Current Concepts
Understanding tolerance, physical dependence and addiction in the use of opioid analgesics Robert E. Enck, MD
Fear of addiction to opioid analgesics remains a major impediment to good pain control. This perception is shared by both the patient and caregivers and is further reinforced by the ongoing battle with illicit drug use as highlighted on the six o’clock news. Physicians are often reluctant to use opioids until “the last” because of their misunderstanding of this problem. In a similar fashion, patients are afraid to start on treatment with the opioids, often despite the presence of severe uncontrolled pain, because they do not want to be “hooked” on these drugs. Many times the patient’s negative perception of opioids is strongly reinforced by family members. Much of the confusion regarding opioids and addiction is related to a
Robert E. Enck, MD, is past president of the Association of Community Cancer Centers, Columbus, Ohio.
poor understanding of terminology, specifically, tolerance, physical dependence and psychological dependence or addiction. Tolerance occurs when, after repeated drug administration, a larger dose must be given to obtain the effects observed with the original dose. On the otherhand, physical dependence refers to an altered physiological state produced by the repeated administration ofa drug to the extent that sudden cessation of the drug results in withdrawal symptoms. Finally, addiction is a behavioral pattern of drug use, characterized by overwhelming involvement with the use of the drug, the securing of its supply, and a tendency to resume use after withdrawal.1 Tolerance Tolerance, or the need forescalating opioid doses to maintain adequate analgesia, appears to develop in all patients receivingopioids chronically.2 The rate of development of this phenomenon, however, varies greatly among cancer patients. Data from animals show that tolerance to morphine occurs inrodents within 24 hours, reaching a maximum within one week. This suggests that more than one week of patient exposure to this drug may lead to tolerance.3 The first indication of tolerance is the patient’s complaint that, compared to initial administration, the duration of analgesia is decreased. Frequently, the patient is labelled a “clock
The American Journal of Hospice & Palliative Care, January/February 1991 Downloaded from ajh.sagepub.com at Purdue University on July 7, 2015
watcher,” a sign that is often misinterpreted by care-givers as an early sign of addiction.4 Studies indicate that there are three patterns of drug use in cancer patients: • Rapidly escalating doses of opioids associated with increasing pain and/or anxiety, • Stable doses ofopioids for long periods of time (weeks to months) without dose escalation or reduction, and • Discontinuance of opioid drugs because of effective analgesia from cancer therapies or anesthetic or neurosurgical approaches. These patterns are independent of the route of drug administration. Progression of painful disease is the overriding factor determining dose escalation.4 Although the rate ofdevelopment of tolerance may vary from patient to patient, a sudden dramatic increase in opioid requirements may well signal progression of cancer rather than the development of tolerance. There appears to be no limit to tolerance. Regardless of current dosage, dose escalation is appropriate when the goal is effective analgesia. The majority of patients treated by the Supportive Care Program at Memorial Sloan-Kettering Cancer Center required doses in the range of 5mg to 300mg of intramuscular morphine
9
equivalents. Some patients required very high doses.4 These high doses are often misinterpreted as inappropriate by inexperienced physicians. They undennedicate patients because of their concern about using only standard doses, rather than seeking adequate analgesia as an endpoint. Of equal importance is the recognition that cross tolerance is incomplete. Changing patients from one opioid analgesic to anothercan improve analgesia. Finally, tolerance to the various opioid side effects occurs at different rates. Tolerance to respiratory depression develops rapidly, whereas, tolerance to constipation develops very slowly, ifat all. The rapid development of tolerance to the respiratory depressant effects of opioids allows for the escalation of doses in some patients to very high levels.4 Physical dependence Physical dependence is a pharmacologic effect of opioids. Withdrawal symptoms occur when the drug is stopped. The severity of withdrawal is a function ofthe duration and dose of the opioid which was discontinued. Patients treated with therapeutic doses of morphine several times a day for one to two weeks will have only mild symptoms that maynot be recognized as withdrawal when the drug is stopped. These symptoms may be even less pronounced when the opioid is one that is slowly eliminated, such as methadone.’ The onset of withdrawal is heralded by the patient’s report of feelings of anxiety, nervousness, irritability, and alternating chills and hot flushes. A prominent withdrawal sign is wetness including salivation, lacrimation, rhinorrhea, and diaphoresis. Nausea and vomiting, abdominal cramps, insomnia, and, rarely, multifocal myoclonus may occur at the peak intensity of the withdrawal syndrome. The timing of withdrawal is a function
ofthe eliminationhalf-life ofthe opioid to which the patienthas become physically dependent. For example, symptoms will appear within six to 12 hours and reach a peak at 24 to 72 hours following cessation of a short half-life drug such as morphine. With methadone, which has a long half-life, withdrawal symptoms may be delayed for 36 to 48 hours. It is important to notethateven in patients in whom pain has been completely relieved by a therapeuticprocedure, it isnecessary to slowly decrease the opioid dose to prevent withdrawal symptoms.2 The usual daily dose required to prevent withdrawal is equal to onefourth of the previous daily dose, and is administeredevery six-hours, or four times per day. This initial withdrawal regimen is administered for two days and then reduced by one-half. This amount is also divided into doses given four times daily, for two days. This procedure should continue until a total daily dose of 10 to 15mg per day is reached. After two days on this dose, the opioid can be stopped. Thus, a patientwho had been receiving 240mg of morphine per day for pain control would require an initial withdrawal dose of 60mg administered in 15mg doses every six-hours.2 The administration of an opioid antagonist, such as naloxone, to a physically dependent patient immediately precipitates the withdrawal syndrome. Patients being treated with repeated doses of a morphine-like agonist to the point where they are physically dependent may experience an opioid withdrawal reaction when given a mixed agonist-antagonist, like pentazocine. Priorexposureto a morphinelike drug has been shown to greatly increase a patient’s sensitivity to the antagonist component of a mixed agonist-antagonist drug. Addiction Tolerance and physical dependence
are predictable pharmacologic effects seen in response to the repeated administration ofopioids in both manand laboratory animals. These effects are distinctly different from the abnormal behavioral patterns seen in some individuals, described by the term psychological dependence or addiction. Addiction is characterized by a continued craving for opioids as manifested by compulsive drug seeking behavior and overwhelming involvement in drug procurement and use. The developmentofaddiction is acornplexphenomenon in which the typeof individual, the reason for drug use, the environment, and the drug play major and, at times, equivalent roles. This concept was well illustrated by the epidemic of addiction seen in Vietnam veterans who rapidly discontinued their heroinuse once home, withoutthe use of maintenance programs and with low rates ofrelapse.4 It is clearly possible for patients taking opioids on a chronicbasis, such as those with cancer pain, to be physically dependent without evidence of addiction. As noted by Angell,5 addiction among patients who receive opioids for painis exceedingly unlikely, and the incidence is probably no greater than 0.1 percent. Further support for this low addiction rate comes from a study by Chapman and Hill.3 These investigators studied 26 patients following bone marrow transplantation who required opioid analgesics for severe oral mucositis. Twelve patients self-administered morphine via a patient-controlled analgesia (PCA) system for two weeks. The other fourteen patients acted as controls and were given morphine by routine staff-controlled continuous infusion procedures. Self-administering patients used significantly less morphine than the controls and still achieved the same amount ofpaincontrol. In addition, the self-administering patients terminated drug use sooner than the control
The American Journal of Hospice & Palliative Care, January/February 1991 Downloaded from ajh.sagepub.com at Purdue University on July 7, 2015
patients. The investigators concluded that the results support the assumption that self-administration of opioids in a medical setting does not put patients at risk for over-medication or addiction.
At Last...
A Video Teaching Tool for the Hospice Medicare Benefit
Conclusion Based on this revieW of the medical literature on tolerance, physical dependence and addictionas they relate to the managementofchronic cancerpain, the follbwing conclUsions ~ireoffered:
Montgomery Hospice Society introduces:
“HOSPIeE
• Tolerance appears to develop in all patients receiving opioids on a chronic basis, and may occur after a week or more of morphine therapy. • Physical dependence is important to understand because of the occurrence of withdrawal symptoms, which may be subtle or significant depending on the duration and dosage of opioids used at the time when these drugs are stopped. Clinically, this problem can be avoided by a gradual decrease in daily opioid doses. • The incidence of addiction in cancer patients taking opioids chronically is probably no greater than 0.1 percentLJ
FOR LIVI\G”
... winner of the National Hospice Organization’s 1989 President’s Award for Non-print Media
This sensitive, 14-minute video: • portrays hospice in a positive, hopeful way • opens dialogue with patients, families, professionals and the public • explains hospice through patients and family • identifies Hospice Medicare Benefit services • comes with guidelines for use
Audiences: • patients, families, significant others • physicians and nurses • social workers and discharge planners • hospital, nursing home, and physician office staffs • volunteers and new staff • board members
References
I Suggested uses:
1. Jaffe ill: Drug addiction and drug abuse. hI:
• patient and family education
Gilman AG, Goodman LS, Rail TW, Murad F, eds. The pharmacological basis of therapeutics, Seventh edition. New York, The Macmillan Publishing Company, 1985;532-581
• professional relations/referrals • new staff orientation • volunteer training
2. Foley KM, Inturrisi CE: Analgesic drug thetapy in cancer pain: principles and practice. Med Clin North Am 1987;71:207-232
• public showings
3. Chapman CR, Hill HF: Prolonged morphine self-administration and addiction liability: evaluation of two theories in a bone marrow transplantation unit. Cancer 1989;63:16361644 4. Foley KM: Controversies in cancer pain: medical perspectives. Cancer 1989;63:22572265 5. AngellM: Thequality of mercy. NEngl JMed 1982;306:98-99
• board and donor education
1
Format/Costs: Available at special introductory prices in VHS format. One cassette—$50, two cassettes—$65, three cassettes—$75, plus shipping. Available for preview and rental at $20 (applicable to purchase) plus shipping.
I
To order:
Call (301) 279-2566 or FAX (301) 309-8791 to order l)y credit card. MasterCard and \ISA ae(’e )ted. Or, sentl 1 cheek or nlonev order (made payal)le to Montgomer~ Hospice Foundation) to: Business Office. Dept. AJ H. Montgomery hospice Society. Twelve Oaks Office Park. The American Journal of Hospice & Palliative Care, January/February 1991 Blvd., Suite 310, Roek%ille. Ml) 20850. Downloaded from ajh.sagepub.com at Purdue University on145() July 7, Research 2015
Understanding tolerance, physical dependence and addiction in the use of opioid analgesics Robert E. Enck, MD
Fear of addiction to opioid analgesics remains a major impediment to good pain control. This perception is shared by both the patient and caregivers and is further reinforced by the ongoing battle with illicit drug use as highlighted on the six o’clock news. Physicians are often reluctant to use opioids until “the last” because of their misunderstanding of this problem. In a similar fashion, patients are afraid to start on treatment with the opioids, often despite the presence of severe uncontrolled pain, because they do not want to be “hooked” on these drugs. Many times the patient’s negative perception of opioids is strongly reinforced by family members. Much of the confusion regarding opioids and addiction is related to a
Robert E. Enck, MD, is past president of the Association of Community Cancer Centers, Columbus, Ohio.
poor understanding of terminology, specifically, tolerance, physical dependence and psychological dependence or addiction. Tolerance occurs when, after repeated drug administration, a larger dose must be given to obtain the effects observed with the original dose. On the otherhand, physical dependence refers to an altered physiological state produced by the repeated administration ofa drug to the extent that sudden cessation of the drug results in withdrawal symptoms. Finally, addiction is a behavioral pattern of drug use, characterized by overwhelming involvement with the use of the drug, the securing of its supply, and a tendency to resume use after withdrawal.1 Tolerance Tolerance, or the need forescalating opioid doses to maintain adequate analgesia, appears to develop in all patients receivingopioids chronically.2 The rate of development of this phenomenon, however, varies greatly among cancer patients. Data from animals show that tolerance to morphine occurs inrodents within 24 hours, reaching a maximum within one week. This suggests that more than one week of patient exposure to this drug may lead to tolerance.3 The first indication of tolerance is the patient’s complaint that, compared to initial administration, the duration of analgesia is decreased. Frequently, the patient is labelled a “clock
The American Journal of Hospice & Palliative Care, January/February 1991 Downloaded from ajh.sagepub.com at Purdue University on July 7, 2015
watcher,” a sign that is often misinterpreted by care-givers as an early sign of addiction.4 Studies indicate that there are three patterns of drug use in cancer patients: • Rapidly escalating doses of opioids associated with increasing pain and/or anxiety, • Stable doses ofopioids for long periods of time (weeks to months) without dose escalation or reduction, and • Discontinuance of opioid drugs because of effective analgesia from cancer therapies or anesthetic or neurosurgical approaches. These patterns are independent of the route of drug administration. Progression of painful disease is the overriding factor determining dose escalation.4 Although the rate ofdevelopment of tolerance may vary from patient to patient, a sudden dramatic increase in opioid requirements may well signal progression of cancer rather than the development of tolerance. There appears to be no limit to tolerance. Regardless of current dosage, dose escalation is appropriate when the goal is effective analgesia. The majority of patients treated by the Supportive Care Program at Memorial Sloan-Kettering Cancer Center required doses in the range of 5mg to 300mg of intramuscular morphine
9
equivalents. Some patients required very high doses.4 These high doses are often misinterpreted as inappropriate by inexperienced physicians. They undennedicate patients because of their concern about using only standard doses, rather than seeking adequate analgesia as an endpoint. Of equal importance is the recognition that cross tolerance is incomplete. Changing patients from one opioid analgesic to anothercan improve analgesia. Finally, tolerance to the various opioid side effects occurs at different rates. Tolerance to respiratory depression develops rapidly, whereas, tolerance to constipation develops very slowly, ifat all. The rapid development of tolerance to the respiratory depressant effects of opioids allows for the escalation of doses in some patients to very high levels.4 Physical dependence Physical dependence is a pharmacologic effect of opioids. Withdrawal symptoms occur when the drug is stopped. The severity of withdrawal is a function ofthe duration and dose of the opioid which was discontinued. Patients treated with therapeutic doses of morphine several times a day for one to two weeks will have only mild symptoms that maynot be recognized as withdrawal when the drug is stopped. These symptoms may be even less pronounced when the opioid is one that is slowly eliminated, such as methadone.’ The onset of withdrawal is heralded by the patient’s report of feelings of anxiety, nervousness, irritability, and alternating chills and hot flushes. A prominent withdrawal sign is wetness including salivation, lacrimation, rhinorrhea, and diaphoresis. Nausea and vomiting, abdominal cramps, insomnia, and, rarely, multifocal myoclonus may occur at the peak intensity of the withdrawal syndrome. The timing of withdrawal is a function
ofthe eliminationhalf-life ofthe opioid to which the patienthas become physically dependent. For example, symptoms will appear within six to 12 hours and reach a peak at 24 to 72 hours following cessation of a short half-life drug such as morphine. With methadone, which has a long half-life, withdrawal symptoms may be delayed for 36 to 48 hours. It is important to notethateven in patients in whom pain has been completely relieved by a therapeuticprocedure, it isnecessary to slowly decrease the opioid dose to prevent withdrawal symptoms.2 The usual daily dose required to prevent withdrawal is equal to onefourth of the previous daily dose, and is administeredevery six-hours, or four times per day. This initial withdrawal regimen is administered for two days and then reduced by one-half. This amount is also divided into doses given four times daily, for two days. This procedure should continue until a total daily dose of 10 to 15mg per day is reached. After two days on this dose, the opioid can be stopped. Thus, a patientwho had been receiving 240mg of morphine per day for pain control would require an initial withdrawal dose of 60mg administered in 15mg doses every six-hours.2 The administration of an opioid antagonist, such as naloxone, to a physically dependent patient immediately precipitates the withdrawal syndrome. Patients being treated with repeated doses of a morphine-like agonist to the point where they are physically dependent may experience an opioid withdrawal reaction when given a mixed agonist-antagonist, like pentazocine. Priorexposureto a morphinelike drug has been shown to greatly increase a patient’s sensitivity to the antagonist component of a mixed agonist-antagonist drug. Addiction Tolerance and physical dependence
are predictable pharmacologic effects seen in response to the repeated administration ofopioids in both manand laboratory animals. These effects are distinctly different from the abnormal behavioral patterns seen in some individuals, described by the term psychological dependence or addiction. Addiction is characterized by a continued craving for opioids as manifested by compulsive drug seeking behavior and overwhelming involvement in drug procurement and use. The developmentofaddiction is acornplexphenomenon in which the typeof individual, the reason for drug use, the environment, and the drug play major and, at times, equivalent roles. This concept was well illustrated by the epidemic of addiction seen in Vietnam veterans who rapidly discontinued their heroinuse once home, withoutthe use of maintenance programs and with low rates ofrelapse.4 It is clearly possible for patients taking opioids on a chronicbasis, such as those with cancer pain, to be physically dependent without evidence of addiction. As noted by Angell,5 addiction among patients who receive opioids for painis exceedingly unlikely, and the incidence is probably no greater than 0.1 percent. Further support for this low addiction rate comes from a study by Chapman and Hill.3 These investigators studied 26 patients following bone marrow transplantation who required opioid analgesics for severe oral mucositis. Twelve patients self-administered morphine via a patient-controlled analgesia (PCA) system for two weeks. The other fourteen patients acted as controls and were given morphine by routine staff-controlled continuous infusion procedures. Self-administering patients used significantly less morphine than the controls and still achieved the same amount ofpaincontrol. In addition, the self-administering patients terminated drug use sooner than the control
The American Journal of Hospice & Palliative Care, January/February 1991 Downloaded from ajh.sagepub.com at Purdue University on July 7, 2015
patients. The investigators concluded that the results support the assumption that self-administration of opioids in a medical setting does not put patients at risk for over-medication or addiction.
At Last...
A Video Teaching Tool for the Hospice Medicare Benefit
Conclusion Based on this revieW of the medical literature on tolerance, physical dependence and addictionas they relate to the managementofchronic cancerpain, the follbwing conclUsions ~ireoffered:
Montgomery Hospice Society introduces:
“HOSPIeE
• Tolerance appears to develop in all patients receiving opioids on a chronic basis, and may occur after a week or more of morphine therapy. • Physical dependence is important to understand because of the occurrence of withdrawal symptoms, which may be subtle or significant depending on the duration and dosage of opioids used at the time when these drugs are stopped. Clinically, this problem can be avoided by a gradual decrease in daily opioid doses. • The incidence of addiction in cancer patients taking opioids chronically is probably no greater than 0.1 percentLJ
FOR LIVI\G”
... winner of the National Hospice Organization’s 1989 President’s Award for Non-print Media
This sensitive, 14-minute video: • portrays hospice in a positive, hopeful way • opens dialogue with patients, families, professionals and the public • explains hospice through patients and family • identifies Hospice Medicare Benefit services • comes with guidelines for use
Audiences: • patients, families, significant others • physicians and nurses • social workers and discharge planners • hospital, nursing home, and physician office staffs • volunteers and new staff • board members
References
I Suggested uses:
1. Jaffe ill: Drug addiction and drug abuse. hI:
• patient and family education
Gilman AG, Goodman LS, Rail TW, Murad F, eds. The pharmacological basis of therapeutics, Seventh edition. New York, The Macmillan Publishing Company, 1985;532-581
• professional relations/referrals • new staff orientation • volunteer training
2. Foley KM, Inturrisi CE: Analgesic drug thetapy in cancer pain: principles and practice. Med Clin North Am 1987;71:207-232
• public showings
3. Chapman CR, Hill HF: Prolonged morphine self-administration and addiction liability: evaluation of two theories in a bone marrow transplantation unit. Cancer 1989;63:16361644 4. Foley KM: Controversies in cancer pain: medical perspectives. Cancer 1989;63:22572265 5. AngellM: Thequality of mercy. NEngl JMed 1982;306:98-99
• board and donor education
1
Format/Costs: Available at special introductory prices in VHS format. One cassette—$50, two cassettes—$65, three cassettes—$75, plus shipping. Available for preview and rental at $20 (applicable to purchase) plus shipping.
I
To order:
Call (301) 279-2566 or FAX (301) 309-8791 to order l)y credit card. MasterCard and \ISA ae(’e )ted. Or, sentl 1 cheek or nlonev order (made payal)le to Montgomer~ Hospice Foundation) to: Business Office. Dept. AJ H. Montgomery hospice Society. Twelve Oaks Office Park. The American Journal of Hospice & Palliative Care, January/February 1991 Blvd., Suite 310, Roek%ille. Ml) 20850. Downloaded from ajh.sagepub.com at Purdue University on145() July 7, Research 2015
