- Email: [email protected]
Controversy in the management of chronic cancer pain: Therapeutic equivalents of IM and PO morphine
42
Columns
Journal of Pain and Symptom Management
Pharmacology Rounds
Controversy in the Management of Chronic Cancer Pain: Therapeutic Equivalents of IM and PO Morphine R o b e r t E Kaiko
It is generally a c c e p t e d that m o r p h i n e , administered orally (PO), is one-sixth as potent as that given intramuscularly (IM). This estimate is based on a 1965 controlled study a n d cited in textbooks as a p p r o p r i a t e when alternating between routes of administration. However, with increased use o f PO m o r p h i n e , this estimate is being challenged. Based on clinical impression, m a n y health professionals now believe that PO m o r p h i n e is one-third to onehalf as potent as IM m o r p h i n e . This article attempts to provide a better u n d e r s t a n d i n g o f this discrepancy.
Relative Analgesic Potency A potency ratio is the dose ratio of two drugs (or different routes o f administration o f o n e drug) that provides equivalent effects. Such ratios provide a basis for choice o f initial dose when a different d r u g and/or route is indicated, and also provides for most valid comparative drug evaluations because side effects (e.g. seda-
This article is adapted from a paper by Dr. Kaiko that will appear in Advances in Pain Research and Therapy: Opioid Analgesics in the Management of Clini. cal Pain, K.M. Foley and C.E. Inturrisi, editors. It will be published later this )ear by Raven Press. Robert Kaiko, Ph.D,, has been associated with the Analgesic Studies Section at Memorial Sloan-Kettering Cancer Center for more than 10 )'ears. He is currently Associate Medical Director of the Purdue Frederick Company in Norwalk Connecticut and Assistant Professor of Pharmacology at Cornell University Medical College in New York.
tion, nausea, and vomiting) can be c o m p a r e d only at equianalgesic doses. Potency ratios are based on various measures a n d characteristics o f analgesia. Measures include pain relief and pain intensity decrease. Ratios based on different measures are usually c o m p a r a b l e . C h a r a c t e r i s t i c s include p e a k effect (highest score) a n d total effect (area u n d e r the time-effect curve). Ratios based on peak and total effect will differ unless treatm e n t s have similar time-effect curves. T h e validity o f a particular ratio depends on the study results and design. T h e design should incorporate controls (e.g., double-blind technique, and r a n d o m i z e d assignment o f patients to treatments) to minimize bias and an assay sensitivity estimate (e.g., ablility of patients to discriminate between graded doses). A ratio is most valid if: test and standard study treatments provide analgesia that are not significantly different in magnitude; a s i g n i f i c a n t . c o m m o n dose-response curve results; and doseresponse curves do n o t d e v i a t e f r o m parallelism. A potency ratio can be assessed in terms o f the confidence one has in it. This confidence can be expressed in terms o f a range within which tile ratio will be f o u n d in 19 out o f 20 times if the study were repeated (95% confidence interval). O n e factor that influences this interval is variation a m o n g patients. T h a t is, these ratios are averages a n d there is every reason to believe that the ratio differs a m o n g patients.
VoL I No. 1 Winter 1986
Experimental Potency Ratio Houde, Wallenstein and Beaver t reported that PO m o r p h i n e is one-sixth as potent as IM drug in total analgesic effect. This was based on studies in 25 patients with chronic cancer pain who received either 30 and 60 mg or 60 and 120 mg PO m o r p h i n e in addition to 8 and 16 mg IM morphine. Most patients completed the 4-way crossover twice. S t u d y c o n d i t i o n s were these: p a t i e n t s received each m o r p h i n e treatment on a separate day; intervening analgesics were other PRN drugs; m o r p h i n e was usually given when pain was severe; m o r p h i n e was given on a doub l e - b l i n d r a n d o m i z e d basis; the average patient's age was 50. Results include these: ratios for total effect approximated one-sixth, ratios for peak effect approximated 1/12; the peak effect o f PO m o r p h i n e was considerably less than that provided by IM drug, but the duration o f analgesia was longer after PO morphine (See Fig. 1). In the discussion, it was pointed out that the data "illustrates the serious errors o f interpretation which could arise were observations made at only one arbitrary time after administration:'
Anecdotal Potency Ratio A 1976 article "~in the Canadian Medical Association Journal, on the use o f the B r o m p t o m mixture, states that if a change to parenteral medication becomes necessary, the equivalent dose o f m o r p h i n e is one-half the previous dose: a patient whose pain had been controlled with 30 mg taken orally would then receive 15 mg intramuscularly. T h e p a p e r that this r e p o r t cites ~ does not, in fact, address IM and PO morphine, but reports experiences with heroin in the management o f chronic cancer pain. An article by Farr ' in a 1978 issue o f Arizona Medicine also proposes a higher ratio and cites two other papers as evidence. Yet neither o f these articles provides specific data on the subject. On the same issue, another researcher in a 1984 review in Pain, 5 cites a letter to the editor o f Lancet. 6 This letter states that clinical experience suggests that oral m o r p h i n e d u r i n g repeated administration has an analgesic efficacy compared to parenteral m o r p h i n e in a ratio ofl:3. However, this report compares controlled release m o r p h i n e tablets to m o r p h i n e
Columns
43
solution and only makes reference tO an IM/PO ratio of one-third as being best according to other sources. These other sources merely reiterate that the appropriate ratio is one-third. T h e r e f o r e there appears to be no evidence in the literature to support a ratio of one-half to one-third. T h e r e have been reports originating from u n d o c u m e n t e d observations in hospices that the IM/PO m o r p h i n e potency ratio is one-half to one-third. Hospice conditions include these: PO m o r p h i n e is usually given repeatedly on an around-the-clock schedule (e.g., q4h) to prevent "pain breakthrough"; most patients receive 5, 10 or 20 mg doses; patients usually receive adjuvant drugs; the average patient's age is about 65. Presumabl); the impression o f a one-half to one-third ratio results from situations where use o f the one-sixth ratio produced unpredictable responses that were more consistent with a higher ratio, or where a one-half to one-third ratio produced comparable responses when alternating between routes. Responses may have included side effects. Observations may have included these: substitution o f IM for PO m o r p h i n e using a one-sixth ratio resulted in "pain breakthrough" prior to the next scheduled dose; substitution o f PO for IM m o r p h i n e using the one-sixth ratio produced side effects; substitutions as above, but using a one-half or one-third ratio, did not result in "pain breakthrough" or side effects.
Arguments For a Different Ratio in Hospices Some consider the "optimal" IM m o r p h i n e dose for moderate to severe pain to be 10 mg. In hospices, 5 to 20 mg PO doses are most common. This may be interpreted to support a high ratio. T h e bioavailablility o f PO to IV m o r p h i n e (and presumably PO to IM) averages between 20 and 40% from study to stud)'. These data have been interpreted as consistent with a onethird ratio. With increasing age, there is a decrease in morphine's clearance from the body Certain factors (e.g., hepatic cirrhosis), that reduce the clearance o f some narcotic analgesics (e.g., meperidine and pentazocine), differentially reduce clearance following PO drug. While hepatic cirrhosis does not appear to alter the
44
bioavailability o f morphine, other pathologies may result in enhanced PO bioavailability in hospice patients. This would be consistent with a higher potency ratio for PO m o r p h i n e in such patients. Conditions in hospice pain m a n a g e m e n t (such as repeated administration o f analgesics and drug scheduling) differ from those in the experiment. Such differences could account for a difference in the potency ratio on the assumption that the minimally effective morphine concentration (MEMC) necessary for the prevention o f pain is lower than that necessary for the reduction o f severe pain. T h e lower the MEMC, the more the potency ratio approaches the POIparenteral bioavailabilit): This is due to differences in the plasma m o r p h i n e timecourse following PO and parenteral dosing: a smaller fraction o f the total area u n d e r the time-concentration curve is above the MEMC following PO as compared to parenteral morphine. T h e presence of adjuvant drugs may also lower the MEMC.
Arguments Against a Difference The 5 to 20 mg doses most c o m m o n in hospices cannot be used to support a high ratio because it is likely that the "optimal" IM morphine dose is relatively small in that setting. It is thought that lower doses are required because the goal is to prevent rather than reduce pain, adjuvants are administered, and an elderly population is being treated. Also, with an average POlparenteral bioavailablility o f 33%, the ratio must be less than one-third on the basis that there is an MEMC and a difference in the IM and PO time-concentration curves. Some suggest that the ratio changes from one-sixth to one-third with repeated administrations due to metabolic or pharmacokinetic factors. Studies have shown this not to be the case. It is likely that substitution o f IM for PO m o r p h i n e results in "p.ain breakthrough" when the one-sixth ratio is used because o f the most c o m m o n indications for a substitution. These include the situation in which PO dosing is not providing an acceptably rapid onset o f action, as may occur when pain is increasing due to advancing disease. A larger IM dose may be required.
Kaiko
Journal of Pain and Symptom Management
Substitution o f PO for IM m o r p h i n e using the one-sixth ratio is said to result in overmedication. Irrespective o f the fact that analgesic potency should not be confused with analgesic potential (the relationship between therapeutic and adverse effects), clinical impression is usually more influenced by side effects than by undermedication. Another argument against a real difference is the confidence interval associated with the experimentally derived estimate. The 95% confidence interval for the one-sixth ratio would likely overlap the interval associated with a onethird ratio. A most convincing argument against a difference is that the experimentally derived ratios o f 1/12 for peak effect and one-sixth for total effect are consistent with a one-third ratio in terms o f duration. T h e one-third ratio may be most relevant to the hospice setting. If the objective in the management o f pain in this setting is to provide an effect through at least four hours, then different treatments must be c o m p a r e d not in terms of peak or total effect, but in terms o f duration or in terms o f effects at four hours. T h e experimental data reveal that 60 mg PO doses provide longer-lasting analgesia than 16 mg IM doses. This is consistent with a "duration" ratio o f more than one-fourth.
Proposed Resolution T h e best argument would be apparent if a properly designed study were carried out in the hospice setting. Determination of a potency ratio requires generation o f dose-response relationships. This is accomplished by manipulating one variable and measuring another. In traditional studies, doses are manipulated and analgesia is measured. Determination o f relative potency in the hospice setting, however, might require manipulation o f analgesia and measurement of doses required to attain different durations o f "pain breakthrough" prevention. Such studies could be carried out with experimental controls that do not jeopardize the effectiveness o f hospice pain management.
~bl. I No. 1 Winter 1986
Columns
45
References 1. Houde, RW, Wallenstein, SL, and Beaver, WT. Clinical measurement of pain. In: de Stevens G, ed. Analgetics. New York:Academic Press, 1965:75-122. 2. Mount BM, Ajemian I, Scott JE Use of the Bromptom mixture in treating the chronic pain of m a l i g n a n t disease. Can Med Assoc J 1976; 115:75-122. 3. Twycross R. Clinical e x p e r i e n c e with diamorphine in advanced malignant disease. I n t J Clin Pharmaco11974;9:184-198.
1.5 F
MORPHINE,LM. vs PO.
I
0
'
1
2
5 4 HOURS
5
6
Legend "Time-effect cura'es for oral (P.O.) and intramuscular (I.M.) m o r p h i n e . Changes in pain intensity (ordinate) are plotted against time after drug administration in hours (abscissa). T h e oral doses r e p r e s e n t the l o g a r i t h m i c m.eans o f the u p p e r and lower oral doses from a series o f sequential experiments. T h e intramuscular dose represents the m e a n o f an 8 a n d 16 mg standard used in the same experiments. All drugs were administered in a r a n d o m o r d e r to 25 patients with pain due to cancer. Differences in the configuration of tlle time effect curves indicate that the ora.lly administered d r u g cannot be considered as acting merely as a diluent of the parenterally administered drug, a n d that estimates o f relative potency will vary depending on which criterion o n e uses: peak effect, d u r a t i o n o f effect, or total e f f e c t " ( F r o m H o u d e , Wallenstein a n d Beaver, with permission.)
4. Farr WC. Oral morphine for control of pain in terminal cancer. Ariz Med 1978;35:167-170. 5. Walsh TD. Oral morphine in chronic cancer pain. Pain 1984;18:1-11. 6. Hanks GW, Rose MM, Aherne GW, Piall EM. Analgesic effect of morphine tablets. Lancet 1981;1:732-733.
Columns
Journal of Pain and Symptom Management
Pharmacology Rounds
Controversy in the Management of Chronic Cancer Pain: Therapeutic Equivalents of IM and PO Morphine R o b e r t E Kaiko
It is generally a c c e p t e d that m o r p h i n e , administered orally (PO), is one-sixth as potent as that given intramuscularly (IM). This estimate is based on a 1965 controlled study a n d cited in textbooks as a p p r o p r i a t e when alternating between routes of administration. However, with increased use o f PO m o r p h i n e , this estimate is being challenged. Based on clinical impression, m a n y health professionals now believe that PO m o r p h i n e is one-third to onehalf as potent as IM m o r p h i n e . This article attempts to provide a better u n d e r s t a n d i n g o f this discrepancy.
Relative Analgesic Potency A potency ratio is the dose ratio of two drugs (or different routes o f administration o f o n e drug) that provides equivalent effects. Such ratios provide a basis for choice o f initial dose when a different d r u g and/or route is indicated, and also provides for most valid comparative drug evaluations because side effects (e.g. seda-
This article is adapted from a paper by Dr. Kaiko that will appear in Advances in Pain Research and Therapy: Opioid Analgesics in the Management of Clini. cal Pain, K.M. Foley and C.E. Inturrisi, editors. It will be published later this )ear by Raven Press. Robert Kaiko, Ph.D,, has been associated with the Analgesic Studies Section at Memorial Sloan-Kettering Cancer Center for more than 10 )'ears. He is currently Associate Medical Director of the Purdue Frederick Company in Norwalk Connecticut and Assistant Professor of Pharmacology at Cornell University Medical College in New York.
tion, nausea, and vomiting) can be c o m p a r e d only at equianalgesic doses. Potency ratios are based on various measures a n d characteristics o f analgesia. Measures include pain relief and pain intensity decrease. Ratios based on different measures are usually c o m p a r a b l e . C h a r a c t e r i s t i c s include p e a k effect (highest score) a n d total effect (area u n d e r the time-effect curve). Ratios based on peak and total effect will differ unless treatm e n t s have similar time-effect curves. T h e validity o f a particular ratio depends on the study results and design. T h e design should incorporate controls (e.g., double-blind technique, and r a n d o m i z e d assignment o f patients to treatments) to minimize bias and an assay sensitivity estimate (e.g., ablility of patients to discriminate between graded doses). A ratio is most valid if: test and standard study treatments provide analgesia that are not significantly different in magnitude; a s i g n i f i c a n t . c o m m o n dose-response curve results; and doseresponse curves do n o t d e v i a t e f r o m parallelism. A potency ratio can be assessed in terms o f the confidence one has in it. This confidence can be expressed in terms o f a range within which tile ratio will be f o u n d in 19 out o f 20 times if the study were repeated (95% confidence interval). O n e factor that influences this interval is variation a m o n g patients. T h a t is, these ratios are averages a n d there is every reason to believe that the ratio differs a m o n g patients.
VoL I No. 1 Winter 1986
Experimental Potency Ratio Houde, Wallenstein and Beaver t reported that PO m o r p h i n e is one-sixth as potent as IM drug in total analgesic effect. This was based on studies in 25 patients with chronic cancer pain who received either 30 and 60 mg or 60 and 120 mg PO m o r p h i n e in addition to 8 and 16 mg IM morphine. Most patients completed the 4-way crossover twice. S t u d y c o n d i t i o n s were these: p a t i e n t s received each m o r p h i n e treatment on a separate day; intervening analgesics were other PRN drugs; m o r p h i n e was usually given when pain was severe; m o r p h i n e was given on a doub l e - b l i n d r a n d o m i z e d basis; the average patient's age was 50. Results include these: ratios for total effect approximated one-sixth, ratios for peak effect approximated 1/12; the peak effect o f PO m o r p h i n e was considerably less than that provided by IM drug, but the duration o f analgesia was longer after PO morphine (See Fig. 1). In the discussion, it was pointed out that the data "illustrates the serious errors o f interpretation which could arise were observations made at only one arbitrary time after administration:'
Anecdotal Potency Ratio A 1976 article "~in the Canadian Medical Association Journal, on the use o f the B r o m p t o m mixture, states that if a change to parenteral medication becomes necessary, the equivalent dose o f m o r p h i n e is one-half the previous dose: a patient whose pain had been controlled with 30 mg taken orally would then receive 15 mg intramuscularly. T h e p a p e r that this r e p o r t cites ~ does not, in fact, address IM and PO morphine, but reports experiences with heroin in the management o f chronic cancer pain. An article by Farr ' in a 1978 issue o f Arizona Medicine also proposes a higher ratio and cites two other papers as evidence. Yet neither o f these articles provides specific data on the subject. On the same issue, another researcher in a 1984 review in Pain, 5 cites a letter to the editor o f Lancet. 6 This letter states that clinical experience suggests that oral m o r p h i n e d u r i n g repeated administration has an analgesic efficacy compared to parenteral m o r p h i n e in a ratio ofl:3. However, this report compares controlled release m o r p h i n e tablets to m o r p h i n e
Columns
43
solution and only makes reference tO an IM/PO ratio of one-third as being best according to other sources. These other sources merely reiterate that the appropriate ratio is one-third. T h e r e f o r e there appears to be no evidence in the literature to support a ratio of one-half to one-third. T h e r e have been reports originating from u n d o c u m e n t e d observations in hospices that the IM/PO m o r p h i n e potency ratio is one-half to one-third. Hospice conditions include these: PO m o r p h i n e is usually given repeatedly on an around-the-clock schedule (e.g., q4h) to prevent "pain breakthrough"; most patients receive 5, 10 or 20 mg doses; patients usually receive adjuvant drugs; the average patient's age is about 65. Presumabl); the impression o f a one-half to one-third ratio results from situations where use o f the one-sixth ratio produced unpredictable responses that were more consistent with a higher ratio, or where a one-half to one-third ratio produced comparable responses when alternating between routes. Responses may have included side effects. Observations may have included these: substitution o f IM for PO m o r p h i n e using a one-sixth ratio resulted in "pain breakthrough" prior to the next scheduled dose; substitution o f PO for IM m o r p h i n e using the one-sixth ratio produced side effects; substitutions as above, but using a one-half or one-third ratio, did not result in "pain breakthrough" or side effects.
Arguments For a Different Ratio in Hospices Some consider the "optimal" IM m o r p h i n e dose for moderate to severe pain to be 10 mg. In hospices, 5 to 20 mg PO doses are most common. This may be interpreted to support a high ratio. T h e bioavailablility o f PO to IV m o r p h i n e (and presumably PO to IM) averages between 20 and 40% from study to stud)'. These data have been interpreted as consistent with a onethird ratio. With increasing age, there is a decrease in morphine's clearance from the body Certain factors (e.g., hepatic cirrhosis), that reduce the clearance o f some narcotic analgesics (e.g., meperidine and pentazocine), differentially reduce clearance following PO drug. While hepatic cirrhosis does not appear to alter the
44
bioavailability o f morphine, other pathologies may result in enhanced PO bioavailability in hospice patients. This would be consistent with a higher potency ratio for PO m o r p h i n e in such patients. Conditions in hospice pain m a n a g e m e n t (such as repeated administration o f analgesics and drug scheduling) differ from those in the experiment. Such differences could account for a difference in the potency ratio on the assumption that the minimally effective morphine concentration (MEMC) necessary for the prevention o f pain is lower than that necessary for the reduction o f severe pain. T h e lower the MEMC, the more the potency ratio approaches the POIparenteral bioavailabilit): This is due to differences in the plasma m o r p h i n e timecourse following PO and parenteral dosing: a smaller fraction o f the total area u n d e r the time-concentration curve is above the MEMC following PO as compared to parenteral morphine. T h e presence of adjuvant drugs may also lower the MEMC.
Arguments Against a Difference The 5 to 20 mg doses most c o m m o n in hospices cannot be used to support a high ratio because it is likely that the "optimal" IM morphine dose is relatively small in that setting. It is thought that lower doses are required because the goal is to prevent rather than reduce pain, adjuvants are administered, and an elderly population is being treated. Also, with an average POlparenteral bioavailablility o f 33%, the ratio must be less than one-third on the basis that there is an MEMC and a difference in the IM and PO time-concentration curves. Some suggest that the ratio changes from one-sixth to one-third with repeated administrations due to metabolic or pharmacokinetic factors. Studies have shown this not to be the case. It is likely that substitution o f IM for PO m o r p h i n e results in "p.ain breakthrough" when the one-sixth ratio is used because o f the most c o m m o n indications for a substitution. These include the situation in which PO dosing is not providing an acceptably rapid onset o f action, as may occur when pain is increasing due to advancing disease. A larger IM dose may be required.
Kaiko
Journal of Pain and Symptom Management
Substitution o f PO for IM m o r p h i n e using the one-sixth ratio is said to result in overmedication. Irrespective o f the fact that analgesic potency should not be confused with analgesic potential (the relationship between therapeutic and adverse effects), clinical impression is usually more influenced by side effects than by undermedication. Another argument against a real difference is the confidence interval associated with the experimentally derived estimate. The 95% confidence interval for the one-sixth ratio would likely overlap the interval associated with a onethird ratio. A most convincing argument against a difference is that the experimentally derived ratios o f 1/12 for peak effect and one-sixth for total effect are consistent with a one-third ratio in terms o f duration. T h e one-third ratio may be most relevant to the hospice setting. If the objective in the management o f pain in this setting is to provide an effect through at least four hours, then different treatments must be c o m p a r e d not in terms of peak or total effect, but in terms o f duration or in terms o f effects at four hours. T h e experimental data reveal that 60 mg PO doses provide longer-lasting analgesia than 16 mg IM doses. This is consistent with a "duration" ratio o f more than one-fourth.
Proposed Resolution T h e best argument would be apparent if a properly designed study were carried out in the hospice setting. Determination of a potency ratio requires generation o f dose-response relationships. This is accomplished by manipulating one variable and measuring another. In traditional studies, doses are manipulated and analgesia is measured. Determination o f relative potency in the hospice setting, however, might require manipulation o f analgesia and measurement of doses required to attain different durations o f "pain breakthrough" prevention. Such studies could be carried out with experimental controls that do not jeopardize the effectiveness o f hospice pain management.
~bl. I No. 1 Winter 1986
Columns
45
References 1. Houde, RW, Wallenstein, SL, and Beaver, WT. Clinical measurement of pain. In: de Stevens G, ed. Analgetics. New York:Academic Press, 1965:75-122. 2. Mount BM, Ajemian I, Scott JE Use of the Bromptom mixture in treating the chronic pain of m a l i g n a n t disease. Can Med Assoc J 1976; 115:75-122. 3. Twycross R. Clinical e x p e r i e n c e with diamorphine in advanced malignant disease. I n t J Clin Pharmaco11974;9:184-198.
1.5 F
MORPHINE,LM. vs PO.
I
0
'
1
2
5 4 HOURS
5
6
Legend "Time-effect cura'es for oral (P.O.) and intramuscular (I.M.) m o r p h i n e . Changes in pain intensity (ordinate) are plotted against time after drug administration in hours (abscissa). T h e oral doses r e p r e s e n t the l o g a r i t h m i c m.eans o f the u p p e r and lower oral doses from a series o f sequential experiments. T h e intramuscular dose represents the m e a n o f an 8 a n d 16 mg standard used in the same experiments. All drugs were administered in a r a n d o m o r d e r to 25 patients with pain due to cancer. Differences in the configuration of tlle time effect curves indicate that the ora.lly administered d r u g cannot be considered as acting merely as a diluent of the parenterally administered drug, a n d that estimates o f relative potency will vary depending on which criterion o n e uses: peak effect, d u r a t i o n o f effect, or total e f f e c t " ( F r o m H o u d e , Wallenstein a n d Beaver, with permission.)
4. Farr WC. Oral morphine for control of pain in terminal cancer. Ariz Med 1978;35:167-170. 5. Walsh TD. Oral morphine in chronic cancer pain. Pain 1984;18:1-11. 6. Hanks GW, Rose MM, Aherne GW, Piall EM. Analgesic effect of morphine tablets. Lancet 1981;1:732-733.