Current concepts
Complications in pain management Robert B. Enck, MD
Although chronic cancer pain may be effectively controlled with a wide variety of phannacologic agents, this is often associated with coincidental untoward side effects. In some cases, these side effects become so burdensome that they interfere with the goal of patient comfort. Therefore, not only is the understanding of pharmacologic intervention important in pain control strategies, but also an appreciation of the side effects and how they are managed is critical to good patientcare. Certain risks have been identified which expose the patient to a greater likelihood of having a drug related complication. Age is a major factor.
Robert E. Enck, MD, is past president of the Association of Community Cancer Centers, Columbus, Ohio.
• Dry mouth during 39 percent
Older patients are more sensitive to opioids and their side effects than younger patients. Prior opioid treatment and the route of administration are also important. For example, sublingual, buccal, and rectal administration of morphine have less side effects when compared to the oral route. The presence of underlying medical problems, especially pulmonary disease, may enhance untoward reactions to pain management therapies. Patients with pulmonary dysfunction are at greater risk for developing opioid-induced respiratory depression than patients with normal lung function. In 1987, Ventafridda et al’ reported their two year experience using the World Health Organization (WHO) three step treatment for cancer pain. In brief, this analgesia ladder starts with non-opioids, such as aspirin, acetaminophen, and other nonsteroidal anti-inflammatory drugs (NSAID). As pain progresses, the next step is the use of weak opioids, codeine for example. Thefinal step, ifpain persists, is utilization of the strong opioids, that is, morphine and related compounds. Adjuvant analgesics may be used as well. The investigators calculatedthe percent of days in which side effects were present during a two month follow up ofpatients treated. Over the entire span of the three step treatment, the most frequent side effects were:
of the follow up days; • Drowsiness, 38 percent; • Constipation, 35 percent; • Sweating, 23 percent; • Nausea and vomiting, 22 percent; • Stomach ache, 17 percent; • Agitation, 16 percent; • Itching, 10 percent; • Blood loss, 6 percent; • No side effects were reported on 24 percent of the days of follow up. Not surprising, there were no side effects in more patients given nonopioids than strong opioids (39 percent versus 21 percent). More dry mouth, drowsiness, constipation and sweating were reported by the patients treated with the strong opioids, predominately morphine, compared to patients given either non-opioids or weak opioids. Dry mouth
Although the study by Ventafridda et al identified dry mouth as the most frequent side effect of treatment using the WHO analgesia ladder, it is difficult to attribute this complication to a single drug since most patients were taking
The American Journal of Hospice & Palliative Care November/December 1992 Downloaded from ajh.sagepub.com at The University of Iowa Libraries on April 20, 2015
morphine and dryness of the mouth. When the results were controlled for concurrent treatment, patients receiving morphine were approximately four times more likely to have a dry mouth of any severity than patients taking weak opioids, non-opioids, or no analgesics. The mechanisms for the adverse effect of morphine were uncleat The authors conclude that recognition of this side effect is important. Careful attention should be paid to oral comfort and hygiene.
Table 1. Clinically Important side effects of opiolds. CNS.related* Drowsiness/sedation Nausea/vomiting Agitation, nightmares, anxiety, euphoria, dysphoria, depression, paranoia, hallucinations Respiratorydepression Non-CNS related Dry mouth Constipation Sweating
Respiratory depression
Itching
In a recent review of analgesic drug therapy for chronic cancer pain, Foley and Inturrisi3 suggest the most common side effects of opioid analgesics are sedation, nausea and vomiting, constipation, and respiratory depression. With the exception of respiratory depression, these are similar to those reported by Ventafridda eta!.1 Respiratory depression is potentially the most serious side effect of opioid therapy. Morphine and related drugs act on brainstem respiratory centers to produce dose dependent respiratory depression. Therapeutic doses of morphine may depress all phases of respiration. However, as carbon dioxide accumulates, it stimulates the respiratory centers resulting in a compensatory increase in respiratory rate which, in turn, hides the degree of respiratory depression. At equivalent doses, all the morphine related drugs produce the same degree of respiratory depression. For these reasons, Foley and Inturrisi3 suggest that patients with impaired respiratory function or bronchial asthma are at greater risk for experiencing clinically significant respiratory depression in response to the usual doses of these drugs. Respiratory depression usually occurs with the acute administration of morphine to an opioid naivepatient and is often accompanied by other signs of
Urinary retention *L~~l in decreasing order of frequency.
multiple drugs. Therefore, the study by White et a!2 is of help in identifying a cause for this complication. These investigators studied the prevalence of dryness of the mouth in patients with cancer to determine ifit was related to the use of morphine. All patients admitted to the Continuing Care Unit, Royal Marsden Hospital, during an eight week periodwere entered intothe study except those who had other reasonsfor having a dry mouth such as receiving radiation therapy, surgery, chemotherapy, or the like. Data was obtained from 199 patients. One hundred thirty-one patients were using opioid analgesics, and 67 were taking morphine. One hundred nineteen of 199 patients (57 percent) reported dryness of the mouth at some time during the course of treatment, of whom 42 (37 percent) had a dry mouth most or all of the time. There was no significant correlation between the severity of the mouth dryness and sex, age, primary diagnosis, reason for admission, wearing dentures, oral candidiasis, orsmoking. Analysis showed a highly significant associationbetween the use of
The American Journal of Hospice & Palliative Care November/December 1992 Downloaded from ajh.sagepub.com at The University of Iowa Libraries on April 20, 2015
central nervous system depression such as sedation and confusion. Tolerance to this effect develops rapidly with repeated drug administration, thus typically allowing opioid analgesics to be used in the management of chroniccancer pain without significant risk of respiratory depression. If respiratory depression occurs, it may be reversed by the administration of the specific opioid antagonist, naloxone. In patients being treatedwith opioids chronically who develop respiratory depression, naloxone diluted 1:10, should be titrated carefully to prevent the precipitation of severe withdrawal symptoms.3 The major central nervous system (CNS) effect of the opioids is sedation or drowsiness. Because of an additive effect, care mustbe exercised in the use of other CNS depressants such as alcohol, barbiturates,and benzodiazepines in combination with opioids. Tolerance to sedation usually develops within the first several days of chronic opioid administration.3 Nausea and vomiting Opioid analgesics produce nausea and vomiting by acting on the medullary chemoreceptor trigger zone. The tendency of these drugs to causenausea and vomiting varies from patient to patient, so there may be some advantage in changing opioids in patients experiencing this side effect. Alternatively, antiemetics may be combined with the opioid. However, the choice of antiemetics is important, since drugs, such as the phenothiazines, may only enhance opioid-induced sedation. Other CNS side effects
Other, less frequent CNS side effects include nightmares, anxiety, agitation, euphoria, dysphoria, depression, paranoia, and hallucinations. These generally occur with high doses of opioids, with the possible exception of meperidine and methadone.4 Ac-
cumulation of the metabolite, normeperidine, in patients treatedchronically with meperidine causes CNS excitation. It is for this reason that this drug is not recommended for use in the management of chronic cancer pain. Care must also be taken when using methadone as well. Because of its long half-life (15 to 30 hours), chronic methadone dosing can lead to drug accumulation leading to over sedation and, rarely, coma. Constipation
Constipation is a common noncentral nervous system side effect of opioid analgesics. These drugs act at multiple sites throughout the gastrointestinal tract and spinal cord to cause a decrease inintestinal secretions and peristalsis. The net effect is constipation.3’5 Tolerance develops very slowly to the smooth muscle effects of opioids so that constipation persists when these drugs are used for chronic pain. When opioids are started, careful attention should be given to managing this side effect. Measures such as increasing ambulation and fluid intake, beginning a diet high in fiber or trying a bulk laxative should be initiated. The daily administration of a stool softener is also helpful.5 Urinary retention
Another peripheral side effect of the opioid analgesics is bladder spasm and an increase in smooth muscle sphincter tone leading to urinary retention. This is most common in older patients and is transient.3 The itching and sweating associated with opioids is most likely related to histamine release. NSAJDs
The nonsteroidal anti-inflammatory drugs (NSAID) are often used in the management of chronic cancer pain. Indeed, this group of drugs comprise the first step of the WHO analgesia ladder. Acetaminophen has minimal
anti-inflammatory effect and lacks the
(psychological dependence), this will be reviewed in a future segment of Current Concepts. Based on this review of the medical literature, the following conclusions regarding chronic pain management complications are offered:
side effect profile of the NSAIDs. Chronic dosing can produce renal damage. Salicylates, such as aspirin, in high doses causes gastric irritation which often limit their use clinically. Also, aspirin interferes with platelet function, at any dose, whichcan lead to bleeding problems.
• In order to preventthe develop-
ment of drug-induced side effects, it is important to recognize and address factors, such as age, during pain management therapy.
Table 2. Clinically important side effects of NSAIDs. Gastrointestinalirritation and ulceration Bleeding dueto platelet dysfunction
• Approximately one-fourth of the patients managed by the WHO analgesia guidelines reported no side effects.
Impaired renal function CNS toxicity including dizziness, anxiety, drowsiness, tinnitus, and confusion
As a group, the NSAIDs produce similar adverse effects but the frequency and severity vary with the individual and the specific drug. The major toxicities of the NSAIDs are gastrointestinal, hematologic, renal, and central nervous system. All NSAJDs can cause dyspepsia and untoward gastrointestinal effects, including bleeding, ulceration and perforation in patients treated chronically with these drugs. They interfere with platelet function and, potentially, can cause bleeding. NSAIDs decrease renal bloodflow, cause fluid retention, and may cause renal failure in some patients, especially the elderly. All NSAIDs can cause dizziness, anxiety, drowsiness, tinnitus and confusion which may occur initially and disappearwith further use. Other less common side effects such as hepatitis, pancreatitis and the like have alsobeen noted.6
• Strong opioids, such as morphine, produce more side effects thaneither non-opioids or weak opioids. • NSAIDs are frequently used in
pain management but are often limited by their side effects,especially gastrointestinal tract irritation.L~
References 1. Ventafridda V. Tamburini M, Caraceni A, et al: A validation study of the WHO method for cancer pain relief. Cancer 1987;59:850-856 2. White ID, Hoskin PJ, Hanks GW, Bliss JM: Morphine and dryness of the mouth. Br Med J 1989;298: 1222-1223 3. Foley KM. Interrisi CE: Analgesic drug therapy in cancer pain: Principles and practice. Med Clin North Am 1987;71:207-232 4. Drugs that cause psychiatric symptoms. Medical Letter 1989;3l:1l3-118 5. Enck RE: Constipation: Etiologies and management. Am JHosp Care 1988;5(5):17-19 6. Drugs for rheumatoid arthritis. Medical Letter 1989;31:6l-64
Conclusion Because ofthe importanceof understanding other pain management complication issues relating to tolerance, physical dependence and addiction
The American Journal of Hospice & Palliative Care November/December 1992 Downloaded from ajh.sagepub.com at The University of Iowa Libraries on April 20, 2015
Complications in pain management Robert B. Enck, MD
Although chronic cancer pain may be effectively controlled with a wide variety of phannacologic agents, this is often associated with coincidental untoward side effects. In some cases, these side effects become so burdensome that they interfere with the goal of patient comfort. Therefore, not only is the understanding of pharmacologic intervention important in pain control strategies, but also an appreciation of the side effects and how they are managed is critical to good patientcare. Certain risks have been identified which expose the patient to a greater likelihood of having a drug related complication. Age is a major factor.
Robert E. Enck, MD, is past president of the Association of Community Cancer Centers, Columbus, Ohio.
• Dry mouth during 39 percent
Older patients are more sensitive to opioids and their side effects than younger patients. Prior opioid treatment and the route of administration are also important. For example, sublingual, buccal, and rectal administration of morphine have less side effects when compared to the oral route. The presence of underlying medical problems, especially pulmonary disease, may enhance untoward reactions to pain management therapies. Patients with pulmonary dysfunction are at greater risk for developing opioid-induced respiratory depression than patients with normal lung function. In 1987, Ventafridda et al’ reported their two year experience using the World Health Organization (WHO) three step treatment for cancer pain. In brief, this analgesia ladder starts with non-opioids, such as aspirin, acetaminophen, and other nonsteroidal anti-inflammatory drugs (NSAID). As pain progresses, the next step is the use of weak opioids, codeine for example. Thefinal step, ifpain persists, is utilization of the strong opioids, that is, morphine and related compounds. Adjuvant analgesics may be used as well. The investigators calculatedthe percent of days in which side effects were present during a two month follow up ofpatients treated. Over the entire span of the three step treatment, the most frequent side effects were:
of the follow up days; • Drowsiness, 38 percent; • Constipation, 35 percent; • Sweating, 23 percent; • Nausea and vomiting, 22 percent; • Stomach ache, 17 percent; • Agitation, 16 percent; • Itching, 10 percent; • Blood loss, 6 percent; • No side effects were reported on 24 percent of the days of follow up. Not surprising, there were no side effects in more patients given nonopioids than strong opioids (39 percent versus 21 percent). More dry mouth, drowsiness, constipation and sweating were reported by the patients treated with the strong opioids, predominately morphine, compared to patients given either non-opioids or weak opioids. Dry mouth
Although the study by Ventafridda et al identified dry mouth as the most frequent side effect of treatment using the WHO analgesia ladder, it is difficult to attribute this complication to a single drug since most patients were taking
The American Journal of Hospice & Palliative Care November/December 1992 Downloaded from ajh.sagepub.com at The University of Iowa Libraries on April 20, 2015
morphine and dryness of the mouth. When the results were controlled for concurrent treatment, patients receiving morphine were approximately four times more likely to have a dry mouth of any severity than patients taking weak opioids, non-opioids, or no analgesics. The mechanisms for the adverse effect of morphine were uncleat The authors conclude that recognition of this side effect is important. Careful attention should be paid to oral comfort and hygiene.
Table 1. Clinically Important side effects of opiolds. CNS.related* Drowsiness/sedation Nausea/vomiting Agitation, nightmares, anxiety, euphoria, dysphoria, depression, paranoia, hallucinations Respiratorydepression Non-CNS related Dry mouth Constipation Sweating
Respiratory depression
Itching
In a recent review of analgesic drug therapy for chronic cancer pain, Foley and Inturrisi3 suggest the most common side effects of opioid analgesics are sedation, nausea and vomiting, constipation, and respiratory depression. With the exception of respiratory depression, these are similar to those reported by Ventafridda eta!.1 Respiratory depression is potentially the most serious side effect of opioid therapy. Morphine and related drugs act on brainstem respiratory centers to produce dose dependent respiratory depression. Therapeutic doses of morphine may depress all phases of respiration. However, as carbon dioxide accumulates, it stimulates the respiratory centers resulting in a compensatory increase in respiratory rate which, in turn, hides the degree of respiratory depression. At equivalent doses, all the morphine related drugs produce the same degree of respiratory depression. For these reasons, Foley and Inturrisi3 suggest that patients with impaired respiratory function or bronchial asthma are at greater risk for experiencing clinically significant respiratory depression in response to the usual doses of these drugs. Respiratory depression usually occurs with the acute administration of morphine to an opioid naivepatient and is often accompanied by other signs of
Urinary retention *L~~l in decreasing order of frequency.
multiple drugs. Therefore, the study by White et a!2 is of help in identifying a cause for this complication. These investigators studied the prevalence of dryness of the mouth in patients with cancer to determine ifit was related to the use of morphine. All patients admitted to the Continuing Care Unit, Royal Marsden Hospital, during an eight week periodwere entered intothe study except those who had other reasonsfor having a dry mouth such as receiving radiation therapy, surgery, chemotherapy, or the like. Data was obtained from 199 patients. One hundred thirty-one patients were using opioid analgesics, and 67 were taking morphine. One hundred nineteen of 199 patients (57 percent) reported dryness of the mouth at some time during the course of treatment, of whom 42 (37 percent) had a dry mouth most or all of the time. There was no significant correlation between the severity of the mouth dryness and sex, age, primary diagnosis, reason for admission, wearing dentures, oral candidiasis, orsmoking. Analysis showed a highly significant associationbetween the use of
The American Journal of Hospice & Palliative Care November/December 1992 Downloaded from ajh.sagepub.com at The University of Iowa Libraries on April 20, 2015
central nervous system depression such as sedation and confusion. Tolerance to this effect develops rapidly with repeated drug administration, thus typically allowing opioid analgesics to be used in the management of chroniccancer pain without significant risk of respiratory depression. If respiratory depression occurs, it may be reversed by the administration of the specific opioid antagonist, naloxone. In patients being treatedwith opioids chronically who develop respiratory depression, naloxone diluted 1:10, should be titrated carefully to prevent the precipitation of severe withdrawal symptoms.3 The major central nervous system (CNS) effect of the opioids is sedation or drowsiness. Because of an additive effect, care mustbe exercised in the use of other CNS depressants such as alcohol, barbiturates,and benzodiazepines in combination with opioids. Tolerance to sedation usually develops within the first several days of chronic opioid administration.3 Nausea and vomiting Opioid analgesics produce nausea and vomiting by acting on the medullary chemoreceptor trigger zone. The tendency of these drugs to causenausea and vomiting varies from patient to patient, so there may be some advantage in changing opioids in patients experiencing this side effect. Alternatively, antiemetics may be combined with the opioid. However, the choice of antiemetics is important, since drugs, such as the phenothiazines, may only enhance opioid-induced sedation. Other CNS side effects
Other, less frequent CNS side effects include nightmares, anxiety, agitation, euphoria, dysphoria, depression, paranoia, and hallucinations. These generally occur with high doses of opioids, with the possible exception of meperidine and methadone.4 Ac-
cumulation of the metabolite, normeperidine, in patients treatedchronically with meperidine causes CNS excitation. It is for this reason that this drug is not recommended for use in the management of chronic cancer pain. Care must also be taken when using methadone as well. Because of its long half-life (15 to 30 hours), chronic methadone dosing can lead to drug accumulation leading to over sedation and, rarely, coma. Constipation
Constipation is a common noncentral nervous system side effect of opioid analgesics. These drugs act at multiple sites throughout the gastrointestinal tract and spinal cord to cause a decrease inintestinal secretions and peristalsis. The net effect is constipation.3’5 Tolerance develops very slowly to the smooth muscle effects of opioids so that constipation persists when these drugs are used for chronic pain. When opioids are started, careful attention should be given to managing this side effect. Measures such as increasing ambulation and fluid intake, beginning a diet high in fiber or trying a bulk laxative should be initiated. The daily administration of a stool softener is also helpful.5 Urinary retention
Another peripheral side effect of the opioid analgesics is bladder spasm and an increase in smooth muscle sphincter tone leading to urinary retention. This is most common in older patients and is transient.3 The itching and sweating associated with opioids is most likely related to histamine release. NSAJDs
The nonsteroidal anti-inflammatory drugs (NSAID) are often used in the management of chronic cancer pain. Indeed, this group of drugs comprise the first step of the WHO analgesia ladder. Acetaminophen has minimal
anti-inflammatory effect and lacks the
(psychological dependence), this will be reviewed in a future segment of Current Concepts. Based on this review of the medical literature, the following conclusions regarding chronic pain management complications are offered:
side effect profile of the NSAIDs. Chronic dosing can produce renal damage. Salicylates, such as aspirin, in high doses causes gastric irritation which often limit their use clinically. Also, aspirin interferes with platelet function, at any dose, whichcan lead to bleeding problems.
• In order to preventthe develop-
ment of drug-induced side effects, it is important to recognize and address factors, such as age, during pain management therapy.
Table 2. Clinically important side effects of NSAIDs. Gastrointestinalirritation and ulceration Bleeding dueto platelet dysfunction
• Approximately one-fourth of the patients managed by the WHO analgesia guidelines reported no side effects.
Impaired renal function CNS toxicity including dizziness, anxiety, drowsiness, tinnitus, and confusion
As a group, the NSAIDs produce similar adverse effects but the frequency and severity vary with the individual and the specific drug. The major toxicities of the NSAIDs are gastrointestinal, hematologic, renal, and central nervous system. All NSAJDs can cause dyspepsia and untoward gastrointestinal effects, including bleeding, ulceration and perforation in patients treated chronically with these drugs. They interfere with platelet function and, potentially, can cause bleeding. NSAIDs decrease renal bloodflow, cause fluid retention, and may cause renal failure in some patients, especially the elderly. All NSAIDs can cause dizziness, anxiety, drowsiness, tinnitus and confusion which may occur initially and disappearwith further use. Other less common side effects such as hepatitis, pancreatitis and the like have alsobeen noted.6
• Strong opioids, such as morphine, produce more side effects thaneither non-opioids or weak opioids. • NSAIDs are frequently used in
pain management but are often limited by their side effects,especially gastrointestinal tract irritation.L~
References 1. Ventafridda V. Tamburini M, Caraceni A, et al: A validation study of the WHO method for cancer pain relief. Cancer 1987;59:850-856 2. White ID, Hoskin PJ, Hanks GW, Bliss JM: Morphine and dryness of the mouth. Br Med J 1989;298: 1222-1223 3. Foley KM. Interrisi CE: Analgesic drug therapy in cancer pain: Principles and practice. Med Clin North Am 1987;71:207-232 4. Drugs that cause psychiatric symptoms. Medical Letter 1989;3l:1l3-118 5. Enck RE: Constipation: Etiologies and management. Am JHosp Care 1988;5(5):17-19 6. Drugs for rheumatoid arthritis. Medical Letter 1989;31:6l-64
Conclusion Because ofthe importanceof understanding other pain management complication issues relating to tolerance, physical dependence and addiction
The American Journal of Hospice & Palliative Care November/December 1992 Downloaded from ajh.sagepub.com at The University of Iowa Libraries on April 20, 2015
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