- Email: [email protected]
Role of Opioid Analgesics
Role of Opioid Analgesics
CHARLES E. INTURRISI, Ph.D. New York, New York
The clinical pharmacology of the narcotic-type analgesics is discussed in depth. Relative analgesic potency, peak and duration of analgesia, oral potency, and adverse effects are reviewed, with an emphasis on the clinical application of this knowledge. The differences among psychologic dependence, physical dependence, and tolerance are carefully delineated. Guidelines are provided for using narcotic-type analgesics in the management of patients with cancer. Analgesics are most commonly employed for relieving acute pain and play an important role in the management of certain patients with chronic pain. Although there are gaps in our knowledge of analgesic pharmacology, the rational and appropriate use of these drugs is based on the pharmacologic knowledge derived from well-controlled clinical trials [1]. The analgesic drugs may be separated into three broadly defined groups: (1) the narcotic-type analgesics (opioids); (2) the non-narcotic analgesics, which include aspirin, acetaminophen, and the nonsteroidal anti-inflammatory drugs; and (3) the "adjuvant" analgesics, which comprise a collection of chemically and pharmacologically diverse drugs. Adjuvant analgesics can be used to enhance the analgesic effects of the narcotics (for example, methotrimeprazine, dextroamphetamine, hydroxyzine, and amitriptyline) or they may be of value in the management of certain painful states (for example, carbamazepine, phenytoin, fluphenazine, tricyclic antidepressants, and steroids) [2]. In this review, I will discuss the selection and use of narcotic-type analgesics with special reference to their use in managing chronic cancer pain. A complete approach to the management of chronic pain requires an assessment of the psychologic factors contributing to the patient's perception of pain. Neurosurgical, anesthesiologic, and/or behavioral procedures may also be indicated. A discussion of these approaches is beyond the scope of this review; however, Posner and Addison have addressed the psychologic factors in their presentations elsewhere in this symposium issue. CLASSIFICATION OF NARCOTIC-TYPE ANALGESICS
From the Department of Pharmacology, Cornell University Medical College, New York, New York. Requests for reprints should be addressed to Dr. Charles E. lnturrisi, Department of Pharmacology, Cornell University Medical College, and Analgesic Studies Section, Memorial Sloan Kettering Cancer Center, Room E-305, 1300 York Avenue, New York, New York 10021 .
A convenient, if not completely satisfactory, classification for the narcotictype analgesics is based on the belief that the intensity of pain, rather than its specific etiology, should determine the analgesic suitable for a particular patient. In Table I are given the narcotic-type analgesics commonly used by the oral route for the relief of mild to moderate pain, whereas in Table II are listed the properties of the narcotic-type analgesics commonly used for severe pain. Within this classification system, there are three groups of narcotic-type analgesics: the morphine-like agonists, the mixed agonist-antagonists, and the partial agonists.
September 10, 1984
The American Journal of Medicine
27
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
TABLE I
Narcotic-Type Analgesics Commonly Used Orally for Mild to Moderate Pain Compared with Aspirin (650 mg)*
Name
Equi-Analgesic Doset (mg)
Peak* (hours)
Duration* (hours)
Comments
Precautions
Morphine-like agonists Codeine
32-65
Oxycodone Meperidine
Propoxyphene
Propoxyphene napsylate
1.5-2
5
50
1-1.5
4-6
3-4 4-5
65-130
Like codeine
100-200
Like codeine
50
Like codeine
"Weak" morphine, often used in combination with non-narcotic an~lgesics; biotransformed, in part, to morphine See Table II Biotransformed to normeperidine, a toxic metabolite
"Weak" narcotic; often used in combination with non-narcotic analgesics; long halflife, biotransformed to potentially toxic metabolite (norpropoxyphene)
Impaired ventilation, bronchial asthma, increased intracranial pressure
Like codeine Normeperidine accumulates with repetitive dosing causing central nervous system excitation; not for patients with impaired renal function or receiving monoamine oxidase inhibitors Propoxyphene and metabolite accumulate with repetitive dosing; overdose complicated by convulsions
Mixed agonist-antagonist Pentazocine
In combination with non-narcotics; in combination with naloxone to discourage parenteral abuse
May cause psychotomimetic effects; may precipitate withdrawal in narcoticdependent patients
•Adapted from [3). tThese doses are recommended starting doses from which the optimal dose for each patient is determined by titration and the maximal dose · limited by adverse effects. *Peak time and duration of analgesia are based on mean values and refer to the stated equi-analgesic doses.
The morphine-like agonists are all morphine surrogates that qualitatively mimic the pharmacologic profile of morphine, including desirable and adverse effects. Meperidine, methadone, levorphanol, heroin, and codeine are examples of morphine-like agonists. The mixed agonistantagonists include pentazocine, butorphanol, and nalbuphine. When administered to patients with pain who have limited prior experience with narcotics, they produce analgesia and other narcotic effects characteristic of morphine. However, there appears to be a ceiling on the capacity of mixed agonist-antagonists to produce respiratory depression. This class of drugs is considered to have a significantly lower abuse liability than the morphine-like agonists. They are not, however, devoid of abuse liability, as evidenced by the fact that pentazocine has been placed in Schedule IV as a controlled substance. Like the mixed agonist-antagonists, the partial agonist, buprenorphine, has less abuse liability than the morphinelike drugs and may precipitate narcotic withdrawal in dependent patients. However, buprenorphine does not produce psychotomimetic effects that can be seen with the mixed agonist-antagonists. It is currently marketed in the United Kingdom and should soon be available for use in this country. 28
September 10, 1984
The American Journal of Medicine
CLINICAL PHARMACOLOGY OF MORPHINE
The narcotic-type analgesics, as typified by morphine, are capable of producing analgesia over a wide range of doses. The analgesic action of morphine is relatively selective; pain may be relieved without the loss of other sensory modalities. Fully effective doses, however, may produce some alterations in consciousness or behavior. Clinically, morphine-induced analgesia does not appear to have a "ceiling effect." That is, as the dose is increased on a logarithmic scale, the increment in analgesia appears to be linear, virtually to the point of loss of consciousness. It is important to note that before loss of consciousness occurs, undesirable effects-notably sedation, mental clouding, nausea and vomiting, and/or respiratory depression-may impose a practical limit on the dose that is useful for any given patient. In usual therapeutic doses, the narcotic-type analgesics do not completely erase the patient's perception of pain. Instead, they change the affective interpretation of the painful experience. Although the patient may report a continued awareness of pain, it has lost much of its distressing quality. The similarities in the pharmacologic properties of the narcotic-type analgesics result from their shared ability to
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
TABLE II
Narcotic Type Analgesics Commonly Used for Severe Pain*
Name
Route
Morphine-like agonists Intramuscular Morphine Oral
Equi-Analgesic Doset (mg)
Peak* (hours)
Duration* (hours)
10 60
0.5-1 1.5-2
4-6 4-7
0.5-1 1-2
4-5 4-6
Meperidine
Intramuscular Oral
75 300§
Methadone
Intramuscular
10
Levorphanol
Oral Intramuscular
20 2
Oxycodone
Oral Oral
4 30§
Intramuscular Oral
(60)
Heroin
5
Hydromorphone
Intramuscular
1.5
Oxymorphone
Oral Intramuscular
7.5 1
Codeine
Intramuscular
130
Oral
200§
Mixed agonist-antagonists Pentazocine Intramuscular Oral
60 180
Like intramuscular morphine Like oral morphine Like intramuscular morphine Like oral morphine 4-6 1
0.5-1 4-5 Like oral morphine
Like intramuscular heroin Like oral morphine Like intramuscular morphine Like intramuscular morphine
Comments
Precautions
Standard of comparison for narcotic type analgesics Slightly shorter acting; moderate to poor oral potency; biotransformed to normeperidine, a toxic metabolite Good oral potency, long plasma half-life Like methadone
Impaired ventilation, bronchial asthma, increased intracranial pressure, liver failure Normeperidine accumulates with repetitive dosing causing central nervous system excitation; not for patients with impaired renal function or receiving monoamine oxidase inhibitors Like morphine, may accumulate with repetitive dosing causing excessive sedation Like methadone
Also available (5 mg doses) in combination with acetaminophen (Percocet) or aspirin (Percodan) which limits dose escalation Slightly shorter acting; biotransformed to active metabolites (e.g., morphine); not available in U.S. Like heroin
Like morphine
Like morphine
Like morphine
Like morphine
Like morphine
Like morphine
Like morphine
Excellent oral potency (see Table I) Like intramuscular morphine Like oral morphine
Mixed agonist-antagonist; less abuse liability than morphine; included in Schedule IV of Controlled Substances Act Like pentazocine but not scheduled
Nalbuphine
Intramuscular
10
Like intramuscular morphine
Butorphanol
Intramuscular
2
Like intramuscular morphine
Like nalbuphine
Partial agonist Buprenorphine
Intramuscular
0.4
Sublingual
0.8
Like intramuscular morphine 2-3 5-6
Partial agonist of the morphine type, less abuse liability than morphine, does not produce psychotomimetic effects, not yet available in U.S.
May cause psychotomimetic effects; may precipitate withdrawal in narcoticdependent patients; not for myocardial infarction Incidence of psychotomimetic effects lower than with pentazocine Like pentazocine
May precipitate withdrawal in narcotic-dependent patients
*Adapted from [3). tThese doses are recommended starting doses from which the optimal dose for each patient is determined by titration and the maximal dose limited by adverse effects. *Peak time and duration of analgesia are based on mean values and refer to the stated equi-analgesic do.ses. §Initial oral doses of these drugs are usually given for less severe pain (see Table 1).
September 10, 1984
The American Journal of Medicine
29
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
bind to stereo-specific opioid receptors located in the brain and spinal cord. The differences in effects among these drugs are believed to be due to the availability of several types of opioid receptors for which the three groups of narcotic-type analgesics have different affinities. As a result, the narcotic-type analgesics differ substantially from one another in a number of characteristics [3]. Important among these are differences in relative analgesic potency, peak and duration of analgesia, and oral potency, which are subsequently discussed. Relative Analgesic Potency. Although narcotic-type analgesics differ in analgesic potency by a factor of nearly 200 (0.4 mg of intramuscular buprenorphine is approximately equi-analgesic to 75 mg of intramuscular meperidine), it is important to remember that, as far as we can tell from controlled clinical trials, the drugs listed in Table II are equal in analgesic efficacy. Therefore, by increasing the dose of a less potent narcotic, one can achieve the same analgesia (equi-effective dose) as that produced by a more potent narcotic-type analgesic. In contrast, if we were to compare the ability of morphine and aspirin to relieve severe cancer pain, we would conclude not only that morphine is more potent than aspirin, but also, more importantly, that morphine possesses the potential for exerting a much greater maximal analgesic effect, that is, it has greater analgesic efficacy than aspirin. Relative potency estimates provide a rational basis for selecting the appropriate dose when initiating analgesic therapy, changing the route of administration, or switching to another narcotic. Table II lists the best estimates of the equi-analgesic doses for narcotic-type analgesics as compared to morphine. It should be emphasized that the equi-analgesic dose is the recommended starting dose, the optimal dose for each patient being determined by titration. Individualization of analgesic dose is the rule rather than the exception. Peak and Duration of Analgesia. The time-action curve of a narcotic analgesic involves a number of factors, including the dose, the intensity of pain, the criteria for analgesia, individual pharmacokinetic variation (the patient's ability to absorb, distribute, biotransform, and eliminate the drug), and the patient's prior experience with narcotics. Therefore, rather than an absolute expression for time-action, the appropriate comparison, as shown in Table II, is the relative duration of action for each analgesic at the dose that produces a peak effect equivalent to that of morphine. When compared in this manner, no parenteral analgesic has a longer duration of action than morphine; meperidine, heroin, and hydromorphone appear, on the average, to be slightly shorter acting. A longer duration of action provides a longer pain-free interval, allowing the patient more freedom in daily activities and possibly providing uninterrupted sleep. Oral Potency. In the management of chronic cancer pain, the oral route of drug administration avoids the dis-
30
September 10, 1984
The American Journal of Medicine
·comfort and potential complications of repeated injections, is more convenient, and can provide a smooth curve of action. However, the narcotics differ substantially with respect to their presystemic elimination-the degree to which they are inactivated as they are absorbed from the gastrointestinal tract and pass through the liver into the systemic circulation. As indicated in Table II, morphine, heroin, hydromorphone, and oxymorphone have ratios of oral to intramuscular potency of 1 to 5 to 1 to 12. Methadone, levorphanol, and oxycodone are subject to less presystemic elimination, resulting in an oral-to-intramuscular potency ratio of at least 1 to 2. Meperidine and pentazocine have intermediate ratios. The failure to recognize these differences often results in a substantial reduction in analgesia when the change from parenteral to oral administration is attempted without upward titration of the dose. Consideration of the oral-to-intramuscular potency ratios in Table II provides the starting point for dose titration. Although morphine and heroin are much less potent when administered orally than when administered by injection, the use of oral solutions of these drugs has enjoyed some popularity in Great Britain and Canada as a method of controlling pain in patients with terminal cancer [4,5]. More recently, controlled studies by Twycross [6] revealed that oral heroin had no advantage over oral morphine and that in most patients a simple aqueous solution of morphine was preferable to "euphoriant elixirs" such as the Brompton cocktail. Furthermore, pharmacokinetic studies comparing oral heroin and morphine in cancer patients have demonstrated that oral heroin is completely biotransformed to morphine prior to systemic absorption, making oral heroin an inefficient method of giving oral morphine [7]. One of the factors considered important by Twycross [8] and Walsh [9] for successful pain control with oral morphine was regular administration, as opposed to "PRN" demand scheduling, in doses sufficient to prevent pain from recurring. Although doses of oral morphine as high as 90 mg every four hours were sometimes needed, the daily amount of drug taken on this regimen was found to be less than that required by conventional on-demand schedules. In patients who are being taken care of at home and are not being closely monitored, one must weigh the advantages of this approach against the risks of masking warnings of serious complications such as cord compression. If not treated promptly, this type of complication may cause the patient irreversible injury and additional suffering [1 0]. Adverse Effects. The narcotic-type analgesics share with morphine the ability to produce a number of adverse effects including respiratory depression, sedation and drowsiness, nausea and vomiting, constipation, and spasm of the biliary and urinary tracts. Respiratory depression is the most serious adverse effect of these drugs. The morphine-like agonists act on brain stem respiratory centers to produce, as a function of dose, increasing res-
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
piratory depression to the point of apnea. In human subjects, death due to overdose of a morphine-like agonist is nearly always due to respiratory arrest. Therapeutic doses of morphine may initially depress all phases of respiratory activity-rate, minute volume, and tidal exchange. However, as carbon dioxide accumulates, it stimulates the respiratory center, resulting in a compensatory increase in respiratory rate that masks the degree of respiratory depression. In equi-analgesic doses, the morphine-like agonists produce an equivalent degree of respiratory depression. For these reasons, people with impaired respiratory function or bronchial asthma are at greatest risk of experiencing clinically significant respiratory depression in response to usual doses of these drugs. Respiratory depression and carbon dioxide retention result in cerebral vasodilation and an increase in cerebrospinal fluid pressure unless carbon dioxide saturation is maintained at normal levels by artificial ventilation (see Precautions, Table II). The treatment of narcotic-induced respiratory depression is discussed later. The dose-response characteristics of the respiratory depression curves of the mixed agonist-antagonists (pentazocine, nalbuphine, and butorphanol) and the partial agonist, buprenorphine, appear to differ from those of the morphine-like drugs. Although therapeutic doses of pentazocine produce respiratory depression equivalent to that produced by morphine, increasing the dose does not ordinarily produce a proportional increase in respiratory depression. Whether this apparent ceiling to respiratory depression offers any clinical advantage is still to be determined. Also, the clinical symptoms of respiratory depression that result from a large overdose of these drugs have not been well defined [11]. In addition to respiratory depression, the narcotic-type analgesics produce sedation and drowsiness. These effects may be useful in certain clinical situations such as preanesthesia, but they are not usually desirable concomitants of analgesia, particularly in ambulatory patients. The central nervous system depressant actions of these drugs can be expected to potentiate the sedative and respiratory depressant effects of sedative-hypnotics, such as alcohol and the barbiturates. Although it has been suggested that methadone produces more sedation than morphine, this has not been supported either by singledose controlled trials [12] or by surveys in hospitalized patients [13]. However, the half-life of methadone is substantially longer than that of morphine, and this could result in cumulative central nervous system depression after the administration of repeated doses for pain. The narcotic-type analgesics also produce nausea and vomiting by acting on the medullary chemoreceptor trigger zone. The incidence of nausea and vomiting is markedly increased in ambulatory patients, suggesting that these drugs also alter vestibular sensitivity. The most common adverse effect of the narcotic-type
analgesics is constipation [11]. These drugs act at multiple sites in the gastrointestinal tract and spinal cord to produce a decrease in intestinal secretions and peristalsis, resulting in a dry stool and constipation. Tolerance develops slowly to the smooth muscle effects of narcotics so that constipation will persist when these drugs are used to treat chronic pain. Narcotic-type analgesics increase smooth muscle tone and can cause bladder spasm and an increase in sphincter tone leading to urinary retention. Biliary tract spasms produced by these drugs can cause a marked increase in pressure in the biliary tract. Clinical studies suggest that equi-analgesic doses of meperidine may produce less biliary spasm than morphine [11]. Fortunately, the effects of the narcotic-type analgesics on the cardiovascular system are generally benign. Morphine causes a decrease in peripheral resistance and an increased capacity of the peripheral vascular compartment (peripheral pooling of blood), resulting in orthostatic hypotension and fainting. These same cardiovascular effects reduce the work load on the heart and, together with the anti-anxiety action of morphine, are believed to be responsible for the efficacy of morphine in relieving the dyspnea of pulmonary edema secondary to acute, leftsided heart failure. Furthermore, by virtue of the ability to decrease myocardial oxygen consumption, cardiac index, left ventricular end-diastolic pressure, and cardiac work, morphine can relieve the severe pain of acute myocardial infarction without producing undesirable cardiovascular effects. The cardiovascular responses to pentazocine and butorphanol differ somewhat from those described for morphine. Pentazocine increases aortic systolic pressure, left ventricular end-diastolic pressure, and mean pulmonary artery pressure, causing an increase in cardiac work. Thus, morphine is the drug of choice for use in patients with an acute myocardial infarction. Repeated administration of large parenteral doses of meperidine (250 mg or more per day) results in the accumulation of normeperidine, a toxic metabolite [14]. This accumulation occurs most rapidly in patients with compromised renal function. Normeperidine-induced toxicity is characterized by central nervous system excitation, including shaky feelings, tremors, twitches, and/or convulsions [14, 15]. The concurrent administration of monoamine oxidase inhibitors and meperidine has been reported to result in severe reactions and even death [16]. Toxic doses of propoxyphene not only produce central nervous system and respiratory depression but also lead to central nervous system excitation that can be manifested as convulsions [17]. The mixed agonist-antagonists produce certain self-limiting psychotomimetic effects not seen with other narcotic-type analgesics. Pentazocine seems to be the worst offender, and nalbuphine the least likely to produce these effects [18]. The properties of the narcotic-type analgesics that are most likely to lead to their being misused, or the patient
September 10, 1984
The American Journal of Medicine
31
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
treated incorrectly, are effects mediated in the central nervous system. These effects are seen following longterm administration and include psychologic dependence, physical dependence, and tolerance. It must be emphasized that even though the development of physical dependence and tolerance are predictable pharmacologic effects seen both in human subjects and in laboratory animals in response to repeated administration of a narcotic, these effects are distinct from psychologic dependence or addiction, the behavioral pattern seen in some subjects. Psychologic dependence is a pattern of drug use characterized by a continued craving for a narcotic. The craving is manifested as compulsive drug-seeking behavior, leading to an overwhelming involvement with the use and procurement of the drug. Anyone who is addicted to narcotics is likely to be physically dependent. However, the term "addiction" cannot be used interchangeably with physical dependence. Thus, it is possible to be physically dependent on a narcotic-type analgesic without being addicted. Fear of addiction leads to the use of inadequate doses of narcotics in hospitalized patients experiencing pain [19]. Some patients are reluctant to take even small doses of narcotics for fear of becoming addicted and will refuse medication. However, studies have shown that when narcotics are properly administered, addiction is rare. Recent surveys of hospitalized medical patients [20] and an analysis of the patterns of drug intake in cancer patients receiving long-term narcotic therapy [21] suggest that medical use of narcotics rarely, if ever, leads to drug abuse or iatrogenic addiction. Physical dependence is manifest by the appearance of withdrawal signs and symptoms characteristic of the well-known abstinence syndrome that occur when a narcotic is abruptly discontinued or when a narcotic antagonist is administered. The severity of withdrawal is a function of the dose and the duration of administration of the narcotic that has been discontinued (that is, the patient's prior narcotic experience). The administration of a narcotic antagonist to a physically dependent patient produces an immediate precipitation of the withdrawal syndrome. Patients who have received repeated doses of a morphine-like agonist to the point of physical dependence may experience a narcotic withdrawal reaction when given a mixed agonist-antagonist. That is, prior exposure to a morphine-like drug can be shown to greatly increase a patient's sensitivity to the antagonist component of a mixed agonist-antagonist [18,22]. Therefore, when used for chronic pain, the mixed agonist-antagonist should be tried before initiating prolonged administration of a morphine-like drug. Tolerance can be said to have developed when a larger dose of a drug is required to maintain the original effect. Tolerance to and physical dependence on the narcotictype analgesics seem to develop on a parallel time course. In a patient who requires an increase in dose to maintain analgesia, that is, a patient who has become tol-
32
September 10, 1984
The American Journal of Medicine
erant, a narcotic-type analgesic should not be abruptly withdrawn even if the patient's pain is suddenly alleviated. It has been suggested that the rate of development of tolerance to the analgesic effect of the mixed agonist-antagonists is slower than that seen with the morphine-like drugs [6,38]. If this observation is confirmed, it would provide the agonist-antagonists with a significant advantage over the morphine-like drugs. GUIDELINES FOR USE OF NARCOTIC-TYPE ANALGESICS IN PATIENTS WITH CANCER
In patients with cancer, the initial goal of effective pain management is to enable the patient to tolerate the diagnostic and therapeutic procedures required to assess and treat the cause of pain. If treating the suspected cause of the pain does not prove effective, symptomatic treatment of pain is begun and is aimed at allowing the patient to remain as functional as possible. This approach emphasizes individualization of therapy. For a more detailed discussion of the guidelines offered here, see Foley [23] and lnturrisi and Foley [3]. Treat the Patient, Not the Symptom. By taking a careful history and performing a thorough physical and neurologic examination, the physician can view the pain complaint within the context of the total evaluation of the patient. Pain treatment-both during the evaluation and after the nature of the pain is understood-does not stop with a prescription; it requires a commitment on the part of the physician and the pain management team to help the patient in achieving adequate pain control. Start with an Analgesic with the Potential to Provide Relief. Selecting a narcotic-type analgesic requires an estimate of the intensity and duration of pain as well as a knowledge of the patient's prior narcotic history. In patients with acute severe pain, parenteral morphine is the drug of choice, unless contraindicated. In patients with mild to moderate pain, an oral analgesic is the appropriate choice (Table 1). If the patient seeking pain relief has found that non-narcotic analgesics do not provide adequate analgesia, advantages can be gained by administering one of the narcotic-type analgesics listed in Table I in combination with a non-narcotic analgesic. For chronic severe pain, the oral route is preferred. Oxycodone, levorphanol, and methadone have good oral potency (Table II). At present, the choice of an oral mixed agonist-antagonist is limited to pentazocine. Know the Pharmacology of the Analgesic. It is essential that the physician has a thorough knowledge of the type of narcotic to be used, the starting analgesic dose for the route of administration chosen, and the peak time and duration of analgesia for the drug, dose, and route selected. In general, orally administered narcotics have a slower onset of action, delayed peak time, and a [onger duration of effect, whereas drugs administered parenterally have a rapid onset of action but a shorter duration of
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
effect. The narcotic-type analgesics differ in their pharmacokinetic characteristics as represented by their plasma elimination half-lives. Methadone, levorphanol, and propoxyphene have relatively long half-lives compared with that of morphine (Table Ill). It is obvious that their relatively longer half-lives are not reflected in the duration of analgesia seen after the administration of a single dose. However, these drugs with longer half-lives will accumulate with repetitive dosing. Therefore, some adjustment of dose and interval may be necessary to prevent excessive sedation. Patients with cirrhosis, renal disease, and patients older than 50 years of age have been reported to exhibit increased central nervous system sensitivity to narcotic-type analgesics (see Table IV) [3]. Administer Analgesics Regularly. For chronic pain, narcotic-type analgesics should be administered on a regular basis that will, if necessary, include awakening the patient. This approach can help to prevent severe pain from recurring and may allow for a reduction in the total amount of drug required per day. There is a caveat: this use of regularly scheduled narcotics may mask warnings of serious complications, as already discussed. Recognize and Treat Adverse Effects Appropriately. The adverse effects of the narcotic-type analgesics that most often limit their use are sedation, nausea and vomiting, constipation, and respiratory depression. Reducing the dose and the interval between doses so that a lower dose is given more frequently may counteract excessive sedation. In addition, other central nervous system depressants-including sedative-hypnotics and anti-anxiety agents that potentiate the sedative effects of narcoticsshould be discontinued. Concurrent administration of dextroamphetamine has been reported to reduce the sedative effects of narcotics [24]. The ability of narcotic-type analgesics to produce nausea and vomiting appears to vary with the drug and the patient; some advantage may result from switching to an equi-analgesic dose of another narcotic. Alternately, an anti-emetic may be used in combination with the narcotic. To prevent constipation, provisions for a regular bowel regimen, including cathartics and stool
TABLE IV
TABLE Ill
Plasma Half-Life Values for Narcotic-Type Analgesics* Drug
Plasma Half-Life (hours)
Morphine Meperidine Normeperidine Methadone Levorphanol Heroint Hydromorphone Pentazocine Nalbuphine Butorphanol Codeine Propoxyphene Norpropoxyphene
2-3.5 3-4 14-21 15-30 12-16 0.05 2-3 2-3
5 2.5-3.5
3 12 30-40
*Adapted from [5). tBiotransformed to acetylmorphine and morphine.
softeners, should be instituted when the use of narcotictype analgesics is begun. Respiratory depression occurs most commonly following initial administration of a narcotic. It is associated with other signs of central nervous system depression, including sedation and mental clouding. Tolerance develops rapidly to this effect with repeated administration of the drug, allowing the narcotic-type analgesics to be used in the management of chronic cancer pain without significant risk of respiratory depression. If respiratory depression occurs, it can be reversed by the administration of the specific narcotic antagonist, naloxone. In patients with respiratory failure who have received narcotics over a prolonged period, naloxone diluted 1:10 should be titrated carefully to prevent the precipitation of severe withdrawal symptoms while the respiratory depression is being reversed. In certain patients, the use of naloxone to reverse drug-induced respiratory depression can be dangerous. To prevent aspiration-associated respiratory compromise with excessive salivation and bronchial spasm, an endotracheal tube should be placed in a comatose patient be-
Undesirable Drug or Disease Interactions of Narcotic-Type Analgesics Drug
Interaction
Result
Meperidine Pentazocine Propoxyphene Meperidine Propoxyphene Morphine Meperidine Methadone Meperidine Any narcotic
Cirrhosis Cirrhosis Cirrhosis Renal failure Renal failure Older than 50 years Phenytoin Rifampin Monoamine oxidase inhibitors Alcohol or other central nervous· system depressants
t Bioavailability and t clearance = accumulation j Bioavailability and t clearance = accumulation t Bioavailability and t clearance = accumulation t Normeperidine, a toxic metabolite = accumulation t Norpropoxyphene, a toxic metabolite = accumulation t Clearance = accumulation t Biotransformation = faster elimination t Biotransformation = faster elimination Excitation, hyperpyrexia, and convulsions Enhanced depressant effects
September 10, 1984
The American Journal of Medicine
33
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
fore naloxone is administered. In patients receiving meperidine long-term, naloxone may precipitate seizures by lowering the seizure threshold and allowing the convulsant activity of the active metabolite, normeperidine, to become evident [14,15]. If naloxone is to be used in these patients, diluted doses, slowly titrated, should be used, and appropriate seizure precautions are advised. Give Each Analgesic an Adequate Trial. To fully assess whether a drug can produce analgesia in a particular patient, the dose should be increased until limiting adverse effects can be seen before switching to an alternate. Use Drug Combinations That Will Enhance Analgesia. In combination, the analgesic effects of the non-narcotic analgesics, aspirin and acetaminophen, are additive with those of narcotic-type analgesics. A good rule to follow, if possible, is to give a non-narcotic with a narcotic analgesic. This not only will provide better analgesia but also will slow the rate of the development of tolerance since tolerance develops only to the narcotic analgesic portion of the dose. Cancer patients, particularly those receiving chemotherapy, have coagulation defects and should avoid aspirin and aspirin-containing preparations such as oxycodone hydrochloride plus aspirin. Acetaminophen is a suitable aspirin substitute in these patients. Other drugs that have been shown in controlled clinical trials to enhance analgesia when used in combination with a narcotic-type analgesic include the following: methotrimeprazine [25], dextroamphetamine [24], and hydroxyzine [26]. Anecdotal evidence suggests that the administration of amitriptyline at bedtime may improve pain management in cancer patients. Watch for the Development of Tolerance. Tolerance appears to develop in all patients receiving narcotic-type analgesics over a prolonged period. The hallmark sign of the development of tolerance is the patient's complaint of a decrease in the duration of effective analgesia. For reasons not yet understood, the rate of development of tolerance varies greatly among cancer patients; some will demonstrate tolerance within days after narcotic therapy is initiated, whereas others will have good control for many months on the same dose. A sudden dramatic increase in narcotic requirements may represent a progression of the cancer rather than the development of tolerance per se [21]. In these patients, objective evidence of progression of disease should be sought and pain management techniques reevaluated accordingly. With the development of tolerance, an increase in the frequency and/or the dose of the narcotic is required to provide continued pain relief. Since the analgesic effect is a logarithmic function of the dose of narcotic, a doubling of the dose may be required to restore full analgesia. There appears to be no limit to the development of tolerance, and with appropriate adjustment of dose, patients can continue to obtain pain relief. In cancer patients with severe pain, narcotic-type anal-
34
September 10, 1984
The American Journal of Medicine
gesics should not be used sparingly or "saved to the last" because of the fear that an increasing narcotic requirement represents a "loss of control." A number of strategies can be used to forestall the development of tolerance in patients with chronic cancer pain. Since tolerance development is a function of the dose and the frequency of administration, it is not surprising that continuous intravenous administration of narcotics results in the rapid development of tolerance. For this and other reasons already cited, the oral route of administration is preferred. When the oral route cannot be used, the alternative is parenteral administration. In the tolerant patient, the availability of a suitable parenteral dosage form-that can provide adequate pain relief without the necessity of injecting an unreasonably large volume of solution into a cachectic patient-may greatly restrict the drug choice. Solubility considerations preclude the administration of morphine concentrations greater than 65 mg/ml [18]. Hydromorphone, which is approximately five times more soluble and nearly seven times more potent than morphine and recently available in a 10 mg/ml parenteral dose form, can provide the flexibility required for dose titration in the tolerant patient. As already discussed, combining narcotics with non-narcotics can enhance analgesia and slow the rate of development of tolerance. From the start, a nonnarcotic such as acetaminophen should be used with the narcotic. In the tolerant patient, methotrimeprazine-a nonopioid analgesic-can be substituted for part of the narcotic analgesic requirement. However, methotrimeprazine can produce excessive sedation and postural hypotension, which may limit its use to patients who must remain in bed. Cross-tolerance among the narcotictype analgesics appears not to be complete. Therefore, an advantage can be gained by switching to an alternate narcotic and selecting half the predicted equi-analgesic dose (given in Table I) as the starting dose. Be Aware of the Development of Physical Dependence and Prevent Withdrawal. The abrupt discontinuation of a narcotic-type analgesic in a patient with significant prior narcotic experience will result in signs and symptoms of the narcotic withdrawal or abstinence syndrome [27]. The onset of withdrawal is characterized by the patient's reporting feelings of anxiety, nervousness, and irritability, and the patient's experiencing alternating chills and hot flushes. Prominent withdrawal signs are "wetness"-salivation, lacrimation, rhinorrhea, and diaphoresis-and gooseflesh. At the peak intensity of withdrawal, patients may experience nausea and vomiting, abdominal cramps, insomnia, and, rarely, multifocal myoclonus. The time-course of the withdrawal syndrome is a function of the elimination half-life of the narcotic on which the patient has become dependent. Following cessation of a drug with a short half-life such as morphine, abstinence symptoms will appear within six to 12 hours and reach a peak at 24 to 72 hours. With methadone, a drug
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
with a long half-life, onset may be delayed for 36 to 48 hours. Therefore, it is important to emphasize that, even in a patient in whom pain has been completely relieved by a procedure (for example, cordotomy), it is necessary to slowly decrease the narcotic dose to prevent withdrawal. Experience indicates that the usual daily dose required to prevent withdrawal is equal to one-fourth of the previous daily dose. This dose, for want of a better term, is called the detoxification dose and is given in four divided doses. The initial detoxification dose is given for two days and then decreased by one-half (administered in four divided doses) for two days until a total daily dose of 10 to 15 mg a day of morphine, or an equivalent dose of another narcotic-type analgesic, is reached. After two days on this last dose, the narcotic can be discontinued [28]. Thus, a patient who had been receiving 240 mg a day of morphine for pain would require an initial detoxification dose of 60 mg given as 15 mg every six hours. Alternately, the patient may be switched to oral methadone for detoxification, using the data in Table II to calculate the equi-effective oral analgesic dose of methadone. Then use one-fourth of this dose as the initial detoxification dose and proceed as just described. As has been previously discussed, the substitution of a mixed agonist-antagonist (Table II) in a patient dependent on a morphine-like agonist will precipitate acute narcotic withdrawal and must be avoided.
Do Not Use Placebos to Assess the Type of Pain. Although its appropriate use is not widely recognized, the placebo response is a potent phenomenon in clinical medicine [29]. In a patient with pain, the relief of pain in response to the parenteral administration of saline solution suggests that this patient, in these specific circumstances, is a placebo-responder. Nothing more or less can be concluded. It does not indicate that the patient's pain is unreal, that is, "psychogenic," or less severe than reported by the patient. This misuse of the placebo response engenders distrust between the patient and the pain management team, which can interfere with adequate pain control. CONCLUSIONS
Administration of the narcotic-type analgesics is the most commonly employed method of managing pain due to cancer. These drugs are convenient to use, and their effects are prompt and reversible. It is necessary to have a working knowledge of their pharmacologic properties and their desirable and undesirable effects. The issues of tolerance, dependence and addiction, as they relate to the cancer patient in pain, should also be well understood. Guidelines have been presented for the selection and use of these drugs in cancer patients.
REFERENCES 1.
Houde RW: On assaying analgesics in man. In: Knighton RS, Dumke PR, eds. Pain, ed 1. Boston: Little, Brown, 1966; 183196. 2. Foley KM: Adjuvant analgesic drugs in the management of cancer pain. In: mediguide to pain, vol 4. New York: Lawrence Dellacorte Publications, 1983; 1-8. 3. lnturrisi CE, Foley KM: Narcotic analgesics in the management of pain. In: Kuhar M, Pasternak G, eds. analgesics: neurochemical, behavioral and clinical perspectives. New York: Raven Press, 1984; 257-288. 4. Twycross RG: Diamorphine and cocaine elixir BPC 1973. J Pharmacol 1974; 212: 153-159. 5. Mount BM, Ajemian I, Scott JF: Use of Brompton mixture in treating the chronic pain of malignant disease. Can Med Assoc J 1975; 1: 10-18. 6. Twycross RG: The Brompton cocktail. In: Bonica JJ, Ventafridda V, eds. advances in pain research and therapy, II. New York; Raven Press, 1979; 291-300. 7. lnturrisi CE, Max M, Foley KM, et al: The pharmacokinetics of heroin in patients with chronic pain. N Engl J Med 1984; 310: 1213-1217. 8. Twycross RG: Morphine and diamorphine in the terminally ill patient. Acta Anesthesiol Scand 1982; 74 (suppl): 128-134. 9. Walsh TO: Oral morphine in chronic cancer pain. Pain 1984; 18: 1-11. 10. Houde RW: Systemic analgesics and related drugs: narcotic analgesics. In: Bonica JJ, Ventafridda V, eds. Advances in pain research and therapy, II. New York; Raven Press, 1979, 263-273, 11. Jaffe JH, Martin WR: Opioid analgesics and antagonists. In: Gilman AG, Goodman AS, Gilman A, eds. The pharmacological basis of therapeutics, ed 6. New York: Macmillan Publishing, 1980; 494-534.
12.
13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
Beaver WT, Wallenstein SL, Houde RW, et al: A clinical comparison of the analgesic effects of methadone and morphine administered intramuscularly, and of orally and parenterally administered methadone. Clin Pharmacol Ther 1967; 8:415426. Miller RR: Clinical effects of parenteral narcotics in hospitalized medical patients. J Clin Pharmacol 1980; 20: 165-171. lnturrisi CE, Umans JG: Pethidine and its active metabolite, norpethidine. Clin in Anesthesiol1983; 1: 123-138. Kaiko RF, Foley KM, Grabinski PY, et al: Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol1983; 13: 180-185. Meyer D, Hallin V: Toxicity secondary to meperidine in patients on monoamine oxidase inhibitors: a case report and critical review. J Clin Psychopharmacol1981; 1:319-321. lnturrisi CE, Colburn WA, Verebey K, et al: Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene. Clin Pharmacol Ther 1982; 31: 157-167. Beaver WT: Management of cancer pain with parenteral medication. JAMA 1980; 244: 2653-2657. Marks RM, Sachar EJ: Undertreatment of medical inpatients with narcotic analgesics. Ann Intern Med 1973; 78: 173-181. Porter J, Jick H: Addiction rare in patients treated with narcotics. N Engl J Med 1980; 302: 123. Kanner RM, Foley KM: Patterns of narcotic drug use in a cancer pain clinic. Ann NY Acad Sci 1981; 362: 161-172. Houde RW: Analgesic effectiveness of the narcotic agonist-antagonists. Br J Clin Pharmacol 1979; 7 (suppl): 297-308. Foley KM: The practical use of narcotic analgesics. In Reidenberg MM, ed. The medical clinics of North America. Philadelphia: WB Saunders, 1982; 1091-1104. Forrest WH Jr, Brown BW Jr, Brown CR, et al: Dextroamphetamine with morphine for treatment of postoperative pain. N
September 10, 1984
The American Journal of Medicine
35
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
25.
Engl J Med 1977; 296: 712-715. Lasagna L, Dekornfeld JJ: Methotrimeprazine: a new phenothiazine derivative with analgetic properties. JAMA 1961; 178:
27.
Jaffe JH: Drug addiction and drug abuse. In: Gilman AG, Goodman AS, Gilman A, eds. The pharmacological basis of therapeutics, ed 6. New York: Macmillan Publishing, 1980; 535-
28.
Rogers AG: 21 problems in pain control-and ways to solve them. Your Patient & Cancer 1981; Sept: 65-75. Goodman JS, Goodman JM, Vogel AV: Knowledge and use of placebos by house officers and nurses. Ann Intern Med 1979;
887-890. 26.
584.
Beaver WT, Freise G: Comparison of the analgesic effects of morphine, hydroxyzine and their combination in patients·with postoperative pain. In: Bonica JJ, Albefessard D, eds. Advances in pain research and therapy. New York: Raven Press, 1976; 553-557.
29.
91: 106-110.
DISCUSSION
Dr. Howard Fields: You mentioned that the oral-to-parenteral ratio is different for different drugs. Will that generally be true for the nonanalgesic effects as well? Is it true for respiratory depressive effects, for example? Dr. William Beaver: Mainly from anecdotal experience, we have learned that, with certain drugs that produce active metabolites and have adverse effects, the oral-to-parenteral efficacy ratio may not be exactly the same as the oral-to-parenteral side effects ratio. For example, with pentazocine, one of its metabolites seems to be able to produce psychotomimetic side effects. You may see more psychotomimetic side effects when this drug is administered orally than when an equi-analgesic dose is administered parenterally because you get the first-pass biotransformation to this active metabolite. It would not surprise me at all if, with meperidine, you would observe the same phenomenon. If you tried to achieve high blood levels of meperidine by giving very large oral doses, you would get normeperidine accumulation with resultant normeperidine toxicity. Dr. Fields: Does tolerance develop more rapidly in patients receiving methadone as an analgesic? Dr. Charles lnturrisi: I have no reason to believe that occurs. My clinical impression is that there are a number of factors that contribute to the development of tolerance, including changes in disease state, which may exacerbate the situation. However, I know of no information that suggests that there are differential rates of development of tolerance among the morphine-like drugs. The only information that is available is from the Addiction Research Center and that would suggest that, with the morphine-like drugs, tolerance develops at about the same rate. When you look at the mixed agonist-antagonists, there seems to be some evidence that perhaps the development of tolerance to some of the morphine-like effects is somewhat slower. The question remains as to whether one could translate this into a slower development of tolerance to analgesia in a clinical situation. Dr. Beaver: I think that the inter-individual variation in the rate of tolerance development to apparently similar
36
September 10, 1984
The American Journal of Medicine
narcotic regimens is so large that it is extremely difficult to make generalizations about differences between drugs. You may have two patients on morphine-one goes for a very long time without much tolerance developing, and the other one requires repeated increases in dosage. Dr. lnturrisi: Another important issue is the relationship between the amount of narcotic analgesic used when the drug is given in fixed doses at regular intervals versus the amount used when as-needed administration is the rule. Dr. Beaver: This is a matter that repeatedly comes up for discussion, particularly in relation to hospices. It is claimed that you can use less narcotic if you give the medication "by the clock" rather than on demand. No controlled clinical studies have been carried out on this issue. Recently, giving narcotics by continuous intravenous infusion has become a popular practice. Last week I saw a patient who, in the course of six days, escalated from a dose-given by continuous intravenous infusion-of about 10 mg of morphine every two hours to 40 mg of morphine per hour. The resident thought that intravenous narcotics was the treatment of choice. The result of this practice may be very similar to what has been observed in animal studies when the investigator is deliberately trying to induce tolerance by keeping the opiate receptor occupied 24 hours a day, never allowing a return to a normal state. We took the patient off intravenous morphine and put him on spaced doses of hydromorphone hydrochloride, and he did quite well. This might actually have been a case of acute tolerance. Dr. Fields: You want to keep the patient free of pain, but, if you maintain high plasma drug levels, you hasten tolerance and lose the effectiveness of the drug. Dr. Robert Addison: I would like to discuss the difference between patients who come into a pain clinic and those who come into a drug abuse facility. In our experience, they seem to be two entirely different groups of people, and their handling of drugs is very dissimilar. One man who had back pain was taking 600 mg of meperidine every day, by injection, for a two-year period for his pain. I explained to him that one of the things we were going to
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
do was reduce his intake of meperidine. When he was admitted to the hospital three weeks later, I said, "Well, I want to reiterate that we are going to reduce your meperidine intake," and he said, "I stopped the day you told me you were not going to give me any more." Now, I am sure he had some sort of withdrawal symptoms, but the ease with which he related his stopping the medication impressed me. Dr. lnturrisi: I think this is clearly a function of the dose that a patient has been receiving and, to some degree, depends on how closely the patient is observed and what the patient knows about withdrawal. This patient may have thought that he had a rather severe cold. He also might have had an upset stomach and did not associate any of these symptoms with withdrawal. Whenever proper studies have been conducted, one can clearly demonstrate that meperidine is a drug of abuse that can produce physical dependence. Its short duration of action means that its effects dissipate very quickly. The implication is not that meperidine in a 600 mg daily dose would not produce physical dependency. There are a set of factors that argue against the patient reporting his symptoms as signs of withdrawal. Dr. Beaver: We have had experiences like this also. What we find, particularly in cancer patients, is that if you find some other way to relieve the pain-neurosurgery, peripheral nerve block, or another treatment-you can take the patients off narcotics relatively easily. They will have some signs of withdrawal but, given the dose that they have been accustomed to, they can be taken off the drug very'easily compared to the street addict. I think the big difference is the psychic dependence of the street addict, who reacts much more violently to a given level of somatic symptom in withdrawal. There is a significant psychic overlay on top of the physical withdrawal syndrome, making detoxification much more difficult. Dr. Addison: In any good detoxification program-and especially with the chronic pain patients-you should give the patients alternatives that are as satisfactory for them to look to as the medication itself.
Dr. Robert Posner: I now think that there is a role for narcotics in the management of intractable nonmalignant pain. Several of my patients with pain due to nerve injury or central nervous system injury get significant relief only with an opioid drug. They have been taking an opioid for years at the same dose. For them, it is very important and very helpful. It is necessary, however, to monitor whether the dose taken remains stable. Once the dose starts to increase, then you have to worry about tolerance. Dr. Stephen Silberstein: Does the use of tranquilizers in addition to narcotics potentiate the action of the narcotics, or is this fiction? Dr. lnturrisi: In general, the use of tranquilizers presents more problems than it solves. Tranquilizers tend to enhance the sedative effect more than they enhance the analgesic effect of a narcotic analgesic. Obviously, if you are treating a patient who has a psychiatric component to his or her pain, then tranquilizers may have a place. In general, I would say that the use of tranquilizers and the use of minor tranquilizers, like diazepam, is not beneficial. The patient does not get adequate pain relief and is very confused. I recommend stopping all medication in this instance, and starting from "square one" again with adequate doses of pain medication. Then, consider the other medications and determine whether they are of any value. Enlisting the Patient's Help in Selecting an Analgesic To enlist the patient's cooperation, communicate the following: • "I will be attentive to your complaints" • "I will believe what you tell me about the pain" • "While we are finding out what is causing your pain, we are going to treat the pain" • "Not all medications are alike; some will work for you and some will not" • "I would like to make a pact with you. First, we are going to try (name of medication), and I want you to tell me when it is working. If it does not work, we will try another medication until we find one that works for you"
September 10, 1984
The American Journal of Medicine
37
CHARLES E. INTURRISI, Ph.D. New York, New York
The clinical pharmacology of the narcotic-type analgesics is discussed in depth. Relative analgesic potency, peak and duration of analgesia, oral potency, and adverse effects are reviewed, with an emphasis on the clinical application of this knowledge. The differences among psychologic dependence, physical dependence, and tolerance are carefully delineated. Guidelines are provided for using narcotic-type analgesics in the management of patients with cancer. Analgesics are most commonly employed for relieving acute pain and play an important role in the management of certain patients with chronic pain. Although there are gaps in our knowledge of analgesic pharmacology, the rational and appropriate use of these drugs is based on the pharmacologic knowledge derived from well-controlled clinical trials [1]. The analgesic drugs may be separated into three broadly defined groups: (1) the narcotic-type analgesics (opioids); (2) the non-narcotic analgesics, which include aspirin, acetaminophen, and the nonsteroidal anti-inflammatory drugs; and (3) the "adjuvant" analgesics, which comprise a collection of chemically and pharmacologically diverse drugs. Adjuvant analgesics can be used to enhance the analgesic effects of the narcotics (for example, methotrimeprazine, dextroamphetamine, hydroxyzine, and amitriptyline) or they may be of value in the management of certain painful states (for example, carbamazepine, phenytoin, fluphenazine, tricyclic antidepressants, and steroids) [2]. In this review, I will discuss the selection and use of narcotic-type analgesics with special reference to their use in managing chronic cancer pain. A complete approach to the management of chronic pain requires an assessment of the psychologic factors contributing to the patient's perception of pain. Neurosurgical, anesthesiologic, and/or behavioral procedures may also be indicated. A discussion of these approaches is beyond the scope of this review; however, Posner and Addison have addressed the psychologic factors in their presentations elsewhere in this symposium issue. CLASSIFICATION OF NARCOTIC-TYPE ANALGESICS
From the Department of Pharmacology, Cornell University Medical College, New York, New York. Requests for reprints should be addressed to Dr. Charles E. lnturrisi, Department of Pharmacology, Cornell University Medical College, and Analgesic Studies Section, Memorial Sloan Kettering Cancer Center, Room E-305, 1300 York Avenue, New York, New York 10021 .
A convenient, if not completely satisfactory, classification for the narcotictype analgesics is based on the belief that the intensity of pain, rather than its specific etiology, should determine the analgesic suitable for a particular patient. In Table I are given the narcotic-type analgesics commonly used by the oral route for the relief of mild to moderate pain, whereas in Table II are listed the properties of the narcotic-type analgesics commonly used for severe pain. Within this classification system, there are three groups of narcotic-type analgesics: the morphine-like agonists, the mixed agonist-antagonists, and the partial agonists.
September 10, 1984
The American Journal of Medicine
27
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
TABLE I
Narcotic-Type Analgesics Commonly Used Orally for Mild to Moderate Pain Compared with Aspirin (650 mg)*
Name
Equi-Analgesic Doset (mg)
Peak* (hours)
Duration* (hours)
Comments
Precautions
Morphine-like agonists Codeine
32-65
Oxycodone Meperidine
Propoxyphene
Propoxyphene napsylate
1.5-2
5
50
1-1.5
4-6
3-4 4-5
65-130
Like codeine
100-200
Like codeine
50
Like codeine
"Weak" morphine, often used in combination with non-narcotic an~lgesics; biotransformed, in part, to morphine See Table II Biotransformed to normeperidine, a toxic metabolite
"Weak" narcotic; often used in combination with non-narcotic analgesics; long halflife, biotransformed to potentially toxic metabolite (norpropoxyphene)
Impaired ventilation, bronchial asthma, increased intracranial pressure
Like codeine Normeperidine accumulates with repetitive dosing causing central nervous system excitation; not for patients with impaired renal function or receiving monoamine oxidase inhibitors Propoxyphene and metabolite accumulate with repetitive dosing; overdose complicated by convulsions
Mixed agonist-antagonist Pentazocine
In combination with non-narcotics; in combination with naloxone to discourage parenteral abuse
May cause psychotomimetic effects; may precipitate withdrawal in narcoticdependent patients
•Adapted from [3). tThese doses are recommended starting doses from which the optimal dose for each patient is determined by titration and the maximal dose · limited by adverse effects. *Peak time and duration of analgesia are based on mean values and refer to the stated equi-analgesic doses.
The morphine-like agonists are all morphine surrogates that qualitatively mimic the pharmacologic profile of morphine, including desirable and adverse effects. Meperidine, methadone, levorphanol, heroin, and codeine are examples of morphine-like agonists. The mixed agonistantagonists include pentazocine, butorphanol, and nalbuphine. When administered to patients with pain who have limited prior experience with narcotics, they produce analgesia and other narcotic effects characteristic of morphine. However, there appears to be a ceiling on the capacity of mixed agonist-antagonists to produce respiratory depression. This class of drugs is considered to have a significantly lower abuse liability than the morphine-like agonists. They are not, however, devoid of abuse liability, as evidenced by the fact that pentazocine has been placed in Schedule IV as a controlled substance. Like the mixed agonist-antagonists, the partial agonist, buprenorphine, has less abuse liability than the morphinelike drugs and may precipitate narcotic withdrawal in dependent patients. However, buprenorphine does not produce psychotomimetic effects that can be seen with the mixed agonist-antagonists. It is currently marketed in the United Kingdom and should soon be available for use in this country. 28
September 10, 1984
The American Journal of Medicine
CLINICAL PHARMACOLOGY OF MORPHINE
The narcotic-type analgesics, as typified by morphine, are capable of producing analgesia over a wide range of doses. The analgesic action of morphine is relatively selective; pain may be relieved without the loss of other sensory modalities. Fully effective doses, however, may produce some alterations in consciousness or behavior. Clinically, morphine-induced analgesia does not appear to have a "ceiling effect." That is, as the dose is increased on a logarithmic scale, the increment in analgesia appears to be linear, virtually to the point of loss of consciousness. It is important to note that before loss of consciousness occurs, undesirable effects-notably sedation, mental clouding, nausea and vomiting, and/or respiratory depression-may impose a practical limit on the dose that is useful for any given patient. In usual therapeutic doses, the narcotic-type analgesics do not completely erase the patient's perception of pain. Instead, they change the affective interpretation of the painful experience. Although the patient may report a continued awareness of pain, it has lost much of its distressing quality. The similarities in the pharmacologic properties of the narcotic-type analgesics result from their shared ability to
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
TABLE II
Narcotic Type Analgesics Commonly Used for Severe Pain*
Name
Route
Morphine-like agonists Intramuscular Morphine Oral
Equi-Analgesic Doset (mg)
Peak* (hours)
Duration* (hours)
10 60
0.5-1 1.5-2
4-6 4-7
0.5-1 1-2
4-5 4-6
Meperidine
Intramuscular Oral
75 300§
Methadone
Intramuscular
10
Levorphanol
Oral Intramuscular
20 2
Oxycodone
Oral Oral
4 30§
Intramuscular Oral
(60)
Heroin
5
Hydromorphone
Intramuscular
1.5
Oxymorphone
Oral Intramuscular
7.5 1
Codeine
Intramuscular
130
Oral
200§
Mixed agonist-antagonists Pentazocine Intramuscular Oral
60 180
Like intramuscular morphine Like oral morphine Like intramuscular morphine Like oral morphine 4-6 1
0.5-1 4-5 Like oral morphine
Like intramuscular heroin Like oral morphine Like intramuscular morphine Like intramuscular morphine
Comments
Precautions
Standard of comparison for narcotic type analgesics Slightly shorter acting; moderate to poor oral potency; biotransformed to normeperidine, a toxic metabolite Good oral potency, long plasma half-life Like methadone
Impaired ventilation, bronchial asthma, increased intracranial pressure, liver failure Normeperidine accumulates with repetitive dosing causing central nervous system excitation; not for patients with impaired renal function or receiving monoamine oxidase inhibitors Like morphine, may accumulate with repetitive dosing causing excessive sedation Like methadone
Also available (5 mg doses) in combination with acetaminophen (Percocet) or aspirin (Percodan) which limits dose escalation Slightly shorter acting; biotransformed to active metabolites (e.g., morphine); not available in U.S. Like heroin
Like morphine
Like morphine
Like morphine
Like morphine
Like morphine
Like morphine
Like morphine
Excellent oral potency (see Table I) Like intramuscular morphine Like oral morphine
Mixed agonist-antagonist; less abuse liability than morphine; included in Schedule IV of Controlled Substances Act Like pentazocine but not scheduled
Nalbuphine
Intramuscular
10
Like intramuscular morphine
Butorphanol
Intramuscular
2
Like intramuscular morphine
Like nalbuphine
Partial agonist Buprenorphine
Intramuscular
0.4
Sublingual
0.8
Like intramuscular morphine 2-3 5-6
Partial agonist of the morphine type, less abuse liability than morphine, does not produce psychotomimetic effects, not yet available in U.S.
May cause psychotomimetic effects; may precipitate withdrawal in narcoticdependent patients; not for myocardial infarction Incidence of psychotomimetic effects lower than with pentazocine Like pentazocine
May precipitate withdrawal in narcotic-dependent patients
*Adapted from [3). tThese doses are recommended starting doses from which the optimal dose for each patient is determined by titration and the maximal dose limited by adverse effects. *Peak time and duration of analgesia are based on mean values and refer to the stated equi-analgesic do.ses. §Initial oral doses of these drugs are usually given for less severe pain (see Table 1).
September 10, 1984
The American Journal of Medicine
29
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
bind to stereo-specific opioid receptors located in the brain and spinal cord. The differences in effects among these drugs are believed to be due to the availability of several types of opioid receptors for which the three groups of narcotic-type analgesics have different affinities. As a result, the narcotic-type analgesics differ substantially from one another in a number of characteristics [3]. Important among these are differences in relative analgesic potency, peak and duration of analgesia, and oral potency, which are subsequently discussed. Relative Analgesic Potency. Although narcotic-type analgesics differ in analgesic potency by a factor of nearly 200 (0.4 mg of intramuscular buprenorphine is approximately equi-analgesic to 75 mg of intramuscular meperidine), it is important to remember that, as far as we can tell from controlled clinical trials, the drugs listed in Table II are equal in analgesic efficacy. Therefore, by increasing the dose of a less potent narcotic, one can achieve the same analgesia (equi-effective dose) as that produced by a more potent narcotic-type analgesic. In contrast, if we were to compare the ability of morphine and aspirin to relieve severe cancer pain, we would conclude not only that morphine is more potent than aspirin, but also, more importantly, that morphine possesses the potential for exerting a much greater maximal analgesic effect, that is, it has greater analgesic efficacy than aspirin. Relative potency estimates provide a rational basis for selecting the appropriate dose when initiating analgesic therapy, changing the route of administration, or switching to another narcotic. Table II lists the best estimates of the equi-analgesic doses for narcotic-type analgesics as compared to morphine. It should be emphasized that the equi-analgesic dose is the recommended starting dose, the optimal dose for each patient being determined by titration. Individualization of analgesic dose is the rule rather than the exception. Peak and Duration of Analgesia. The time-action curve of a narcotic analgesic involves a number of factors, including the dose, the intensity of pain, the criteria for analgesia, individual pharmacokinetic variation (the patient's ability to absorb, distribute, biotransform, and eliminate the drug), and the patient's prior experience with narcotics. Therefore, rather than an absolute expression for time-action, the appropriate comparison, as shown in Table II, is the relative duration of action for each analgesic at the dose that produces a peak effect equivalent to that of morphine. When compared in this manner, no parenteral analgesic has a longer duration of action than morphine; meperidine, heroin, and hydromorphone appear, on the average, to be slightly shorter acting. A longer duration of action provides a longer pain-free interval, allowing the patient more freedom in daily activities and possibly providing uninterrupted sleep. Oral Potency. In the management of chronic cancer pain, the oral route of drug administration avoids the dis-
30
September 10, 1984
The American Journal of Medicine
·comfort and potential complications of repeated injections, is more convenient, and can provide a smooth curve of action. However, the narcotics differ substantially with respect to their presystemic elimination-the degree to which they are inactivated as they are absorbed from the gastrointestinal tract and pass through the liver into the systemic circulation. As indicated in Table II, morphine, heroin, hydromorphone, and oxymorphone have ratios of oral to intramuscular potency of 1 to 5 to 1 to 12. Methadone, levorphanol, and oxycodone are subject to less presystemic elimination, resulting in an oral-to-intramuscular potency ratio of at least 1 to 2. Meperidine and pentazocine have intermediate ratios. The failure to recognize these differences often results in a substantial reduction in analgesia when the change from parenteral to oral administration is attempted without upward titration of the dose. Consideration of the oral-to-intramuscular potency ratios in Table II provides the starting point for dose titration. Although morphine and heroin are much less potent when administered orally than when administered by injection, the use of oral solutions of these drugs has enjoyed some popularity in Great Britain and Canada as a method of controlling pain in patients with terminal cancer [4,5]. More recently, controlled studies by Twycross [6] revealed that oral heroin had no advantage over oral morphine and that in most patients a simple aqueous solution of morphine was preferable to "euphoriant elixirs" such as the Brompton cocktail. Furthermore, pharmacokinetic studies comparing oral heroin and morphine in cancer patients have demonstrated that oral heroin is completely biotransformed to morphine prior to systemic absorption, making oral heroin an inefficient method of giving oral morphine [7]. One of the factors considered important by Twycross [8] and Walsh [9] for successful pain control with oral morphine was regular administration, as opposed to "PRN" demand scheduling, in doses sufficient to prevent pain from recurring. Although doses of oral morphine as high as 90 mg every four hours were sometimes needed, the daily amount of drug taken on this regimen was found to be less than that required by conventional on-demand schedules. In patients who are being taken care of at home and are not being closely monitored, one must weigh the advantages of this approach against the risks of masking warnings of serious complications such as cord compression. If not treated promptly, this type of complication may cause the patient irreversible injury and additional suffering [1 0]. Adverse Effects. The narcotic-type analgesics share with morphine the ability to produce a number of adverse effects including respiratory depression, sedation and drowsiness, nausea and vomiting, constipation, and spasm of the biliary and urinary tracts. Respiratory depression is the most serious adverse effect of these drugs. The morphine-like agonists act on brain stem respiratory centers to produce, as a function of dose, increasing res-
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
piratory depression to the point of apnea. In human subjects, death due to overdose of a morphine-like agonist is nearly always due to respiratory arrest. Therapeutic doses of morphine may initially depress all phases of respiratory activity-rate, minute volume, and tidal exchange. However, as carbon dioxide accumulates, it stimulates the respiratory center, resulting in a compensatory increase in respiratory rate that masks the degree of respiratory depression. In equi-analgesic doses, the morphine-like agonists produce an equivalent degree of respiratory depression. For these reasons, people with impaired respiratory function or bronchial asthma are at greatest risk of experiencing clinically significant respiratory depression in response to usual doses of these drugs. Respiratory depression and carbon dioxide retention result in cerebral vasodilation and an increase in cerebrospinal fluid pressure unless carbon dioxide saturation is maintained at normal levels by artificial ventilation (see Precautions, Table II). The treatment of narcotic-induced respiratory depression is discussed later. The dose-response characteristics of the respiratory depression curves of the mixed agonist-antagonists (pentazocine, nalbuphine, and butorphanol) and the partial agonist, buprenorphine, appear to differ from those of the morphine-like drugs. Although therapeutic doses of pentazocine produce respiratory depression equivalent to that produced by morphine, increasing the dose does not ordinarily produce a proportional increase in respiratory depression. Whether this apparent ceiling to respiratory depression offers any clinical advantage is still to be determined. Also, the clinical symptoms of respiratory depression that result from a large overdose of these drugs have not been well defined [11]. In addition to respiratory depression, the narcotic-type analgesics produce sedation and drowsiness. These effects may be useful in certain clinical situations such as preanesthesia, but they are not usually desirable concomitants of analgesia, particularly in ambulatory patients. The central nervous system depressant actions of these drugs can be expected to potentiate the sedative and respiratory depressant effects of sedative-hypnotics, such as alcohol and the barbiturates. Although it has been suggested that methadone produces more sedation than morphine, this has not been supported either by singledose controlled trials [12] or by surveys in hospitalized patients [13]. However, the half-life of methadone is substantially longer than that of morphine, and this could result in cumulative central nervous system depression after the administration of repeated doses for pain. The narcotic-type analgesics also produce nausea and vomiting by acting on the medullary chemoreceptor trigger zone. The incidence of nausea and vomiting is markedly increased in ambulatory patients, suggesting that these drugs also alter vestibular sensitivity. The most common adverse effect of the narcotic-type
analgesics is constipation [11]. These drugs act at multiple sites in the gastrointestinal tract and spinal cord to produce a decrease in intestinal secretions and peristalsis, resulting in a dry stool and constipation. Tolerance develops slowly to the smooth muscle effects of narcotics so that constipation will persist when these drugs are used to treat chronic pain. Narcotic-type analgesics increase smooth muscle tone and can cause bladder spasm and an increase in sphincter tone leading to urinary retention. Biliary tract spasms produced by these drugs can cause a marked increase in pressure in the biliary tract. Clinical studies suggest that equi-analgesic doses of meperidine may produce less biliary spasm than morphine [11]. Fortunately, the effects of the narcotic-type analgesics on the cardiovascular system are generally benign. Morphine causes a decrease in peripheral resistance and an increased capacity of the peripheral vascular compartment (peripheral pooling of blood), resulting in orthostatic hypotension and fainting. These same cardiovascular effects reduce the work load on the heart and, together with the anti-anxiety action of morphine, are believed to be responsible for the efficacy of morphine in relieving the dyspnea of pulmonary edema secondary to acute, leftsided heart failure. Furthermore, by virtue of the ability to decrease myocardial oxygen consumption, cardiac index, left ventricular end-diastolic pressure, and cardiac work, morphine can relieve the severe pain of acute myocardial infarction without producing undesirable cardiovascular effects. The cardiovascular responses to pentazocine and butorphanol differ somewhat from those described for morphine. Pentazocine increases aortic systolic pressure, left ventricular end-diastolic pressure, and mean pulmonary artery pressure, causing an increase in cardiac work. Thus, morphine is the drug of choice for use in patients with an acute myocardial infarction. Repeated administration of large parenteral doses of meperidine (250 mg or more per day) results in the accumulation of normeperidine, a toxic metabolite [14]. This accumulation occurs most rapidly in patients with compromised renal function. Normeperidine-induced toxicity is characterized by central nervous system excitation, including shaky feelings, tremors, twitches, and/or convulsions [14, 15]. The concurrent administration of monoamine oxidase inhibitors and meperidine has been reported to result in severe reactions and even death [16]. Toxic doses of propoxyphene not only produce central nervous system and respiratory depression but also lead to central nervous system excitation that can be manifested as convulsions [17]. The mixed agonist-antagonists produce certain self-limiting psychotomimetic effects not seen with other narcotic-type analgesics. Pentazocine seems to be the worst offender, and nalbuphine the least likely to produce these effects [18]. The properties of the narcotic-type analgesics that are most likely to lead to their being misused, or the patient
September 10, 1984
The American Journal of Medicine
31
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
treated incorrectly, are effects mediated in the central nervous system. These effects are seen following longterm administration and include psychologic dependence, physical dependence, and tolerance. It must be emphasized that even though the development of physical dependence and tolerance are predictable pharmacologic effects seen both in human subjects and in laboratory animals in response to repeated administration of a narcotic, these effects are distinct from psychologic dependence or addiction, the behavioral pattern seen in some subjects. Psychologic dependence is a pattern of drug use characterized by a continued craving for a narcotic. The craving is manifested as compulsive drug-seeking behavior, leading to an overwhelming involvement with the use and procurement of the drug. Anyone who is addicted to narcotics is likely to be physically dependent. However, the term "addiction" cannot be used interchangeably with physical dependence. Thus, it is possible to be physically dependent on a narcotic-type analgesic without being addicted. Fear of addiction leads to the use of inadequate doses of narcotics in hospitalized patients experiencing pain [19]. Some patients are reluctant to take even small doses of narcotics for fear of becoming addicted and will refuse medication. However, studies have shown that when narcotics are properly administered, addiction is rare. Recent surveys of hospitalized medical patients [20] and an analysis of the patterns of drug intake in cancer patients receiving long-term narcotic therapy [21] suggest that medical use of narcotics rarely, if ever, leads to drug abuse or iatrogenic addiction. Physical dependence is manifest by the appearance of withdrawal signs and symptoms characteristic of the well-known abstinence syndrome that occur when a narcotic is abruptly discontinued or when a narcotic antagonist is administered. The severity of withdrawal is a function of the dose and the duration of administration of the narcotic that has been discontinued (that is, the patient's prior narcotic experience). The administration of a narcotic antagonist to a physically dependent patient produces an immediate precipitation of the withdrawal syndrome. Patients who have received repeated doses of a morphine-like agonist to the point of physical dependence may experience a narcotic withdrawal reaction when given a mixed agonist-antagonist. That is, prior exposure to a morphine-like drug can be shown to greatly increase a patient's sensitivity to the antagonist component of a mixed agonist-antagonist [18,22]. Therefore, when used for chronic pain, the mixed agonist-antagonist should be tried before initiating prolonged administration of a morphine-like drug. Tolerance can be said to have developed when a larger dose of a drug is required to maintain the original effect. Tolerance to and physical dependence on the narcotictype analgesics seem to develop on a parallel time course. In a patient who requires an increase in dose to maintain analgesia, that is, a patient who has become tol-
32
September 10, 1984
The American Journal of Medicine
erant, a narcotic-type analgesic should not be abruptly withdrawn even if the patient's pain is suddenly alleviated. It has been suggested that the rate of development of tolerance to the analgesic effect of the mixed agonist-antagonists is slower than that seen with the morphine-like drugs [6,38]. If this observation is confirmed, it would provide the agonist-antagonists with a significant advantage over the morphine-like drugs. GUIDELINES FOR USE OF NARCOTIC-TYPE ANALGESICS IN PATIENTS WITH CANCER
In patients with cancer, the initial goal of effective pain management is to enable the patient to tolerate the diagnostic and therapeutic procedures required to assess and treat the cause of pain. If treating the suspected cause of the pain does not prove effective, symptomatic treatment of pain is begun and is aimed at allowing the patient to remain as functional as possible. This approach emphasizes individualization of therapy. For a more detailed discussion of the guidelines offered here, see Foley [23] and lnturrisi and Foley [3]. Treat the Patient, Not the Symptom. By taking a careful history and performing a thorough physical and neurologic examination, the physician can view the pain complaint within the context of the total evaluation of the patient. Pain treatment-both during the evaluation and after the nature of the pain is understood-does not stop with a prescription; it requires a commitment on the part of the physician and the pain management team to help the patient in achieving adequate pain control. Start with an Analgesic with the Potential to Provide Relief. Selecting a narcotic-type analgesic requires an estimate of the intensity and duration of pain as well as a knowledge of the patient's prior narcotic history. In patients with acute severe pain, parenteral morphine is the drug of choice, unless contraindicated. In patients with mild to moderate pain, an oral analgesic is the appropriate choice (Table 1). If the patient seeking pain relief has found that non-narcotic analgesics do not provide adequate analgesia, advantages can be gained by administering one of the narcotic-type analgesics listed in Table I in combination with a non-narcotic analgesic. For chronic severe pain, the oral route is preferred. Oxycodone, levorphanol, and methadone have good oral potency (Table II). At present, the choice of an oral mixed agonist-antagonist is limited to pentazocine. Know the Pharmacology of the Analgesic. It is essential that the physician has a thorough knowledge of the type of narcotic to be used, the starting analgesic dose for the route of administration chosen, and the peak time and duration of analgesia for the drug, dose, and route selected. In general, orally administered narcotics have a slower onset of action, delayed peak time, and a [onger duration of effect, whereas drugs administered parenterally have a rapid onset of action but a shorter duration of
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
effect. The narcotic-type analgesics differ in their pharmacokinetic characteristics as represented by their plasma elimination half-lives. Methadone, levorphanol, and propoxyphene have relatively long half-lives compared with that of morphine (Table Ill). It is obvious that their relatively longer half-lives are not reflected in the duration of analgesia seen after the administration of a single dose. However, these drugs with longer half-lives will accumulate with repetitive dosing. Therefore, some adjustment of dose and interval may be necessary to prevent excessive sedation. Patients with cirrhosis, renal disease, and patients older than 50 years of age have been reported to exhibit increased central nervous system sensitivity to narcotic-type analgesics (see Table IV) [3]. Administer Analgesics Regularly. For chronic pain, narcotic-type analgesics should be administered on a regular basis that will, if necessary, include awakening the patient. This approach can help to prevent severe pain from recurring and may allow for a reduction in the total amount of drug required per day. There is a caveat: this use of regularly scheduled narcotics may mask warnings of serious complications, as already discussed. Recognize and Treat Adverse Effects Appropriately. The adverse effects of the narcotic-type analgesics that most often limit their use are sedation, nausea and vomiting, constipation, and respiratory depression. Reducing the dose and the interval between doses so that a lower dose is given more frequently may counteract excessive sedation. In addition, other central nervous system depressants-including sedative-hypnotics and anti-anxiety agents that potentiate the sedative effects of narcoticsshould be discontinued. Concurrent administration of dextroamphetamine has been reported to reduce the sedative effects of narcotics [24]. The ability of narcotic-type analgesics to produce nausea and vomiting appears to vary with the drug and the patient; some advantage may result from switching to an equi-analgesic dose of another narcotic. Alternately, an anti-emetic may be used in combination with the narcotic. To prevent constipation, provisions for a regular bowel regimen, including cathartics and stool
TABLE IV
TABLE Ill
Plasma Half-Life Values for Narcotic-Type Analgesics* Drug
Plasma Half-Life (hours)
Morphine Meperidine Normeperidine Methadone Levorphanol Heroint Hydromorphone Pentazocine Nalbuphine Butorphanol Codeine Propoxyphene Norpropoxyphene
2-3.5 3-4 14-21 15-30 12-16 0.05 2-3 2-3
5 2.5-3.5
3 12 30-40
*Adapted from [5). tBiotransformed to acetylmorphine and morphine.
softeners, should be instituted when the use of narcotictype analgesics is begun. Respiratory depression occurs most commonly following initial administration of a narcotic. It is associated with other signs of central nervous system depression, including sedation and mental clouding. Tolerance develops rapidly to this effect with repeated administration of the drug, allowing the narcotic-type analgesics to be used in the management of chronic cancer pain without significant risk of respiratory depression. If respiratory depression occurs, it can be reversed by the administration of the specific narcotic antagonist, naloxone. In patients with respiratory failure who have received narcotics over a prolonged period, naloxone diluted 1:10 should be titrated carefully to prevent the precipitation of severe withdrawal symptoms while the respiratory depression is being reversed. In certain patients, the use of naloxone to reverse drug-induced respiratory depression can be dangerous. To prevent aspiration-associated respiratory compromise with excessive salivation and bronchial spasm, an endotracheal tube should be placed in a comatose patient be-
Undesirable Drug or Disease Interactions of Narcotic-Type Analgesics Drug
Interaction
Result
Meperidine Pentazocine Propoxyphene Meperidine Propoxyphene Morphine Meperidine Methadone Meperidine Any narcotic
Cirrhosis Cirrhosis Cirrhosis Renal failure Renal failure Older than 50 years Phenytoin Rifampin Monoamine oxidase inhibitors Alcohol or other central nervous· system depressants
t Bioavailability and t clearance = accumulation j Bioavailability and t clearance = accumulation t Bioavailability and t clearance = accumulation t Normeperidine, a toxic metabolite = accumulation t Norpropoxyphene, a toxic metabolite = accumulation t Clearance = accumulation t Biotransformation = faster elimination t Biotransformation = faster elimination Excitation, hyperpyrexia, and convulsions Enhanced depressant effects
September 10, 1984
The American Journal of Medicine
33
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
fore naloxone is administered. In patients receiving meperidine long-term, naloxone may precipitate seizures by lowering the seizure threshold and allowing the convulsant activity of the active metabolite, normeperidine, to become evident [14,15]. If naloxone is to be used in these patients, diluted doses, slowly titrated, should be used, and appropriate seizure precautions are advised. Give Each Analgesic an Adequate Trial. To fully assess whether a drug can produce analgesia in a particular patient, the dose should be increased until limiting adverse effects can be seen before switching to an alternate. Use Drug Combinations That Will Enhance Analgesia. In combination, the analgesic effects of the non-narcotic analgesics, aspirin and acetaminophen, are additive with those of narcotic-type analgesics. A good rule to follow, if possible, is to give a non-narcotic with a narcotic analgesic. This not only will provide better analgesia but also will slow the rate of the development of tolerance since tolerance develops only to the narcotic analgesic portion of the dose. Cancer patients, particularly those receiving chemotherapy, have coagulation defects and should avoid aspirin and aspirin-containing preparations such as oxycodone hydrochloride plus aspirin. Acetaminophen is a suitable aspirin substitute in these patients. Other drugs that have been shown in controlled clinical trials to enhance analgesia when used in combination with a narcotic-type analgesic include the following: methotrimeprazine [25], dextroamphetamine [24], and hydroxyzine [26]. Anecdotal evidence suggests that the administration of amitriptyline at bedtime may improve pain management in cancer patients. Watch for the Development of Tolerance. Tolerance appears to develop in all patients receiving narcotic-type analgesics over a prolonged period. The hallmark sign of the development of tolerance is the patient's complaint of a decrease in the duration of effective analgesia. For reasons not yet understood, the rate of development of tolerance varies greatly among cancer patients; some will demonstrate tolerance within days after narcotic therapy is initiated, whereas others will have good control for many months on the same dose. A sudden dramatic increase in narcotic requirements may represent a progression of the cancer rather than the development of tolerance per se [21]. In these patients, objective evidence of progression of disease should be sought and pain management techniques reevaluated accordingly. With the development of tolerance, an increase in the frequency and/or the dose of the narcotic is required to provide continued pain relief. Since the analgesic effect is a logarithmic function of the dose of narcotic, a doubling of the dose may be required to restore full analgesia. There appears to be no limit to the development of tolerance, and with appropriate adjustment of dose, patients can continue to obtain pain relief. In cancer patients with severe pain, narcotic-type anal-
34
September 10, 1984
The American Journal of Medicine
gesics should not be used sparingly or "saved to the last" because of the fear that an increasing narcotic requirement represents a "loss of control." A number of strategies can be used to forestall the development of tolerance in patients with chronic cancer pain. Since tolerance development is a function of the dose and the frequency of administration, it is not surprising that continuous intravenous administration of narcotics results in the rapid development of tolerance. For this and other reasons already cited, the oral route of administration is preferred. When the oral route cannot be used, the alternative is parenteral administration. In the tolerant patient, the availability of a suitable parenteral dosage form-that can provide adequate pain relief without the necessity of injecting an unreasonably large volume of solution into a cachectic patient-may greatly restrict the drug choice. Solubility considerations preclude the administration of morphine concentrations greater than 65 mg/ml [18]. Hydromorphone, which is approximately five times more soluble and nearly seven times more potent than morphine and recently available in a 10 mg/ml parenteral dose form, can provide the flexibility required for dose titration in the tolerant patient. As already discussed, combining narcotics with non-narcotics can enhance analgesia and slow the rate of development of tolerance. From the start, a nonnarcotic such as acetaminophen should be used with the narcotic. In the tolerant patient, methotrimeprazine-a nonopioid analgesic-can be substituted for part of the narcotic analgesic requirement. However, methotrimeprazine can produce excessive sedation and postural hypotension, which may limit its use to patients who must remain in bed. Cross-tolerance among the narcotictype analgesics appears not to be complete. Therefore, an advantage can be gained by switching to an alternate narcotic and selecting half the predicted equi-analgesic dose (given in Table I) as the starting dose. Be Aware of the Development of Physical Dependence and Prevent Withdrawal. The abrupt discontinuation of a narcotic-type analgesic in a patient with significant prior narcotic experience will result in signs and symptoms of the narcotic withdrawal or abstinence syndrome [27]. The onset of withdrawal is characterized by the patient's reporting feelings of anxiety, nervousness, and irritability, and the patient's experiencing alternating chills and hot flushes. Prominent withdrawal signs are "wetness"-salivation, lacrimation, rhinorrhea, and diaphoresis-and gooseflesh. At the peak intensity of withdrawal, patients may experience nausea and vomiting, abdominal cramps, insomnia, and, rarely, multifocal myoclonus. The time-course of the withdrawal syndrome is a function of the elimination half-life of the narcotic on which the patient has become dependent. Following cessation of a drug with a short half-life such as morphine, abstinence symptoms will appear within six to 12 hours and reach a peak at 24 to 72 hours. With methadone, a drug
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
with a long half-life, onset may be delayed for 36 to 48 hours. Therefore, it is important to emphasize that, even in a patient in whom pain has been completely relieved by a procedure (for example, cordotomy), it is necessary to slowly decrease the narcotic dose to prevent withdrawal. Experience indicates that the usual daily dose required to prevent withdrawal is equal to one-fourth of the previous daily dose. This dose, for want of a better term, is called the detoxification dose and is given in four divided doses. The initial detoxification dose is given for two days and then decreased by one-half (administered in four divided doses) for two days until a total daily dose of 10 to 15 mg a day of morphine, or an equivalent dose of another narcotic-type analgesic, is reached. After two days on this last dose, the narcotic can be discontinued [28]. Thus, a patient who had been receiving 240 mg a day of morphine for pain would require an initial detoxification dose of 60 mg given as 15 mg every six hours. Alternately, the patient may be switched to oral methadone for detoxification, using the data in Table II to calculate the equi-effective oral analgesic dose of methadone. Then use one-fourth of this dose as the initial detoxification dose and proceed as just described. As has been previously discussed, the substitution of a mixed agonist-antagonist (Table II) in a patient dependent on a morphine-like agonist will precipitate acute narcotic withdrawal and must be avoided.
Do Not Use Placebos to Assess the Type of Pain. Although its appropriate use is not widely recognized, the placebo response is a potent phenomenon in clinical medicine [29]. In a patient with pain, the relief of pain in response to the parenteral administration of saline solution suggests that this patient, in these specific circumstances, is a placebo-responder. Nothing more or less can be concluded. It does not indicate that the patient's pain is unreal, that is, "psychogenic," or less severe than reported by the patient. This misuse of the placebo response engenders distrust between the patient and the pain management team, which can interfere with adequate pain control. CONCLUSIONS
Administration of the narcotic-type analgesics is the most commonly employed method of managing pain due to cancer. These drugs are convenient to use, and their effects are prompt and reversible. It is necessary to have a working knowledge of their pharmacologic properties and their desirable and undesirable effects. The issues of tolerance, dependence and addiction, as they relate to the cancer patient in pain, should also be well understood. Guidelines have been presented for the selection and use of these drugs in cancer patients.
REFERENCES 1.
Houde RW: On assaying analgesics in man. In: Knighton RS, Dumke PR, eds. Pain, ed 1. Boston: Little, Brown, 1966; 183196. 2. Foley KM: Adjuvant analgesic drugs in the management of cancer pain. In: mediguide to pain, vol 4. New York: Lawrence Dellacorte Publications, 1983; 1-8. 3. lnturrisi CE, Foley KM: Narcotic analgesics in the management of pain. In: Kuhar M, Pasternak G, eds. analgesics: neurochemical, behavioral and clinical perspectives. New York: Raven Press, 1984; 257-288. 4. Twycross RG: Diamorphine and cocaine elixir BPC 1973. J Pharmacol 1974; 212: 153-159. 5. Mount BM, Ajemian I, Scott JF: Use of Brompton mixture in treating the chronic pain of malignant disease. Can Med Assoc J 1975; 1: 10-18. 6. Twycross RG: The Brompton cocktail. In: Bonica JJ, Ventafridda V, eds. advances in pain research and therapy, II. New York; Raven Press, 1979; 291-300. 7. lnturrisi CE, Max M, Foley KM, et al: The pharmacokinetics of heroin in patients with chronic pain. N Engl J Med 1984; 310: 1213-1217. 8. Twycross RG: Morphine and diamorphine in the terminally ill patient. Acta Anesthesiol Scand 1982; 74 (suppl): 128-134. 9. Walsh TO: Oral morphine in chronic cancer pain. Pain 1984; 18: 1-11. 10. Houde RW: Systemic analgesics and related drugs: narcotic analgesics. In: Bonica JJ, Ventafridda V, eds. Advances in pain research and therapy, II. New York; Raven Press, 1979, 263-273, 11. Jaffe JH, Martin WR: Opioid analgesics and antagonists. In: Gilman AG, Goodman AS, Gilman A, eds. The pharmacological basis of therapeutics, ed 6. New York: Macmillan Publishing, 1980; 494-534.
12.
13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
Beaver WT, Wallenstein SL, Houde RW, et al: A clinical comparison of the analgesic effects of methadone and morphine administered intramuscularly, and of orally and parenterally administered methadone. Clin Pharmacol Ther 1967; 8:415426. Miller RR: Clinical effects of parenteral narcotics in hospitalized medical patients. J Clin Pharmacol 1980; 20: 165-171. lnturrisi CE, Umans JG: Pethidine and its active metabolite, norpethidine. Clin in Anesthesiol1983; 1: 123-138. Kaiko RF, Foley KM, Grabinski PY, et al: Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol1983; 13: 180-185. Meyer D, Hallin V: Toxicity secondary to meperidine in patients on monoamine oxidase inhibitors: a case report and critical review. J Clin Psychopharmacol1981; 1:319-321. lnturrisi CE, Colburn WA, Verebey K, et al: Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene. Clin Pharmacol Ther 1982; 31: 157-167. Beaver WT: Management of cancer pain with parenteral medication. JAMA 1980; 244: 2653-2657. Marks RM, Sachar EJ: Undertreatment of medical inpatients with narcotic analgesics. Ann Intern Med 1973; 78: 173-181. Porter J, Jick H: Addiction rare in patients treated with narcotics. N Engl J Med 1980; 302: 123. Kanner RM, Foley KM: Patterns of narcotic drug use in a cancer pain clinic. Ann NY Acad Sci 1981; 362: 161-172. Houde RW: Analgesic effectiveness of the narcotic agonist-antagonists. Br J Clin Pharmacol 1979; 7 (suppl): 297-308. Foley KM: The practical use of narcotic analgesics. In Reidenberg MM, ed. The medical clinics of North America. Philadelphia: WB Saunders, 1982; 1091-1104. Forrest WH Jr, Brown BW Jr, Brown CR, et al: Dextroamphetamine with morphine for treatment of postoperative pain. N
September 10, 1984
The American Journal of Medicine
35
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
25.
Engl J Med 1977; 296: 712-715. Lasagna L, Dekornfeld JJ: Methotrimeprazine: a new phenothiazine derivative with analgetic properties. JAMA 1961; 178:
27.
Jaffe JH: Drug addiction and drug abuse. In: Gilman AG, Goodman AS, Gilman A, eds. The pharmacological basis of therapeutics, ed 6. New York: Macmillan Publishing, 1980; 535-
28.
Rogers AG: 21 problems in pain control-and ways to solve them. Your Patient & Cancer 1981; Sept: 65-75. Goodman JS, Goodman JM, Vogel AV: Knowledge and use of placebos by house officers and nurses. Ann Intern Med 1979;
887-890. 26.
584.
Beaver WT, Freise G: Comparison of the analgesic effects of morphine, hydroxyzine and their combination in patients·with postoperative pain. In: Bonica JJ, Albefessard D, eds. Advances in pain research and therapy. New York: Raven Press, 1976; 553-557.
29.
91: 106-110.
DISCUSSION
Dr. Howard Fields: You mentioned that the oral-to-parenteral ratio is different for different drugs. Will that generally be true for the nonanalgesic effects as well? Is it true for respiratory depressive effects, for example? Dr. William Beaver: Mainly from anecdotal experience, we have learned that, with certain drugs that produce active metabolites and have adverse effects, the oral-to-parenteral efficacy ratio may not be exactly the same as the oral-to-parenteral side effects ratio. For example, with pentazocine, one of its metabolites seems to be able to produce psychotomimetic side effects. You may see more psychotomimetic side effects when this drug is administered orally than when an equi-analgesic dose is administered parenterally because you get the first-pass biotransformation to this active metabolite. It would not surprise me at all if, with meperidine, you would observe the same phenomenon. If you tried to achieve high blood levels of meperidine by giving very large oral doses, you would get normeperidine accumulation with resultant normeperidine toxicity. Dr. Fields: Does tolerance develop more rapidly in patients receiving methadone as an analgesic? Dr. Charles lnturrisi: I have no reason to believe that occurs. My clinical impression is that there are a number of factors that contribute to the development of tolerance, including changes in disease state, which may exacerbate the situation. However, I know of no information that suggests that there are differential rates of development of tolerance among the morphine-like drugs. The only information that is available is from the Addiction Research Center and that would suggest that, with the morphine-like drugs, tolerance develops at about the same rate. When you look at the mixed agonist-antagonists, there seems to be some evidence that perhaps the development of tolerance to some of the morphine-like effects is somewhat slower. The question remains as to whether one could translate this into a slower development of tolerance to analgesia in a clinical situation. Dr. Beaver: I think that the inter-individual variation in the rate of tolerance development to apparently similar
36
September 10, 1984
The American Journal of Medicine
narcotic regimens is so large that it is extremely difficult to make generalizations about differences between drugs. You may have two patients on morphine-one goes for a very long time without much tolerance developing, and the other one requires repeated increases in dosage. Dr. lnturrisi: Another important issue is the relationship between the amount of narcotic analgesic used when the drug is given in fixed doses at regular intervals versus the amount used when as-needed administration is the rule. Dr. Beaver: This is a matter that repeatedly comes up for discussion, particularly in relation to hospices. It is claimed that you can use less narcotic if you give the medication "by the clock" rather than on demand. No controlled clinical studies have been carried out on this issue. Recently, giving narcotics by continuous intravenous infusion has become a popular practice. Last week I saw a patient who, in the course of six days, escalated from a dose-given by continuous intravenous infusion-of about 10 mg of morphine every two hours to 40 mg of morphine per hour. The resident thought that intravenous narcotics was the treatment of choice. The result of this practice may be very similar to what has been observed in animal studies when the investigator is deliberately trying to induce tolerance by keeping the opiate receptor occupied 24 hours a day, never allowing a return to a normal state. We took the patient off intravenous morphine and put him on spaced doses of hydromorphone hydrochloride, and he did quite well. This might actually have been a case of acute tolerance. Dr. Fields: You want to keep the patient free of pain, but, if you maintain high plasma drug levels, you hasten tolerance and lose the effectiveness of the drug. Dr. Robert Addison: I would like to discuss the difference between patients who come into a pain clinic and those who come into a drug abuse facility. In our experience, they seem to be two entirely different groups of people, and their handling of drugs is very dissimilar. One man who had back pain was taking 600 mg of meperidine every day, by injection, for a two-year period for his pain. I explained to him that one of the things we were going to
PAIN MANAGEMENT SYMPOSIUM-INTURRISI
do was reduce his intake of meperidine. When he was admitted to the hospital three weeks later, I said, "Well, I want to reiterate that we are going to reduce your meperidine intake," and he said, "I stopped the day you told me you were not going to give me any more." Now, I am sure he had some sort of withdrawal symptoms, but the ease with which he related his stopping the medication impressed me. Dr. lnturrisi: I think this is clearly a function of the dose that a patient has been receiving and, to some degree, depends on how closely the patient is observed and what the patient knows about withdrawal. This patient may have thought that he had a rather severe cold. He also might have had an upset stomach and did not associate any of these symptoms with withdrawal. Whenever proper studies have been conducted, one can clearly demonstrate that meperidine is a drug of abuse that can produce physical dependence. Its short duration of action means that its effects dissipate very quickly. The implication is not that meperidine in a 600 mg daily dose would not produce physical dependency. There are a set of factors that argue against the patient reporting his symptoms as signs of withdrawal. Dr. Beaver: We have had experiences like this also. What we find, particularly in cancer patients, is that if you find some other way to relieve the pain-neurosurgery, peripheral nerve block, or another treatment-you can take the patients off narcotics relatively easily. They will have some signs of withdrawal but, given the dose that they have been accustomed to, they can be taken off the drug very'easily compared to the street addict. I think the big difference is the psychic dependence of the street addict, who reacts much more violently to a given level of somatic symptom in withdrawal. There is a significant psychic overlay on top of the physical withdrawal syndrome, making detoxification much more difficult. Dr. Addison: In any good detoxification program-and especially with the chronic pain patients-you should give the patients alternatives that are as satisfactory for them to look to as the medication itself.
Dr. Robert Posner: I now think that there is a role for narcotics in the management of intractable nonmalignant pain. Several of my patients with pain due to nerve injury or central nervous system injury get significant relief only with an opioid drug. They have been taking an opioid for years at the same dose. For them, it is very important and very helpful. It is necessary, however, to monitor whether the dose taken remains stable. Once the dose starts to increase, then you have to worry about tolerance. Dr. Stephen Silberstein: Does the use of tranquilizers in addition to narcotics potentiate the action of the narcotics, or is this fiction? Dr. lnturrisi: In general, the use of tranquilizers presents more problems than it solves. Tranquilizers tend to enhance the sedative effect more than they enhance the analgesic effect of a narcotic analgesic. Obviously, if you are treating a patient who has a psychiatric component to his or her pain, then tranquilizers may have a place. In general, I would say that the use of tranquilizers and the use of minor tranquilizers, like diazepam, is not beneficial. The patient does not get adequate pain relief and is very confused. I recommend stopping all medication in this instance, and starting from "square one" again with adequate doses of pain medication. Then, consider the other medications and determine whether they are of any value. Enlisting the Patient's Help in Selecting an Analgesic To enlist the patient's cooperation, communicate the following: • "I will be attentive to your complaints" • "I will believe what you tell me about the pain" • "While we are finding out what is causing your pain, we are going to treat the pain" • "Not all medications are alike; some will work for you and some will not" • "I would like to make a pact with you. First, we are going to try (name of medication), and I want you to tell me when it is working. If it does not work, we will try another medication until we find one that works for you"
September 10, 1984
The American Journal of Medicine
37