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Effects of morphine on the dyspnea of terminal cancer patients
Vol. 2 Xu. 6 Ilecember 1990
Journal of Pain and Symptom Management
341
Eduardo Bruera, MD, Karen MacmiHan, RN, Jim Pitker, RT, and R. Neil MacDonald, MD Palliative Care Wnit, Edmonton General Hos@ul, Edmonton, Canada
--
Abstract We re@rt an open, uncontrolled study designed to assess the @e&s of subcutaneous (SC) morphine 011! dyspnea of terminal cancer. Twenty patients with dyspnea cazcsed by restrictive respiratory failure received an SC dose of morphine
In&o&&uIa __
_
.
.^
Dyspnea or breathlessness has been dehned as an uncomfortable awareness of breathing. This symptom is experienced under conditions in which there is an inordinately high ventilatory demand relative to the ability to breathe.
.
Address reprint requests to: Eduardo Bruera, MD, Palliative Care Unit, Edmonton General Hospital, 1 I 111 Jasper Avenue, Edmonton, Alberta T5K OL4, Canada. Acceptedfor publication: November 2, 1989.
Q U.S. Cancer Pain Relief Committee, 1990 Published by Elsevier, New York, New York
Its major physical evidence is tachypnea.‘e2 Dyspnea occurs in 29%-74% of patients with terminal cancer,3v4 and it is perceived as one of the most devastating symptoms .by the patient and family. Although narcotics have been suggested to be beneficial for the treatment of dyspnea in terminal cancer patients,3-5 no prospective studies have been made in this population. The purpose of this study was to assess the effects of morphine on dyspitea, phvsical signs of respiratory failure, and saturation of oxygen and expiratory concentration of CO2 in patients with dyspnea caused by terminal cancer.
0885-9924/90/$9.50
PW
and Meihak
Twenty coosecutive patients lqith terminal cancer who were admitted to the PalliativeCare Unit, Edmonton General Hospital,between Ckt&r 1988 and April 1939 were admitted to this study. The mean age was 64 + 17 years. Nine patients were female. The primarytumor was lung in eight cases, breast and ovary in four cases each, colon in two cases, and stomach and esophagus in one case each, The cause of dyspnea was p~~ive tung tumor in seven case3, Iuug mcstastasis in five cases, pleural effusion in four cases, ca~~n~matou$ ~ymphan~ti~in two cakes, pneumonia in one case, and pulmonary fibrosis in one case. All patients had severe dippy at retltbecause of rest~ctive ~spi~to~ fa3ure. In none of the patientfiwas there any clinical evidence or history of airway obstruction. All patients were receiving contin~lo~~soxygen using masks or nasal prongs at a rate of 2-6 L/n&. All patients were fully conscious and &owed no evidence of cognitive failure as detetined by clinical examination and at least two determinations with the mini-mental state questionnaire.p Of the 20 patients, 15 (75%) were receiving oral narcotics for the treatment of cancer pain. In all cases*narcotics were adminis&z& intermittently every 4 hr. In all patients, after H hr rest and immediately priorto the next scheduled dose of narcotics, the following assessments were made. I, ~~~ Dyspnea was rne~u~ using a visual analog scale (0: no shortness of breath; 106: worst &ortr~~~of breath), This method has been found to be reliible in the assessment of dyspnca,7” 2. Ru.$Wor~&Pb,’Respiratoryratt was determined over a l-min interval twice. and the results wets averaged. An index of respiratory effort was cozzputed as follows:
The v&es could range from 1 to 6. 3. ckeitasky:Arterial oxygen saturation and end-tidal PACO, was determined using a com-
puterized combined pulse oxymeter and endtidal CO9 unit (Criticare Systems Inc, Milwaukee, WI). This unit has an accuracy of -c-3% for oxygen saturation values between 40% and MO%,,and 5: 2 mm Mg for end-tidal CO, values between 0 and 99 mm Hg. This system has heen found to be reliable for anesthesiology practiceP Because of the palliative tzture of the care of our p&en&, arterial bfood g$xsesare usui3lly not detern:ined even in presence of severe respiratory distress. 4. Pain: In the 15 patients with chronic cancer pain, a visual analog scale (0 = no pain; 100 = worst pain) was used. After the baseline itssessment, patients were administered a subcutaneous injection of morphine. In the 15 patients who were receiving oral na~~tics, the test dose was equivalent to 2.5 riws the regular dose. This dose was chosen irnorder to produce ~ignifi~nt pha~~co~o~c effect in patients who had probably developed some tolerance, without causing exaesuive toxicity. The dose was administered at the time of &eir scheduled analgesic dose. In the five patients who were not receiving narcotics, the dose was 5 mg of morphine sulfate (the usual initial dose of parenteral morphine for cancer pain). The average dose administer was 28 2 22 mg.
Following the test dose, the assessment of dyspnea and pain was repeated every 15 min for 150 min. The assessment of respiratory rate, respiratory effort score, apd oximetry was repeated 45 min after the injection of morphine. Oxygen administration was kept unchanged for the duration of the study. Results were analyzed using thr paired t te,lt according to the Statistical Package for the So&J !Mences. I*
‘Table 2 summa~zes the results after SC morphine. There was a significant improvement in dyspnea without any significant change in respiratory rate, respiratory effort, or changes in saturation of CO, or PaGas. In patients with pain, the e&t of morphine on dytpnea had a &orter duration than the analgesic effect (Figure 1). results were not significantly different between patients who had been receiving mor-
VoL I No. 6 Decembm 1990
Morphinefor &pnea of Teminad Came-r
Table I
Results After the Admi~~s~tion
Dyspnea (0- 100) Respiratory rate Respiratory effort score (l-6) Saturation of 0, Concentration of respiratory CO, Pain (0- 100)
of ~o~~e*
Before morphine
45 Min After Mo~~inF
P
68 +, 32 32 -c 7
34 + 25 31+9
3.5 + 1.8 8’7 + IO
3.2 + 1.9 86 f 11
NS NS
31 + 12 35 ‘- 21
33 + 9 14 -t 12
NS
*Results expressed as mean f SD.
phine (n -9 1st and those who had not (n = 5). Toxicity was miaimal and consisted of nausea in two cases and sedation in two cases; in all cases, toxicity was reported by patients who were not receiving narcotics. Ninetee of the 20 patients reported improved dyspnea after SC morphine and continued to receive the same dose for dyspnea on an as-needed basis, with continued re8ef.
Our results e**ggest that morphine can improve the symptom of dyspnea witbout significantly changing respiratory rate, saturation of Os, or expiratory CO,. Other studies have evaluated alcohol, caffeine, dihydrocodeine, diazepam, and promethazine in patients with
343
dyspnea caused by chronic airway obstruction. 1leg4 Caffeine and diazepam do not appear to have a significant effect,“J* but promethazinc, alcohol, and dihydrocodeine were able to uce dyspnea in double-blind, placebo-contr&cd ttiaI~.‘~*‘* Alcohol has been suggested to help dyspnea bj releasing endorphins.ls Morphine’s mechanism of action in reducing dyspnea is unsown, but our data suggest that it might reduce the perception of dygt:rea withour an accompanying physiologic change, since in our patients a reduction indyspnea was not accompanied by a reduction in~entiiation. Although patients felt more comfortable, they did not appear to be more comfortable to the observer. The possibility of mo~hine-induced improvement in lung function or decrease in 0, consumption has also been suggested.ttJ* Tbese results need TVbe confirmed in a double-blind study. It is not clear from our experience whether morphine is useful for chronic management of dyspnea. Our data (Figure 1) suggest that its duration of action on dyspnea is much shorter than the analgesic effects. Furthermore, in a 2-week study of dihydrocodone, patients with chronic airway obstruction had very poor tolerance to the side effects of the narcotic.r2 However, OUEpatients tolerated the morphine very well, because most had already developed tolerance to the most frequent side edfects of narcotics, such as nausea, sedation, and dizzinessi Future controlled trials should caref uily determine sedation and cognitive function in order to establish if decreased dysp-
DYSPNEA (N&O)
PAIN (N=l!i)
MINUTES
Fig. 1. Change in mean dyrtpnea and mean pain aft&r SC morphine. Results expressed as mean 2 SE.
nea is a specific effect or the result of a more general rno~~rne-induced obtu~dation.16 Results with diazepam suggest that increased sedation does not result in decreased complaints of
dyspnea.14 The absence of a ~~i~~lt difference in response between patients ~ceiving morphine (n = 15) and morphine-naive patients (n = 5) does not mean that such difference might not exist, ~~~icul~riy because of the smatl number of patients studied, However, if this finding is confirmed, it could ix due to the fact that patients who are receiving narcotics were administered a dose 2.5 times higher than their usual dose in order to ove~ome ~tent~l tolerance. We conclude that SC morphine appears to
improve dyspnea at doses that do not compromise respiratoryfunction. Controlled trials are needed to confirm this finding.
5. BillingsJA. Dyspnea, cough and other respiratory s~ptoms. In: Billings JA, ed. Qutpatient management of advanced cancer. Philadelphia: JB Lippincott, 1985:83. 6. Knights E, Folstein MF. Unsuspected emotional and cognitive disturbance in medical patients. Ann Intern Med 1977;87:723-724. 7. Mahler D, Weinberg D, Wells C, et al. The measurement of dyspnea. Chest 1984;85:751-758. 8. Adams L, Lane R, Shea S, et al. Breathlessness during different forms of ventilatory stimulation. Clin Sc 1985:6~663-672. 9. Alexander C, Teller L, Gross J, et al. Principles of pulse oximetry: theoretical and practical considerations. Anesthesiology 1987;65:1lo- 118. 10, Statistical Package for the Social Sciences. Chicago: McGraw-Hill, 1986. 11. Woodcock A, Gross E, Cellert A, et al, Effects of dihydrocodeine, alcohol, and caffeine on breathlessness and exercise toltrance in patients with chronic obstructive lung disease and normal blood gases. N Engl J Med 1981;305:1611-1617.
References 1. Wasserman K, Casaburi R. Dyspnea: physiolo~c and ~thophysiolo~~l mechanisms. Annu Rev Med 1988;39:503-515. 2. Altosc:M. Assessment and management of breathlessness. Chest 1985;88:773-81s.
3. Baines M. Control of other symptoms. fn: Saunders CM. ed. The management of terminal disease. Chicago:Year Book, 1978. 4. Billings JA. The management of common symptams. In: BillingJA, ed. Outpatient management of ~vao~ed cancer. Philadelphia: JS Lippinc~tt, 1985:41.
12. Woodcock A, Gross E, Geddes D. Drug treatment of breathlessness: continuing effect of diazepam and promethazine in patients with chronic airway obst~ction. Br Med J 1~1:283:~3-346.
13. Bar-or D, Marx J, Good J, Breathlessness, alcohol and opiates [Letter]. N Engl J Ned 1981;305: 1363. 14. Woodcock A, Johnson M, Geddes D. Breathlessness, alcohol ancl opiates [Letter]. N Engl J Med 1981:305:1313-~314. 15. Foley K. The treatment of cancer pain. N Engl J Med 1985;313:84-93. 16. Bruera E, MacMillan K, Kuehn N, et al. The cognitive effects of the administration of narcotics. Pain 1989;39: 13- 16.
Journal of Pain and Symptom Management
341
Eduardo Bruera, MD, Karen MacmiHan, RN, Jim Pitker, RT, and R. Neil MacDonald, MD Palliative Care Wnit, Edmonton General Hos@ul, Edmonton, Canada
--
Abstract We re@rt an open, uncontrolled study designed to assess the @e&s of subcutaneous (SC) morphine 011! dyspnea of terminal cancer. Twenty patients with dyspnea cazcsed by restrictive respiratory failure received an SC dose of morphine
In&o&&uIa __
_
.
.^
Dyspnea or breathlessness has been dehned as an uncomfortable awareness of breathing. This symptom is experienced under conditions in which there is an inordinately high ventilatory demand relative to the ability to breathe.
.
Address reprint requests to: Eduardo Bruera, MD, Palliative Care Unit, Edmonton General Hospital, 1 I 111 Jasper Avenue, Edmonton, Alberta T5K OL4, Canada. Acceptedfor publication: November 2, 1989.
Q U.S. Cancer Pain Relief Committee, 1990 Published by Elsevier, New York, New York
Its major physical evidence is tachypnea.‘e2 Dyspnea occurs in 29%-74% of patients with terminal cancer,3v4 and it is perceived as one of the most devastating symptoms .by the patient and family. Although narcotics have been suggested to be beneficial for the treatment of dyspnea in terminal cancer patients,3-5 no prospective studies have been made in this population. The purpose of this study was to assess the effects of morphine on dyspitea, phvsical signs of respiratory failure, and saturation of oxygen and expiratory concentration of CO2 in patients with dyspnea caused by terminal cancer.
0885-9924/90/$9.50
PW
and Meihak
Twenty coosecutive patients lqith terminal cancer who were admitted to the PalliativeCare Unit, Edmonton General Hospital,between Ckt&r 1988 and April 1939 were admitted to this study. The mean age was 64 + 17 years. Nine patients were female. The primarytumor was lung in eight cases, breast and ovary in four cases each, colon in two cases, and stomach and esophagus in one case each, The cause of dyspnea was p~~ive tung tumor in seven case3, Iuug mcstastasis in five cases, pleural effusion in four cases, ca~~n~matou$ ~ymphan~ti~in two cakes, pneumonia in one case, and pulmonary fibrosis in one case. All patients had severe dippy at retltbecause of rest~ctive ~spi~to~ fa3ure. In none of the patientfiwas there any clinical evidence or history of airway obstruction. All patients were receiving contin~lo~~soxygen using masks or nasal prongs at a rate of 2-6 L/n&. All patients were fully conscious and &owed no evidence of cognitive failure as detetined by clinical examination and at least two determinations with the mini-mental state questionnaire.p Of the 20 patients, 15 (75%) were receiving oral narcotics for the treatment of cancer pain. In all cases*narcotics were adminis&z& intermittently every 4 hr. In all patients, after H hr rest and immediately priorto the next scheduled dose of narcotics, the following assessments were made. I, ~~~ Dyspnea was rne~u~ using a visual analog scale (0: no shortness of breath; 106: worst &ortr~~~of breath), This method has been found to be reliible in the assessment of dyspnca,7” 2. Ru.$Wor~&Pb,’Respiratoryratt was determined over a l-min interval twice. and the results wets averaged. An index of respiratory effort was cozzputed as follows:
The v&es could range from 1 to 6. 3. ckeitasky:Arterial oxygen saturation and end-tidal PACO, was determined using a com-
puterized combined pulse oxymeter and endtidal CO9 unit (Criticare Systems Inc, Milwaukee, WI). This unit has an accuracy of -c-3% for oxygen saturation values between 40% and MO%,,and 5: 2 mm Mg for end-tidal CO, values between 0 and 99 mm Hg. This system has heen found to be reliable for anesthesiology practiceP Because of the palliative tzture of the care of our p&en&, arterial bfood g$xsesare usui3lly not detern:ined even in presence of severe respiratory distress. 4. Pain: In the 15 patients with chronic cancer pain, a visual analog scale (0 = no pain; 100 = worst pain) was used. After the baseline itssessment, patients were administered a subcutaneous injection of morphine. In the 15 patients who were receiving oral na~~tics, the test dose was equivalent to 2.5 riws the regular dose. This dose was chosen irnorder to produce ~ignifi~nt pha~~co~o~c effect in patients who had probably developed some tolerance, without causing exaesuive toxicity. The dose was administered at the time of &eir scheduled analgesic dose. In the five patients who were not receiving narcotics, the dose was 5 mg of morphine sulfate (the usual initial dose of parenteral morphine for cancer pain). The average dose administer was 28 2 22 mg.
Following the test dose, the assessment of dyspnea and pain was repeated every 15 min for 150 min. The assessment of respiratory rate, respiratory effort score, apd oximetry was repeated 45 min after the injection of morphine. Oxygen administration was kept unchanged for the duration of the study. Results were analyzed using thr paired t te,lt according to the Statistical Package for the So&J !Mences. I*
‘Table 2 summa~zes the results after SC morphine. There was a significant improvement in dyspnea without any significant change in respiratory rate, respiratory effort, or changes in saturation of CO, or PaGas. In patients with pain, the e&t of morphine on dytpnea had a &orter duration than the analgesic effect (Figure 1). results were not significantly different between patients who had been receiving mor-
VoL I No. 6 Decembm 1990
Morphinefor &pnea of Teminad Came-r
Table I
Results After the Admi~~s~tion
Dyspnea (0- 100) Respiratory rate Respiratory effort score (l-6) Saturation of 0, Concentration of respiratory CO, Pain (0- 100)
of ~o~~e*
Before morphine
45 Min After Mo~~inF
P
68 +, 32 32 -c 7
34 + 25 31+9
3.5 + 1.8 8’7 + IO
3.2 + 1.9 86 f 11
NS NS
31 + 12 35 ‘- 21
33 + 9 14 -t 12
NS
*Results expressed as mean f SD.
phine (n -9 1st and those who had not (n = 5). Toxicity was miaimal and consisted of nausea in two cases and sedation in two cases; in all cases, toxicity was reported by patients who were not receiving narcotics. Ninetee of the 20 patients reported improved dyspnea after SC morphine and continued to receive the same dose for dyspnea on an as-needed basis, with continued re8ef.
Our results e**ggest that morphine can improve the symptom of dyspnea witbout significantly changing respiratory rate, saturation of Os, or expiratory CO,. Other studies have evaluated alcohol, caffeine, dihydrocodeine, diazepam, and promethazine in patients with
343
dyspnea caused by chronic airway obstruction. 1leg4 Caffeine and diazepam do not appear to have a significant effect,“J* but promethazinc, alcohol, and dihydrocodeine were able to uce dyspnea in double-blind, placebo-contr&cd ttiaI~.‘~*‘* Alcohol has been suggested to help dyspnea bj releasing endorphins.ls Morphine’s mechanism of action in reducing dyspnea is unsown, but our data suggest that it might reduce the perception of dygt:rea withour an accompanying physiologic change, since in our patients a reduction indyspnea was not accompanied by a reduction in~entiiation. Although patients felt more comfortable, they did not appear to be more comfortable to the observer. The possibility of mo~hine-induced improvement in lung function or decrease in 0, consumption has also been suggested.ttJ* Tbese results need TVbe confirmed in a double-blind study. It is not clear from our experience whether morphine is useful for chronic management of dyspnea. Our data (Figure 1) suggest that its duration of action on dyspnea is much shorter than the analgesic effects. Furthermore, in a 2-week study of dihydrocodone, patients with chronic airway obstruction had very poor tolerance to the side effects of the narcotic.r2 However, OUEpatients tolerated the morphine very well, because most had already developed tolerance to the most frequent side edfects of narcotics, such as nausea, sedation, and dizzinessi Future controlled trials should caref uily determine sedation and cognitive function in order to establish if decreased dysp-
DYSPNEA (N&O)
PAIN (N=l!i)
MINUTES
Fig. 1. Change in mean dyrtpnea and mean pain aft&r SC morphine. Results expressed as mean 2 SE.
nea is a specific effect or the result of a more general rno~~rne-induced obtu~dation.16 Results with diazepam suggest that increased sedation does not result in decreased complaints of
dyspnea.14 The absence of a ~~i~~lt difference in response between patients ~ceiving morphine (n = 15) and morphine-naive patients (n = 5) does not mean that such difference might not exist, ~~~icul~riy because of the smatl number of patients studied, However, if this finding is confirmed, it could ix due to the fact that patients who are receiving narcotics were administered a dose 2.5 times higher than their usual dose in order to ove~ome ~tent~l tolerance. We conclude that SC morphine appears to
improve dyspnea at doses that do not compromise respiratoryfunction. Controlled trials are needed to confirm this finding.
5. BillingsJA. Dyspnea, cough and other respiratory s~ptoms. In: Billings JA, ed. Qutpatient management of advanced cancer. Philadelphia: JB Lippincott, 1985:83. 6. Knights E, Folstein MF. Unsuspected emotional and cognitive disturbance in medical patients. Ann Intern Med 1977;87:723-724. 7. Mahler D, Weinberg D, Wells C, et al. The measurement of dyspnea. Chest 1984;85:751-758. 8. Adams L, Lane R, Shea S, et al. Breathlessness during different forms of ventilatory stimulation. Clin Sc 1985:6~663-672. 9. Alexander C, Teller L, Gross J, et al. Principles of pulse oximetry: theoretical and practical considerations. Anesthesiology 1987;65:1lo- 118. 10, Statistical Package for the Social Sciences. Chicago: McGraw-Hill, 1986. 11. Woodcock A, Gross E, Cellert A, et al, Effects of dihydrocodeine, alcohol, and caffeine on breathlessness and exercise toltrance in patients with chronic obstructive lung disease and normal blood gases. N Engl J Med 1981;305:1611-1617.
References 1. Wasserman K, Casaburi R. Dyspnea: physiolo~c and ~thophysiolo~~l mechanisms. Annu Rev Med 1988;39:503-515. 2. Altosc:M. Assessment and management of breathlessness. Chest 1985;88:773-81s.
3. Baines M. Control of other symptoms. fn: Saunders CM. ed. The management of terminal disease. Chicago:Year Book, 1978. 4. Billings JA. The management of common symptams. In: BillingJA, ed. Outpatient management of ~vao~ed cancer. Philadelphia: JS Lippinc~tt, 1985:41.
12. Woodcock A, Gross E, Geddes D. Drug treatment of breathlessness: continuing effect of diazepam and promethazine in patients with chronic airway obst~ction. Br Med J 1~1:283:~3-346.
13. Bar-or D, Marx J, Good J, Breathlessness, alcohol and opiates [Letter]. N Engl J Ned 1981;305: 1363. 14. Woodcock A, Johnson M, Geddes D. Breathlessness, alcohol ancl opiates [Letter]. N Engl J Med 1981:305:1313-~314. 15. Foley K. The treatment of cancer pain. N Engl J Med 1985;313:84-93. 16. Bruera E, MacMillan K, Kuehn N, et al. The cognitive effects of the administration of narcotics. Pain 1989;39: 13- 16.