Percocet, Tylox) are generally made available on a PRN basis, usually at intervals of two to four hours, for exacerbations of pain. Such exacerbations, referred to as "breakthrough pain," may be spontaneous, related to specific activities, or, if the dose of the basal analgesic is insufficient, may occur regularly just prior to the next scheduled dose. When specific pain producing activities has been identified, patients should be instructed to utilize PRN doses prior to activity. When the patient experiences end of dose failure, the dose of long acting analgesic should be increased.

Because narcotic therapy for pain is such an integral part of the medical treatment of terminally ill patients and so often causes concern by the patient and family and misunderstanding with medical providers, this book will now discuss in detail many of the factors involved in the use of narcotics in the terminally ill.

2.05 Routes of Administration

Traditionally, opioid narcotics were given by injection just beneath the skin (sub-cutaneous), or, less frequently, into the muscle or by vein. Because the early preparations were short acting, they required multiple (4 to 6 or more) injections a day, thereby necessitating the presence of nursing services or family members willing and able to give the injections.

Happily, these significant drawbacks were avoided when it became evident that proper formulation of morphine could be given effectively by mouth and, even more recently, with the development of "transdermal administration," using skin patches made with the potent narcotic, fentanyl (TDS-Fentanyl). Thanks to these advances making oral or patch administration the treatment of choice, pain can almost always be effectively controlled by informed members of a home support system even in the absence of continual medical supervision. In addition, alternative methods of administration have been developed which do not require continuous medical supervision if these more established methods fail, as discussed below.

The following compares the risks and benefits of the various routes of administration. In many cases, more than one route may be used at the same time in the same patient to treat different types of pain or pain of varying severity.

A. Intravenous Injections

Because it avoids the need for the drug to be absorbed, intravenous injection is the fastest means of obtaining narcotic pain relief. It is also associated with the most pain relief for the dose and, for most preparations, is not excessively expensive. Although the intravenous route provides the most rapid onset of analgesia, the duration of pain relief after a single dose is shorter than with other routes, making it inappropriate as the primary route of administration in most patients who suffer persistent pain of moderate or greater severity. On occasions, however, if for instance there is another need for a continuous intravenous infusion line, a continuous intravenous drip of narcotics may be reasonable for persistent pain control. When, however, there is no real need for an intravenous line, oral or transdermal administration is clearly preferable as the I.V. line always interferes to some degree with the comfort of the patient.

B. Subcutaneous Infusion under the Skin

Many physicians find continuous administration of narcotics dissolved in very small quantities of salt water through a needle directly under the skin to be preferable to intravenous administration in the home unless there is an additional need for an I.V. line. Absorption of opioids from under the skin is rapid and blood stream levels can be quickly stabilized to give continuous pain relief. Morphine and hydromorphone (Dilaudid) are most commonly employed for subcutaneous infusions, usually in very high concentrations which may require only one or two ounces of fluid to be given each day.

C. Intramuscular Injections

Narcotic injections directly into the muscle is usually avoided because it tends to be painful and inconvenient, and absorption from muscle is not very reliable.

D. Oral Administration

Oral administration of narcotics is the preferred route whenever possible because it is the most convenient and cost-effective. Oral opioids, including morphine, are available in tablet, capsule, and liquid forms and in immediate and controlled-release forms. Controlled-release tablets become immediately released when crushed and are therefore not appropriate for long-term therapy in patients who are unable to swallow whole tablets.

While oral administration is preferred, in some patients it is not practical. This most commonly occurs when there is persistent nausea and vomiting, pain or disability with swallowing, fear that pills will "go down the wrong way" (be aspirated) into the lungs, when severe pain requires more immediate relief, or when the patient suffers from delirium, confusion, stupor, or other changes in the mental status.

E. Buccal Mucosal Administration

At the time of writing this book, attempts are underway to develop means of administering narcotics (morphine, fentanyl-Duragesic) through the lining of the mouth either by using a concentrated liquid (elixir) or lozenges to be held against the cheek or under the tongue. They may now be available.

F. Rectal Administration

The rectal route of administration using a narcotic suppository may be used when patients have nausea or vomiting or are fasting for surgery or special testing. It is not appropriate if there is irritation around the rectal area which can be made worse by placement of a suppository, if there is diarrhea, or if the patient is unable to insert a suppository himself or herself. Like oral administration, the absorption of the drug is less than total and must pass in the blood through the liver where it is partly inactivated to get to the rest of the body, so larger dosage must be used than when given intravenously. Like oral administration, this means is also inexpensive and most appropriate for long-term administration for stable pain, not for acute pain.

G. Transdermal Administration

Transdermal administration goes directly into the blood stream without going through the liver and therefore requires doses very similar to those used for injections. At present, fentanyl (TDS-Fentanyl) is the drug which is typically used with transdermal applications. Four patch sizes are available, made to provide absorption of 25, 50, 75, or 100 mgs per hour. The maximal recommended daily dose is 300 mg/hour. If this dose fails to relieve pain, it is suggested an alternative means of administration be tried. Patches are made to last 3 days. Absorption requires 12 to 18 hours to obtain adequate blood levels, so the patches are not appropriate if rapid pain relief is required. Transdermal fentanyl (TDS-Fentanyl) is therefore most appropriate when pain is relatively constant with infrequent episodes of breakthrough pain.

H. Nasal Administration

The transnasal route is an alternative delivery method that may be useful when patients are no longer able to tolerate the oral route. Unfortunately, the only commonly used narcotic formulated for nasal use is butorphanol (Stadol), which is rapidly absorbed from the nasal mucosa. Because it is not a full acting narcotic, it is not the best formulation for control of chronic pain, but may be particularly helpful for acute headache.

I. Administration into the Central Nervous System

Narcotics may be administered through catheters placed within the spinal canal or even directly into the fluid which bathes the brain (cerebro-spinal fluid). These methods are only used when pain cannot be controlled by oral, transdermal, subcutaneous, or intravenous routes or when side effects such as confusion and nausea limit the use of sufficient narcotics by simpler means to relieve pain. Administration through catheters is much more expensive and inconvenient to use, as they require experienced, meticulous technique, significant family and professional support systems, and sophisticated follow-up, which is not always available. Their use is also more likely to be associated with acute respiratory depression.

Once the narcotic administration through such catheters has been shown to be effective, a permanent device capable of delivering narcotics directly into the cerebro-spinal fluid can be implemented, thereby decreasing the need for constant medical monitoring.

Morphine is the most commonly used intraspinal drug. Alternative opioids such as hydromorphone (Dilaudid), fentanyl (Duragesic), or sufentanil (Sufenta) have been used intraspinally to manage cancer pain and may be useful substitutes, especially when the patient experiences general side effects from morphine which is partially absorbed from the spinal fluid into the general circulation. Intraspinal use of narcotics tends to be most effective clinically when the patientís pain is localized in the legs and lower part of the body. Introduction of narcotics directly into the fluid bathing the brain is most commonly used for severe headache or pains involving the neck area.

[For more information comparing the methods of administration, see the table in the Appendix to this chapter]

2.06 Opioids in the Ladder Approach

Narcotics, especially the less powerful ones such as codeine, are often used from the beginning for the treatment of moderate to severe pain. But even when initial pain therapy with non-narcotics is successful, this success is usually not lasting and narcotics are likely to be required for pain relief at some time before cancer reaches the terminal phase.

When narcotics are added to NSAIDs in the treatment of pain, the most effective NSAID is normally continued in the same dosage as was found to be maximally effective prior to the institution of the narcotic. The NSAID is not stopped.

When treatment with the NSAIDs is associated with insufficient relief of pain or is poorly tolerated, the addition of a member of the class of drugs referred to as the "weak opioids," such as codeine, or oxycodone (Percodan, Percocet, Tylox), or an "intermediate" opioid, such as hydrocodone (Hycodan, among others], is recommended. While there is probably no ceiling dose for the weak opioids themselves, because they are often prescribed as part of a combination analgesics with acetaminophen or aspirin, and because the dose of these additional components are limited, the dose of the total preparation is artificially limited. If this were not the case, the distinction between the so-called "weak" and "potent" opioids would probably disappear and the "weak" opioids would probably be used in larger dosage similar to the more potent opioids.

In general, because codeine is so constipating, oxycodone (Percodan, Percocet, Tylox) is a better choice among the "weak" opioids. It is also more readily available as a single drug preparation, making it easier to regulate dosage. While there may be legal pressure to use these drugs in increasing dosage because they are viewed to be less addicting, it may not be wise, as switching to a more potent opioid is likely to be a better course of action.

Note propoxyphene (Darvon) is purposely omitted from this scheme as not being an appropriate drug for the treatment of terminally ill patients.

2.07 Opioid Narcotics; Method of Action

Opioids relieve pain by a means entirely different from the NSAIDs, which are primarily effective in reducing local inflammation. The pain which is produced in the body by local inflammation and injury must ultimately be perceived by certain cells within the brain. For this to happen, the local inflammation or injury must initiate the passage of an impulse over a series of interconnecting nerve cells which run between the site of pain production and the pain receipting cells in the brain. Although passage of the impulse along the nerves acts more like an electric current, passage from cell to cell requires the release of certain chemicals (neuro-transmitters) from the surface of the previous cell in the line of transmission. These chemicals in turn activate specific areas on the surface of the next nerve cell (receptor cites) in the chain which then provides for further passage of the impulse down its length through the "electrical" current so as to cause the release of the chemical required to stimulate the next cell in the series. The point of action of the narcotic is at the specific receptor cite on the cell surface which perceives the presence of the chemical. Opioid analgesics work by blocking these specific receptor cites both within and outside the brain and spinal cord.

2.08 Different Opioid Narcotics

Many opioid narcotics are available, although morphine is by far the most commonly used. Although their mechanisms of action are similar, the dosage of the various chemicals varies considerably and one frequently will work when another has failed. A major difference among the various narcotics is that some are available only for injections or for oral use, while others are available in different types of preparations, giving the physician a wide choice of drugs to use in any one individual and at any one time. To avoid confusion, it may be important to understand the interaction of these drugs and the relative strength.

Most of the commonly used opioid narcotics belong to a class of drugs referred to as "full agonists" because they work directly on the receptor site. The full agonists include morphine, hydromorphone (Dilaudid), codeine, oxycodone (Percodan, Percocet, Tylox), hydrocodone (Hycodan), methadone (Dolophine), levorphanol (Levo-Dromoran), and fentanyl (Duragesic). This is only important to know because being of the same class of drugs, they do not antagonize each other and are additive in their effects. Full agonists are of particular importance in the treatment of cancer pain because they do not have a ceiling to their pain killing effect and therefore the dosage can continually be increased as long and as high as required.

Unlike the full agonists, narcotics such as pentazocine (Talwin), butorphanol tartrate (Stadol), dezocine (Dalgan), and nalbuphine hydrochloride (Nubain) are considered mixed agonists. These drugs are similar to the NSAIDs in having an analgesic ceiling above which additional dosages do not increase their effectiveness because they do not work on all receptors. In recent years, these drugs have not been widely recommended, in part because their use with the more common full agonists can cause interference with the effect of the full agonist precipitating a withdrawal syndrome and increased pain.

Morphine is the most commonly used opioid for moderate to severe pain for many reasons. First, because it can be administered by many routes. Second, because it is available in a wide variety of dosages, including long-acting preparations. Third, because it is so widely studied in the past making its actions extremely well known to the medical community. Fourth, because it is inexpensive. In contrast to morphine, which has continually gained increased popularity, Demerol and Talwin, narcotics widely used in the past, have become much less popular over recent years and should probably be avoided in most situations. An increasingly popular narcotic is fentanyl (Duragesic or TDS-Fentanyl) because of the ease with which it can be used in skin patches, a method now being advocated even before oral morphine in many situations.

2.09 Different "Potent" Opioid Narcotics

A. Morphine

Morphine is the most commonly used opioid narcotic, oral morphine being most physicianís drug of choice in the management of moderate or severe chronic cancer pain. Oral morphine comes in both short-acting (MSIR, Roxanol) and long-acting forms (MS Contin, Oramorph). The short-release tablets allow fast absorption, with peak blood levels (corresponding to maximum pain relief) appearing in 20 to 90 minutes and effective pain relief usually lasting approximately four to six hours, although this may vary considerably from patient to patient and may be even less than four hours. The amount of medication absorbed after an oral dose varies from about 35% to 75% of that given, making the oral dose of morphine approximately twice that of injectable forms. Morphine tends to be removed from the body more slowly in patients over 50 years of age, which may explain why older patients usually [but not always] require relatively lower doses of morphine for the same analgesic effect. Using slow-release tablets, morphine administration can be reduced to twice a day, although a few patients may require dosing every eight hours to maintain effective pain relief even with the long-acting preparations. In general, every 12-hour administration of slow-release morphine and every four-hour administration of short-release oral morphine provides similar analgesic efficacy and side-effect profiles in the treatment of chronic pain. Morphine also can be administered by rectal, subcutaneous, and spinal routes.

B. Hydromorphone (Dilaudid)

Dilaudid can be administered orally, rectally, and by intravenous or subcutaneous injection, but its main use is when it is desirable to give constant pain therapy through continuous infusion of a solution containing the drug under the skin. It is more potent than morphine and acts even more quickly, making it useful for acute, severe, breakthrough pain. It may also be useful in patients who fail to tolerate morphine well. Because of its short duration of action, administration is likely to be required every two to three hours.

C. Methadone (Dolophine)

Methadone is particularly useful because of its long acting effects, but, because it remains in the body so long, runs the risk of build-up and overdosing if too many doses are given in too short a time. This is made more likely to happen by the large variance in dose requirements experienced by different patients. Doses are usually given at eight hour intervals, but many physicians use six or twelve hour intervals, and this may vary from patient to patient. Methadone is also effective and well tolerated by rectal and intravenous administration, but should not be used under the skin.

When switching to methadone from other drugs, the dose required is often found to be considerably less than would be predicted from charts comparing the strengths of the various narcotic analgesics. Overall, Methadone has certain advantages over the other strong opioid analgesics: (1) it is much less expensive than the others, (2) it generally requires much less frequent administration, (3) it has a high potential to control pain which is unresponsive to morphine or other opioids because there is reduced cross-tolerance, and (4) it has less problems with side-effects of break down products in the body. The main problem with Methadone is its lack of predictability because of the marked variation from patient to patient and the fact it is hard to determine its expected effect when switching from one opioid to another.

D. Fentanyl (Duragesic or TDS-Fentanyl)

Fentanyl is a synthetic narcotic approximately 75 times more potent than morphine and with characteristics that make it particularly good for use by administration in skin patches for chronic pain therapy. Fentanyl is especially useful in skin patches because of its high potency, skin compatibility, and small chemical size making for easy absorption through the skin. Patches are available in four doses set to release 25, 50, 75 or 100 micrograms per hour for anywhere for up to three days. In these doses, it is well tolerated, but higher doses are likely to cause side effects such as vomiting, sleepiness, and respiratory depression. Transdermal fentanyl (TDS-Fentanyl) is not appropriate for acute pain and breakthrough pain, but newer fentanyl tablets are being developed to be sucked on and absorbed through the lining of the mouth in order to meet the need for a rapid onset of pain relief.

E. Levorphanol (Levo-Dromoran)

Levorphanol resembles methadone (Dolophine), in that it is very long acting allowing dosing every 8-12 hours but, like methadone, is commonly associated with accumulation of drug and excessive sedation. It is more powerful than morphine and therefore is effective in lower dosage.

F. Meperidine (Demerol)

Although extensively used for postoperative pain, meperidine is not recommended for the treatment of chronic pain because chronic use leads to a build-up of breakdown products within the body causing tremors, muscle jerking and seizures, especially in patients with kidney problems.

2.10 Patient-Controlled Analgesia (PCA).

Patient controlled analgesia (PCA) is a major advance in pain control. It can be used orally by patient self ingestion of pills, but is more commonly employed using a special pump which is set to inject small quantities of narcotics through a catheter placed within a vein, under the skin, or within the spinal canal, in which case it empties directly into the spinal fluid. PCA was largely developed for use in post-operative patients, in which it is usually the only source of pain control. But in treating terminally ill patients it is usually used along with continuous around the clock narcotics orally or by patch, the patient supplementing the continuous medication with PCA when break-through pain occurs. The amount of extra pain medication self administered by the patient may also help indicate how much additional pain medication should be added to the around-the-clock dosages.

PCA has been found to be safe for both home and hospitalized patients, but should not be used for sedated and confused patients. It has not been found to increase the rate of development of tolerance or the total amount of narcotics given if good pain relief is obtained. Use of PCA is particularly satisfying because it helps maintain patient independence and control by matching drug delivery to the self-determined need for analgesia.

2.11 General Principles of Narcotic Use

1. Best results are normally obtained using continuous dosing. This is usually done by using a longer acting oral preparation such as morphine or by using a skin patch. Around-the-clock administration of narcotics allows each dose to become effective before the previous dose has lost its effectiveness and therefore avoids peaks and valleys with associated poor pain relief.

2. When pain is aggravated or is expected to be aggravated by a procedure or event, a single dose of short acting narcotic may be used in addition to the background long-acting medication. A patient may also be given PRN doses for the first 24 to 48 hours when a new drug is started to define the best daily dosing requirements for that individual patient.

3. Dosage typically requires adjustment over time as background pain levels vary and tolerance develops. Because of this variation and tolerance, daily doses of morphine ranging from 60 to 3000 mgms. may be required to adequately relieve cancer pain and should not be considered to be abnormal at either end. [Discussed below]

4. With the exception of fentanyl delivered by the transdermal route, there is no ceiling or maximal recommended dose for full opioid agonists, as discussed above. In fact, very large doses of morphine, e.g., well more than ten times the normal dose, may be needed for severe pain and is likely to be well tolerated if tolerance has developed over time.

5. Published tables vary in the suggested doses of other narcotics which are equivalent to morphine. This is in part because individual patients react differently to the different compounds. While the table can give a guide as to appropriate starting doses, clinical response must be monitored for each individual patient to actually achieve the appropriate dose.

6. When tolerance develops for one drug, there is also likely to be some tolerance for a different opioid narcotics, but not to the same extent as for the original drug. This means when shifting drug, a lower dose of the new drug is likely to be as effective as the higher equivalent dose of the original drug for which the body has developed tolerance.

7. It is usually advisable to try several different oral opioid narcotics before switching routes of administration. In most instances, failure of oral administration is next followed with the use of skin patches, or the patches may be used first or earlier in the sequence of drugs tried. Only when multiple failures have occurred does it become appropriate to try the more complicated invasive approach to relieve persistent pain. For example, patients who are too sleepy or who develop nausea when taking oral morphine should first be tried on another oral medication to see if pain relief can be obtained without the side effect. If this doesnít work, a fentanyl skin patch may be tried. Because of individual variation in response, this is likely to find a drug which both works and does not cause unreasonable side effects.

8. Constipation is an almost universal complication of opioid use, and all patients should receive prophylactic stimulant laxative therapy unless otherwise contraindicated (e.g., if the patient has chronic diarrhea). Sedation is a frequent side effect of initial opioid use or following increased dosage, but usually does not require treatment because the body quickly develops tolerance to their sedative effects.

9. Many people fear large doses of opioid narcotics will cause undue respiratory depression, but this is most unusual because large doses are always preceded by the use of smaller doses during which time the body develops tolerance to its respiratory effect. In patients with underlying respiratory disease, this concern may be more legitimate.

10. True hypersensitivity reactions to opioids are rare. If patients experience such reactions, it is often possible to administer a different opioid safely. For example, patients allergic to morphine are likely to tolerate fentanyl or methadone and vice versa.

11. All effects of opioid narcotics can be reversed by giving an opioid antagonist such as naloxone (Narcan). It should only be used in an acute emergency, however, because its use completely blocks the pain relief which is being experiencing and can cause excruciating pain and seizure.

12. Opioid tolerance and physical dependence do not equate with "addiction."

13. Whatever the cause, a change of opioids using equivalent doses may decrease side-effects while maintaining pain control in some patients. Opioid rotation often is necessary to obtain satisfactory long-term pain control in cancer patients.

2.12 Dose and Choice of Narcotics

The appropriate dose of narcotics is the amount of opioid that controls pain with the fewest side effects. The need for increased doses of opioid often reflects progression of the disease, as well as the development of tolerance. Either cause may lead to the need for more frequent administration as well as increased dosage. Some idea of the dosage which may be required can be gathered from a recent report by Dr. Portenoy, a well-known specialist in the treatment of cancer pain, who reports that while the average dose of morphine for cancer patients may be 100-200 mgms. per day, some patients may require over 1,000 mgms per day, the largest dose being noted to be over 35,000 mgms. per day.

An important part of finding the right dose is using slow titration. This means that until pain is relieved, the next dose is usually increased by about twenty-five percent over the previous dose. Points to keep in mind include:

n Titration. Increase or decrease the next dose by one-quarter to

one-half of the previous dose.

n Route conversion. When changing from the oral to the rectal route, begin with the oral dose, then titrate upward frequently and carefully. Lower doses are required for parenteral (non-oral) routes but are similar when given into a vein, under the skin, or directly by injection into a muscle.

n Schedule. Prevent recurring pain rather than having to subdue it. Give analgesics on a regular schedule to prevent a loss of effectiveness between doses.

n Tolerance. Assume patients actively abusing heroin or prescription opioids (including methadone) have some pharmacologic tolerance which will require higher starting doses and shorter dosing intervals.

n Cessation of opioids. When a patient becomes pain free as a result of cancer treatment or palliation (e.g., nerve destruction), gradually decrease the opioid to avoid the symptoms of withdrawal. [The speed of possible withdrawal varies from one narcotic to another.]

n Opioid therapy in special populations. Specific guidelines for opioid use should be used with the elderly, children, persons physically or cognitively impaired, and known or suspected drug abusers.

[See table in Appendix of this chapter for dose equivalents.]

2.13 Side Effects of Narcotic Administration

Treatment with opioid narcotics frequently causes side effects, but in most cases they are transient and manageable. Proper identification and therapy for these side effects is critical to effective pain relief, as they are too often viewed by the patient and family as immovable barriers to effective therapy. To the contrary, they should instead be considered temporary challenges to the creativity of physician and family to minimize their effects through tailoring of the pain management program to the needs of the particular patient. Of particular importance in this regard is the need to avoid a belief the patient is "allergic" to the drug, a rare occurrence which requires permanent discontinuation of the drug, as opposed to suffering one of the many common dose related side effects that can be managed by proper switching and dosing of drugs.

Constipation and sedation are the most common side effects associated with narcotics. Other common side effects include confusion, nausea and vomiting, depressed respirations (breathing), dry mouth, difficulties urinating, itching, muscle spasms, poor mentation, euphoria, sleep disturbances, sexual dysfunction, skin irritation with patches, and inappropriate secretion of ADH, a hormone which causes decreased urine production. Because constipation is so common, it is wise to act prophylactically to try to avoid its development. Because the other side-effects vary so much from patient to patient, they are best treated only when clinical observation shows them to be present.

2.14 Treatment of Narcotic Side Effects

A. Constipation

Constipation is a common problem associated with opioid administration. It is also frequently aggravated by other factors associated with terminal illness, such as decreased food and water intake and disease of the bowel itself. In addition, it may mask other important medical conditions such as bowel obstruction or fecal impaction, both of which may be aggravated by overly aggressive treatment of the apparent constipation. Mild constipation can usually be managed by an increase in fiber consumption and the use of a mild laxative such as milk of magnesia. These agents should be administered on a regular schedule, barring contraindications. Severe constipation occurs as a result of opioid induced slowing of intestinal contractions and can be treated with a stimulating cathartic drug, e.g., bisacodyl (Dulcolax), standardized senna concentrate (Senokot), or hyperosmotic agents (e.g., lactulose or sorbitol). Oral laxatives can be taken at bedtime, and rectal suppositories can be used in the morning if needed. Stool softeners are of limited usefulness.

B. Nausea and Vomiting

Narcotic induced nausea is frequently relieved with the passage of time. It may also be treated with specific drugs such as Compazine or other phenothiazines, or with sea sickness medications. [Note: These drugs may cause increased sedation.]

C. Sedation

Sedation is common when opioid doses are increased substantially, but tolerance usually develops rapidly with relief of sedation within a week. Persistent drug induced sedation is usually best treated by reducing the amount of narcotic given in each dose and increasing the dosage frequency. In some patients switching to another opioid may reduce the sedative effects. CNS stimulants such as caffeine, amphetamines and Ritalin may be added to increase alertness if the above approach is ineffective in reducing sedation.

Persistent sedation unrelieved by dose manipulation and changing of narcotics may lead the physician to search for an alternative approach to pain relief using surgery or placement of catheters within the central nervous system for more localized administration of analgesics. At times, especially toward the end of life, permanent sedation may be desired and the narcotic effect welcomed by patient and family alike.

 

D. Mental Clouding

At times opioids cause mental changes more severe than sedation, better described as somnolence, confusion and/or delirium. Mild confusion is relatively common and usually acceptable during the period required for tolerance to develop, while severe delirium can usually be avoided if narcotic doses are not increased too rapidly. Even when this happens during initial therapy or in response to the need for an increased dose, withholding drug for a brief period usually leads to reversal. To the contrary, when the patient becomes rapidly confused or delirious while on base-line narcotics, it is suggestive of a process other than narcotic side-effect and must be evaluated for new problems either of the brain or other major organ system within the body.

E. Respiratory Depression (depressed breathing)

Patients receiving long-term opioid therapy generally develop tolerance to the respiratory depressant effects of these agents so treatment is seldom required. When it is required, the administration of naloxone (Narcan) is effective, but risks a rapid exacerbation of pain. Therefore, unless there is an acute emergency, it should initially be given in small doses.

F. Subacute Overdose

Far more common than acute respiratory depression, subacute overdose manifests as slowly progressive (hours to days) somnolence and respiratory depression. When this happens, the withholding of one or two doses will usually reverse the symptoms. Medication can then be restarted at a lower dose, usually twenty-five percent less than the previous dose.

2.15 Influence of Concurrent Medical Conditions on Pharmacotherapy

The presence of other medical conditions in cancer patients and the medications taken for them may influence the best choice of narcotics to be used for pain management. Common medications or classes of medications that produce clinically significant drug interactions with narcotics include alcohol (as in elixirs) and other mental depressants such as phenytoin (Dilantin), as well as rifampin [an antibiotic mostly used for tuberculosis but also for some other infections] and certain antidepressants referred to as monoamine oxidase inhibitors. [Now largely replaced by the tricyclic and newer SSI antidepressants, Prozac, Zoloft, Effexor, Paxil, and Serzone discussed below.]

Coexisting conditions also may influence the type and doses of opioids administered. For example, patients with newly recognized cancer pain who have been recently treated with opioids for another reason, such as surgery, may require higher than the recommended starting doses because they are opioid tolerant. Blood clotting abnormalities, low white blood counts, and infection may contraindicate the use of spinal catheters or other regional anesthetic techniques because the risks of bleeding or "seeding" of infection are increased.

2.16 Narcotic Tolerance and Addiction

If there is one lesson to be learned from this book, the author would wish it to be the difference between the expected occurrence of narcotic tolerance and physical dependence, both of which must be anticipated as part of pain therapy with narcotics, and addiction, which is extremely uncommon in the setting of terminal illness. Failure to separate the two is undoubtedly the leading cause for unrelieved pain in the terminally ill, and also the major factor in producing the publicís distrust of the medical profession as it deals with the terminally ill patient.

The word "tolerance" refers to a time-related progressive resistance of the body to the effects of a particular drug such that increasing dosage of the drug is required to obtain the same effect previously achieved with a lower dose. Fortunately, the same process which requires increased dosage to obtain the same pain relief also occurs with side effects, so that the increased dosage required for pain relief usually does not result in increased side effects. This means as long as there is no ceiling on the amount of drug which can be given and as long as increasing dosage remains effective, the only significant problem resulting is a matter of how many pills must be taken and the associated increase in cost. Of course, progression of the underlying disease may also require an increased narcotic dose, in which case, because the increase is not based on tolerance, side effects are likely to increase along with increased pain relief.

A concurrent factor in narcotic treatment of pain is the development of physical dependence, which means the bodyís metabolism has changed to expect the presence of the drug in the system and to react negatively if it is absent. Although such potential negative reaction must be expected with the long term use of narcotics for pain relief, the absence of any need to ever withdraw the drug from a terminally ill patient makes this potential problem irrelevant, provided the patient continues to receive proper medical attention.

In contrast, the term "addiction," refers to a state of mind in which there is continual craving for the medication leading to compulsive behavior to obtain the drug and an overwhelming involvement in drug procurement and use. Unlike tolerance and physical dependence, which routinely occurs when narcotics are used, addiction is extremely rare when opioids are used for relief of pain in the terminally ill. In one large study of cancer patients, only seven cases of addiction were found among 25,000 patients receiving narcotics. Of course, if the patient was a narcotic addict before they developed cancer, the addiction remains and only complicates the treatment.

When the body becomes dependent on a drug, its absence leads to certain symptoms referred to as a "withdrawal syndrome." The appearance of a withdrawal syndrome may occur as early as 2 weeks after the initiation of opioid therapy if narcotics are withheld and typically manifested itself as anxiety, irritability, chills and hot flashes, joint pains, tearing, running nose, sweating, nausea, vomiting, abdominal cramps and diarrhea. Although these symptoms are similar to those reported in narcotic addicts who have been denied drugs, it does not imply psychological dependence or addiction, for if the pain were to be miraculously relieved, once these initial symptoms were appropriately treated the patient would not seek out the drug and would not exhibit the loss of control and compulsive use patterns which characterizes narcotic addiction. This difference has been attributed to the fact that when treating the pain of terminal illness, there is no psychological dependence, only a reliance on the drug for pain relief. Although most patients with cancer take opioids for more than 2 weeks, it has been repeatedly shown when pain is otherwise relieved, patients almost never continue to seek narcotics once appropriate dose reduction has been undertaken -- a very simple process in the absence of pain. [Note: Recent experience with cancer patients undergoing bone marrow transplantation in which large doses of narcotics are often required for a prolonged period after transplant but can then be stopped has served to reassure the medical community such use of narcotics does not lead to the production of truly addicted individuals, even in the presence of tolerance and physical dependence.]

When cancer develops in a previously addicted individual, the difficulties of drug management are understandably complicated. In general it is believed the best course of treatment in this situation is to treat the claimed pain as real, recognizing pain to always be a perception and that the perception is likely to be real to the patient even if influenced by the bodyís desire for more drug. As well stated by Dr. Foley, a world renowned cancer therapist at Memorial Sloan-Kettering in New York: "So what? Pain is pain and it should be relieved." After years of research in treating the pain of terminal disease her message is the opposite of Nancy Reaganís, "Just say yes to drugs."

Of equal importance in pain relief is the avoidance of so-called "pseudo-addiction," in which inadequate treatment of true pain produces a situation in which the patient displays the same manipulative behavior normally associated with addicts in the search for adequate pain relief -- recurrent hospital E.R. visits, doctor-shopping, recurrent phone calls to doctors, and other apparently aggressive drug-seeking behavior. Unfortunately, this situation is highly likely to result from over concern by physicians who ask the patient to describe their experience of pain in detail and then, when the patients are highly graphic in their descriptions, react to them as being undue complainers.

In summarizing the issue of adequate pain relief and going even further than suggested by the DHHS, the Council on Ethical and Judicial Affairs of the American Medical Association in a report related to physician-assisted suicide in a 1994 journal, 10 Issues in Law & Medicine 91-97 (1994) wrote:

"The first priority for the care of patients facing severe pain as a result of a terminal illness or chronic condition should be the relief of their pain. Fear of addiction to pain medications should not be a barrier to the adequate relief of pain. Nor should physicians be concerned about legal repercussions or sanctions by licensing boards. The courts and regulatory bodies readily distinguish between use of narcotic drugs to relieve pain in dying patients and use in other situations. Indeed, it is well accepted both ethically and legally that pain medications may be administered in whatever dose necessary to relieve the patient's suffering, even if the medication has the side effect of causing addiction or of causing death through respiratory depression."

This statement by the Council of the AMA does present an issue worthy of further consideration. Because narcotics are sedating and may further interfere with thought processes already limited by the cause of the terminal disease, it is wise for those who will be caring for a terminal patient to discuss preferences of the patient at a time when thought processes are clear. What will the patient want when pain progresses and greater narcotic use will be required for relief? When forced to choose between suffering from pain and being able to interact with friends and family members, how much sedation does the patient expect to want? Obviously, decisions made beforehand are open to change in the future, but it is much easier for physicians and family to agree on the appropriate level of pain therapy if and when the time comes if the patientís own basic desires have also been made known beforehand.

Many patients will request doses of analgesics which do not control their pain fully in order to meet a goal of continuing to interact with their families. In such situations, physicians are more likely to consider other means of controlling pain, such as using adjuvant drugs or mechanical interventions for pain relief.

Caregivers should also discuss with patients how they would balance the value of obtaining more relief from higher doses of pain killers against the potential risk of respiratory depression. Although the development of tolerance is likely to prevent this from happening, it is worth discussing for the rare situation in which large increases in narcotic doses are required in the last stages of the illness outstripping the bodyís ability to develop tolerance.

2.17 Adjuvant Drug Therapies

The terms "adjuvant drugs" or "adjuvant drug therapies" are commonly used to describe the use of certain medications which are not normally considered pain relievers along with either narcotic and non-narcotic analgesics because they have been shown to enhance the effective level of pain relief. [Note that medications which relieve side effects of analgesics, such as laxatives, could be considered adjuvant drugs because they permit higher dosing of narcotics, but the term is usually limited in use to those medications designed to treat co-existing symptoms which have been found to secondarily improve analgesia.] The groups of drugs most commonly used in association with pain therapy for terminal illness are (1) corticosteroids -- drugs related to the anti-inflammatory drug, cortisone; (2) anti-depressants -- which have their own specific effect on nerve transmission in the brain and which often enhances the effect of narcotics; (3) anti-epileptics -- drugs initially developed for the treatment of epilepsy, but which also have independent effects on nerve conduction in the brain; and (4) specific drugs used to interfere with nerve transmission and referred to as "neuroleptics."

In initiating adjuvant drug therapy, it must be remembered that unlike true pain relievers, the onset of analgesia may be delayed by days or even weeks after initiating therapy, and the quality of analgesia is less closely linked to dose increases. As a result, serial trials of each class of co-analgesics, and even of different agents within the same class, is often indicated.

A. Corticosteroids

The corticosteroids provide a wide range of potentially beneficial effects. These include mood elevation, interference with local inflammation, reduced nausea and vomiting, and appetite stimulation. They may also be used to reduce swelling of the brain and spinal cord, most commonly in situations involving increased pressure within the skull and spinal column. As such, they may be particularly helpful in the relief of headaches when they are due to tumors within the skull or in the relief of pain related to compression of the spinal cord within the spine.

Although corticosteroids are known to frequently be associated with severe side effects when used for extended periods in chronic illnesses, the doses required to improve the pain relief of narcotics and the short period of time for which it is likely to be required minimizes any worry about significant side effects when used in terminally ill patients.

B. Anticonvulsants

The anticonvulsants [carbamazepine (Tegretol), phenytoin (Dilantin), valproic acid (Depakene), and clonazepam (Klonopin)] and the more specific neuroleptics are principally used to manage pain of nerve origin, especially pains typically described as "shooting" or "burning" in nature. In addition, they may be helpful in other pains of nervous origin such as those caused by tumor invasion of the nerve, radiation nerve damage, surgical scarring of the nerves, Shingles -- a viral infection of the nerves, and similar conditions. Side effects of therapy can be serious, but these risks are generally low compared to the potential benefits in most terminally ill patients.

The most commonly used pure neuroleptic, methotrimeprazine (Levoprome) may be particularly helpful if the patient experiences narcotic induced constipation by reducing the required dose of the opioid. It may also be helpful in relieving nausea and anxiety.

C. Antidepressants

Like the anticonvulsants and neuroleptics, the tricyclic antidepressants [such as amitriptyline (Elavil), imipramine (Tofranil), desipramine (Norpramin), clomipramine (Anafranil), and nortriptyline (Pamelor)] are most useful in treating pain coming directly from nerve irritation. Although referred to as "anti-depressants," it is inappropriate to think of their use in the treatment of pain as requiring the presence of depression to be effective, for they have direct analgesic properties in addition to antidepressant properties. Even in the absence of clinical depression, they may increase the analgesic effects of opioids either by stimulating the pain inhibitory pathways discussed above or by increasing the blood levels of circulating opioids. The toxic effects of these drugs are important, for they are fairly common -- dry mouth, dizziness when standing, sleepiness and confusion, being among the most common.

Although less well investigated, there is reason to believe the newer group of SSI antidepressants, fluoxetine (Prozac), sertralin (Zoloft), venlafaxine (Effexor), paroxetine (Paxil), and nefazodone (Serzone), are also likely to be helpful in enhancing the action of opioids, although it is hard to tell how much of their effects relate to their anti-depressant action and how much they are truly adjuvants in pain relief.

D. Other Drugs

Many ongoing studies are investigating the use of other common drugs in the management of pain in terminal illness. One such group of studies is looking at derivatives of commonly used local anesthetics, such as lidocaine (Xylocaine) intravenously for relief of neurologic pain. Another group of studies is investigating the use of the new bisphosphonates, developed to prevent calcium loss from bones, in the treatment of bone pain associated with cancer.

Other drugs may also be helpful along with those listed above. Hydroxyzine (Vistaril, Atarax) is primarily an antihistamine which also is a mild anti-anxiety drug. With both sedative and analgesic properties, it may be particularly useful in treating the anxious patient with pain, and may also be helpful to relieve nausea. Additional help may be obtained from the use of psychostimulants, such as amphetamines and Ritalin, which may be used to relieve sedation.

[See table in Appendix of this chapter for adjuvant drugs used in the treatment of pain.]

 

2.18 Reversible Medication Failures

When we speak of "medication failures" we usually refer to situations in which appropriate medications fail to control the clinical process -- infections progress in spite of antibiotics, blood pressure remains high in spite of the use of anti-hypertensive, or cancer fails to respond to appropriate chemotherapeutic agents. In contrast, failure to control pain in terminal illness is usually due to inappropriate therapy, and by far the most common form of inappropriate therapy is undertreatment. This has led a recent widely quoted study to conclude: "the most common form of narcotic abuse in the care of the dying is the undertreatment of pain" leading to "psychiatric comorbidity, altered immune function, impaired function, diminished quality of life, loss of autonomy, ... suffering ... and suicide."

The most frequent causes of undertreatment of cancer-related pain have been said to be: (1) a discrepancy between patient and physician in judging the severity of the patient's pain, (2) the reluctance to prescribe opioid analgesics for fear of developing addiction, tolerance, and side effects, (3) the fact analgesic treatment is not of primary importance in the health care system, (4) the high cost of analgesic medications, which are nonrefundable and not readily available in some countries, and (5) the fact analgesic treatment often is considered only for advanced and terminal cancer patients.

In future chapters we will discuss true medication failures, situations in which the best of palliative therapy fails to adequately control pain. In the rest of this chapter we address situations in which inadequate therapy results from potentially reversible social factors involving physicians, patients, families, finances, and the law. These reversible factors are particularly distressing for they represent unwarranted causes of pain in the terminally ill, leading to depression, magnification of other symptoms, unrelenting suffering, and requests for euthanasia.

2.19 Inadequate Pain Therapy/Health Care Providers

A. Educational Failures

It is difficult to explain or justify the frequent failure of modern medicine to adequately treat pain in the terminally ill. Fortunately, recognition of this sad state of affairs has led many medical organizations to produce guidelines and educational materials for physicians stressing the importance of adequate narcotic pain therapy, the unwarranted over concern about its risks, and the frequency of inadequate treatment. Among these organizations are the World Health Organization, the American Pain Society, the American Society of Clinical Oncology, the Oncology Nursing Society, and the American Society of Anesthesiologists, as well as the guidelines discussed above from the Department of Health and Human Services, and the U.S. Agency for Health Care Policy Research.

Most commentators suggest the basic problem has been lack of physician education, pointing out the value of morphine for pain relief was better established as a mainstay of patient care at the end of the last century than now. This lack of proper education seems well documented. A recent report of the American Medical Association on medical education covering the years 1993 to 1994, showed only 5 of 126 medical schools in the United States required a separate course in the care of the dying. Of 7048 residency programs, only 26 percent offered a course on the medical and legal aspects of care at the end of life as a regular part of the curriculum. According to a survey of 1068 accredited residency programs in family medicine, internal medicine, and pediatrics as well as fellowship programs in geriatrics, each resident or fellow coordinates the care of 10 or fewer dying patients annually.

This lack of physician knowledge seems to have been further magnified in the recent past by lack of hospital commitments to the care of patients at the end of life and an unexplained separation of traditional hospital care and training from that potentially available in hospice program. For example, only 17% of schools offering students rotations in hospice care, and only half of these requiring such study of care for the terminally ill.

Another major cause for physicianís apparent lack of knowledge about pain relief would seem to stem from the late recognition of the effectiveness of oral narcotics in treating chronic pain and the misunderstanding within the profession itself of the differences between tolerance, dependence, and addiction. As late as 1971 the A.M.A. Drug Evaluation Manual considered morphine not to be effective when given by mouth, largely because early studies of its use orally employed inadequate doses.

Until recently, tolerance was considered to be a major drawback to the use of narcotics, but this misunderstanding failed to acknowledge that if (1) the same tolerance develops for side effects, (2) the cost of the drug is modest, (3) there is no ceiling on how much drug can be used, and (4) increased dosages do not lead to the behavior we associate with addiction, then tolerance is not necessarily harmful. In fact, because tolerance for one drug does not necessarily produce tolerance for another in the group, tolerance gives the potential for renewing the effectiveness of narcotics by switching, which would not be possible if the drugs just lost their effectiveness in the absence of tolerance.

Another failure of the medical profession has been its over concern regarding addiction. Almost forty years ago the author was told using narcotics over a short period for acute pain or post-operatively did not lead to addiction, but somehow the wrong message was emphasized. The important factor in this legitimate observation was not that the treatment was only confined in time, but that it was used specifically for pain relief and not to

relieve other forms of emotional suffering. Only recently has it

become evident chronic treatment of pain with narcotics does indeed produce tolerance and physical dependency, but not addiction.

B. Inadequate Pain Assessment

Somewhat different from the physiciansí failure to properly evaluate the risk versus benefits of narcotics in the treatment of chronic pain has been the failure to properly measure pain and to recognize the numerous factors which obscure the adequate reporting of pain.

Take, for instance, the now evident connection between the perception of multiple pains. It has now been clearly shown when a patient has multiple pains, a mild pain is essentially blocked out by the more severe pain. This means if the patient has multiple pains and the physician asks how bad the pain is, the patient will answer relative to the most severe pain and not a lesser pain. In these circumstances, if the more severe pain is relieved, when asked how their pain is, the patient is likely to reflect the severity of the second most painful site -- but it is likely to be reported as more severe than it would have been reported in the continued presence of the more severe source of pain.

These factors were not understood until physicians started to chart pain severity routinely on a daily basis, each time asking the patient to evaluate each pain on some objective scale of one type or another. Doing this, it soon became apparent many different charts had to be kept, because most cancer patients who experienced pain did so at more than one location. Only when these separate charts were analyzed did it become apparent the reporting of overall pain was likely to be determined almost exclusively by the most severe, with little reference to the others. As a result, physicians were routinely led to both underestimate the severity of pain and also to underestimate the degree of pain relief experienced from increasing dosage of narcotics.

In addition, physicians were slow to realize the admission of pain by patients was made difficult by other psychic and social factors, leading to underestimation of pain, or by the patientís lack of ability to express pain when also suffering from sedation or delusional thoughts. As these problems are most troublesome during short patient visits, it is not surprising recent studies of the phenomena of undertreatment repeatedly shows the assessment of pain severity by nurses and house officers varies significantly from that of the patient, often suggesting even greater levels of pain symptomatology.

 

2.20 Inadequate Pain Therapy/Social Problems/Patients

A. Under-Reporting of Pain by Patients

Many factors have been cited for patientsí failure to adequately report pain to their treating physician with resultant undermining of adequate pain therapy.

First, many patients are concerned that if they spend significant time discussing their pain with their physicians, this will distract the physician from taking time to plan treatment for the underlying disease, a process the patient is likely to be more concerned about than the acute relief of pain.

Second, patients may be reluctant to be honest, for they suspect, but do not want to face the reality, that increased pain often indicates greater spread of the disease. By so doing, they discount the other common situation in which increased pain is the result of tolerance and not directly related to the spread of disease.

Third, many patients are preoccupied with being good patients, and are afraid they will be seen as bad patients by doctors and family if they ask for increased doses of narcotics. Others want to please physicians and family by giving the appearance they are improving by demanding less pain medication. Still others fear they are likely to be abandoned if perceived to be bad patients.

Fourth, many patients have misbeliefs about narcotics -- that taking the drugs will decrease the bodyís ability to fight the disease, or that higher doses will invariably lead to additional side effects -- especially sedation and respiratory depression. They have heard the talk about narcotics hastening death, and fail to realize this is only likely to be true in the very end-stages when purposeful or required sedation leads to decreased fluid intake.

Fifth, many are afraid taking increased doses early is likely to lead to a situation in which narcotics will lose their effectiveness, not understanding this can be overcome by simply increasing the dose.

Finally, patients, like physicians, are likely to be overly concerned with the threat of developing an addiction, because the same opioids used by patient for pain relief are used by addicts for mood effects. It has been said the one most provable effect of the "War on Drugs" has been its ability to instill fear in the patient who legitimately requires narcotic use.

B. Inappropriate Administration of Pain Medication

Patients and their families often have trouble understanding and remembering the details of any proposed plan for managing pain -- best avoided using a written treatment plan. Instructions for pain relief should include the specific drugs to be taken; the type and purpose of each medication (for example, "for chronic pain," "for acute pain," "for anxiety," "for inability to sleep," "for anxiety," etc.), when the drug should be taken, whether it should be taken regularly or only when a certain type of pain is present, and the likely side effects of each drug. In addition, the plan should pay attention to the prevention or treatment of side effects, specific precautions to follow when taking a pain medication, and whom to notify about pain problems or concerns about the medication. [See the previous chapter for a suggested form]

2.21 Inadequate Pain Therapy/Social Problems/Cultural and Religious

A. Misunderstanding of Religious Principles

If asked to express themselves on these issues, most people would express a belief modern medicine is overly aggressive in treating terminal illness, but this belief is not uniform, with close to one third believing everything possible should be done to prolong life. Although this belief may be cultural or personal, it often stems from religious beliefs which may or may not be proper interpretations of the religious dogma on which it is thought to be based. If one believes erroneously that their religion requires prolongation of life whenever possible and also believes the use of narcotics shortens life, it is understandable why a patient might fight total pain relief through their use.

The Roman Catholic Church and most mainstream Protestant denominations accept the principles of palliative care in treating the terminally ill, but many followers are confused by the subtleties used to express these beliefs. For instance, "the Church" in question may express the idea it is not necessary "to impose a heroic way of acting as a general rule," but at the same time might express the belief suffering may be a means of spiritual growth. How is the layman to interpret these two statements together?

While most religions accepts the concept of "double-effect," therapy in which medication required for pain relief may be employed even if it runs the risk of accelerating death [discussed in detail later] this is frequently unknown by its followers. In addition, while the religion might accept the practice of withholding burdensome or useless therapy from someone who is dying, it might not accept the concept that artificial nutrition and hydration is a burdensome therapy, thus leaving it to the individual patient to make such determinations.

Jewish law in particular is likely to produce confusion. On one hand Jewish law says human life has "infinite value," therefore one may not do anything to hasten death, including, at least in some orthodox interpretations, withdrawing or withholding artificial nutrition and hydration. On the other hand, under Jewish law one need not prolong the dying process, so if a therapy is not effective in prolonging life, it need not be offered, and palliative care, including hospice care, would therefore become acceptable.

B. Problems of Communication

Another increasing problem in America is the large number of patients who do not share a common language or culture with their health care providers. In the absence of a common language it is difficult to express the subtle differences between the severity of pain or the impact of other factors on its perception. And in the absence of cultural understanding, it is hard for providers to interpret the needs and concerns of the patient -- leading, invariably, to prolonged use of survival-based medicine with undertreatment of pain. One situation in which this is particularly common has to do with Asiatic and Hispanic cultures in which discussions normally occur more with family than with the individual patient, leaving physicians who have grown accustomed to dealing directly with patients at a loss as to how to proceed.

2.22 Inadequate Pain Therapy/Social Problems/Cost-Containment

Wide variations in the cost of pain management between different approaches and different drugs as well as poor coverage by many third party payers makes pain therapy in the terminally ill one of the most serious victims of modern cost-containment. It is therefore no surprise it has been shown low-income people experience greater pain and suffering from cancer than do other Americans, and a disproportionate share of people who are inadequately treated for pain are minorities.

Differences in insurance coverage is also likely to lead to inappropriate usage of different modalities of treatment. Medicare, for example, may not reimburse for outpatient oral narcotics but may reimburse for pain management in an inpatient facility. Thus, "a person may well have reimbursement for the $4,000.00 cost of patient controlled analgesia (PCA) morphine but will have no coverage for $100.00 of oral morphine solution."

2.23 Inadequate Pain Therapy/Social Problems/Poor Communications

Patients frequently have little knowledge of how to communicate their perceptions of pain. In spite of recent changes which give the patient increased control over his or her own care, most patients do not understand their right to refuse treatment, to demand that physicians withdraw burdensome treatments, or to direct an approach to therapy based on palliative care emphasizing pain relief over prolongation of life. Moreover, because few patients have written advance directives expressing their wishes and appointing appropriate agents to see they are carried out, once the patient loses the ability to make decisions, the patientís desires no longer dictate the course of therapy. In short, there is an enormous need for both professional and public education to ensure patients fully understand their options for care at the end of life and to express these wishes both in writing and orally to their family and physicians.

One area of special importance relates to the proper use of emergency cardio-pulmonary resuscitation (CPR) in the terminally ill patient. While CPR has a good outcome in certain clinical situations, patients with severe underlying medical illness almost never survive to be discharged from the hospital even if resuscitation is initially successful. Despite this dismal outcome in the terminally ill, and even though survival often has no effect but to prolong suffering, absent a signed request by the patient not to have CPR performed, the law requires it be undertaken even when logic would say it should be refused. To prevent this from happening, a special do-not-resuscitate (DNR) order form should be used as part of routine palliative care for patients expected to die because such sudden arrests result in instantaneous loss of consciousness and leads to a peaceful death.

2.24 Inadequate Pain Therapy/Legal Problems

A. Threatened Recriminations

Unfortunately, the war on drugs has resulted in a number of both federal and state laws and regulations which are intended to reduce illicit drug consumption but have the unintended effect of limiting drug availability for terminally ill patients. These include such rules as requiring special prescription forms, limiting the number of pills prescribed per form or the dosage which can be prescribed, the number of refills allowed, the length of time for which the prescription is intended or requiring those taking strong opiates to register as drug users. Laws which restrict the amount of narcotic which can be ordered in a single prescription are particularly troublesome in situations in which a patient has developed considerable tolerance, thus requiring large doses of narcotics which may require multiple prescriptions in a single day.

Another growing problem is the expansion of laws requiring triple prescriptions for narcotics. A triple prescription has three copies -- one stays with the physician; one staying with the pharmacist, and one being forwarded by the pharmacy to the Drug Enforcement Administration (DEA). Triple prescriptions are aimed at procuring fuller monitoring of the prescribing habits of every physician by the DEA, but close oversight is threatening to physicians. Although passed with the best of intent as part of the war on drugs, the World Health Organization has observed that although multiple-copy prescription programs are intended to reduce careless prescribing, "health care workers may be reluctant to prescribe, stock or dispense opioids as they feel that there is a possibility of their professional licenses being suspended or revoked by the governing authority in cases where large quantities of opioids are provided to an individual, even though the medical need for such drugs can be proved."

The threat of malpractice leading to defensive medicine is well-known, but the threat of losing oneís license to practice medicine for over prescribing narcotics is equally threatening, especially when the language used in state regulations is vague and the means to determine the appropriateness of use is ambiguous. As a result, just as physicians may order unnecessary testing to avoid malpractice, they may underprescribe narcotics using combinations of analgesics including weak opioids like codeine instead of morphine for fear of losing their licensure to practice medicine. As has been pointed out, "it can become a real challenge for physicians to treat pain adequately when, for instance, the back of every Ohio physician's license includes ten activities which may jeopardize his or her license, with six of the ten pertaining to activities of illegal prescription writing, mostly for narcotics."

B. Practical Difficulties

Practical difficulties may also arise once the appropriate prescription is written. Many pharmacies, concerned about crime, paperwork, and regulatory oversight, either do not carry narcotics or stock only a limited number of drugs in only a few dosage forms. Moreover, some state laws restrict prescribing controlled substances to addicts in such a way as to make it almost impossible for a physician to feel comfortable prescribing narcotics to known addicts who also suffer from cancer or similar pain-evoking diseases. Pharmacies located near or associated with cancer centers and hospices often are better stocked. In addition, many health maintenance organizations and government-funded hospitals restrict their patients to drugs from formularies which may be limited in the drugs or dosage forms available.

2.25 Summary

The following from Marilyn Webbís book, The Good Death: The New American Search to Reshape the End of Life, (Bantam, New York, 1997) taken from various publications written by Dr. Foley strikes the author as an excellent summary of the factors related to the problem of undertreatment of pain in terminal illness:

1. "Donít limit drugs for fear of an overdose." Junkies frequently overdose -- but they are seeking an immediate rush from one high-dose single injection and use materials of unknown concentration. In contrast, "proper treatment for pain is a steady dose of opioids, given around the clock, either orally, in a high-tech, continued-supply patch or pump, or in an IV drip. Tolerance to the drugs builds up, and the body safely adjusts."

"Pain acts as a brake. It stimulates the nervous system, greatly decreasing the chance of serious side effects like respiratory depression .... Those who are still fearful of an accidental overdose should know that doctors normally get ample warning preceding respiratory depression. If health-care professionals are available, specific medications can be given that immediately reverse the problem."

2. "When narcotics are used for pain control, there is little risk of addiction." While narcotic use can cause physical dependence, similar physical dependence can also occur with other drugs -- narcotics are not unique in so doing. Thatís why doctors need to taper off on drug dosages instead of stopping them abruptly when any drug is used that produces physical dependence. In contrast, psychological addiction -- which is what junkies have -- is a completely different story, requiring far more than tapering when the drug is stopped.

3. "Believe the patient." A person in pain doesnít always scream, writhe, cry, moan. Chronic (long-term) pain can show up as depression; it has gone on so long that life seems hardly worth living. Only those in acute pain (short-term, intense, recently acquired pain, e.g., the result of surgery) act the way most of us believe tormented people act. To find out how great someoneís pain really is, a complete pain assessment is necessary.

To help physicians, patients must learn to be more articulate about describing pain. (Is it dull? Burning? Stabbing?) Those differences indicate different sources of pain, which need to be differently treated. (Even if the source remains unknown, however, the pain should be treated.)

4. "Severe pain can occur for months or years before someone dies." It is acceptable to use narcotics for all of those months or years. Pain relief contributes to a human beingís ability to lead a normal life. Aside from the agony it causes, undertreated pain can interfere both with quality of life and with a patientís ability even to try to fight off illness and heal.

5. "A patient need not forgo morphine or another narcotic now in the hope that it will still be effective when the pain gets worse. It will. Since there is no medical or legal ceiling on how much one can take, doses can keep being increased."

6. "Pain relief is always the objective when someone is dying, even if the high doses might have the unintended consequence of contributing to death." Sometimes, doctors increase the dose of narcotics to control the pain and the patient gets sleepy. Sometimes, a sedating medicine is used specifically to induce unconsciousness because there is no other way to get symptom relief. As long as this is done openly (that is, mentally aware patients and caregivers are informed) experts say this can be appropriate therapy at the end of life.

 

APPENDIX: CHAPTER 2. PAIN THERAPY USING DRUGS

Table 1 - NSAIDs; Taken from a report of the Department of Health and Human Services

Drug

Usual dose for adults and children
> 50kg body weight

Usual dose for children {1} and adults {2}
< 50kg body weight

Acetaminophen and over-the-counter NSAIDs
Acetaminophen {3}

650 mg q 4 h

975 mg q 6 h

10-15 mg/kg q 4 h

15-20 mg/kg q 4 h

rectal

Aspirin {4}

650 mg q 4 h

975 mg q 6 h

10-15 mg/kg q 4 h

15-20 mg/kg q 4 h

rectal

Ibuprofen (Motrin, others) 400-600 mg q 6 h 10 mg/kg q 6-8 h {5}
Prescription NSAIDs
Carpofen (Rimadyl) 100 mg tid  
Choline magnesium trisalicylate {6} (Trlisate) 1 000-1 500 tid 25 mg/kg tid
Choline salicylate (Arthropan) {6} 870 mg q 3-4 h  
Diflunisal (Dolobid) {7} 500 mg q 12 h  
Etodolac (Lodine) 200-400 mg q 6-8 h  
Fenoprofen calcium (Nalfon) 300-600 mg q 6 h  
Ketoprofen (Orudis) 25-60 mg q 6-8 h  
Ketorolac tromethamine {8} (Toradol) 10 mg q 4-6 h to a maximum of 40 mg/day  
Magnesium salicylate (Doan's, Magan, Mobidin, others) 650 mg q 4 h  
Meclofenamate sodium (Meclomen) {9} 50-100 mg q 6 h  
Mefenamic acid (Ponstel) 250 mg q 6 h  
Naproxen (Naprosyn) 250-275 mg q 6-8 h  
Naproxen sodium (Anaprox) 275 mg q 6-8 h  
Sodium salicylate (Generic) 325-650 mg q 3-4 h  
Parenteral NSAIDs
Ketorolac tromethamine {8}, {10} (Toradol) 60 mg initially, then 30 mg q 6 h Itramuscular dose not to exceed 5 days  

 

Table of Contents Introduction Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7
Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 Chapter 13 Chapter 14 Chapter 15 Chapter 16 Chapter 17

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