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1167
Dose Ratio between Morphine and Methadone in
Patients with Cancer Pain
A Retrospective Study
Peter G. Lawlor, M.B.1
Ken S. Turner, B.Sc.1
John Hanson, M.Sc.2
Eduardo D. Bruera, M.D.1
BACKGROUND. Current equianalgesic reference tables, based largely on single dose
studies, give dose ratios of 1:1 to 4:1 for oral morphine to oral methadone, which
possibly are inaccurate in patients with cancer pain who are exposed to multiple
1
Palliative Care Program, Grey Nuns Community Health Centre, Edmonton, Alberta, Canada.
2
Department of Epidemiology, Prevention, and
Screening, Cross Cancer Institute, University of
Alberta, Edmonton, Alberta, Canada.
doses of these opioids. The purpose of this study was to determine the equianalgesic dose ratio between morphine and methadone in patients with cancer pain and
to establish whether the dose ratio changes as a function of previous opioid dose.
METHODS. A retrospective analysis of consecutive rotations involving morphine
and methadone using standard selection criteria identified a total of 20 evaluable
rotations (14 from morphine to methadone and 6 from methadone to morphine).
Opioid doses and pain intensity levels pre- and postrotation were analyzed.
RESULTS. Median dose ratios (lower-upper quartiles) for morphine to methadone
and methadone to morphine rotations were 11.36 (range, 5.98–16.27) and 8.25
(range, 4.37–11.3), respectively (P Å 0.23). Combining all 20 rotations, a unified
median dose ratio of 11.2 (range, 5.06–13.24) was calculated. There was no significant difference in pain intensity levels pre- and postrotation as recorded on a
visual analogue scale. Univariate correlational analysis of dose ratio and the level
of daily morphine dose prior to rotation revealed a Spearman correlation coefficient of 0.86 (P Å 0.0001). In patients receiving ú1165 mg per day prior to methadone rotation, a median dose ratio of 16.84 (range, 12.25–87.95) was observed,
which was approximately 3 times higher compared with a median dose ratio of
5.42 (range, 2.95–9.09) (P Å 0.007) for the 50% of patients receiving lower morphine
doses.
CONCLUSIONS. The results highlight the general underestimation of methadone
potency and the consequent risk of potential life-threatening toxicity. The strongly
positive correlation between dose ratio and previous morphine dose suggests the
need for a highly individualized and cautious approach when rotating from morphine to methadone in patients with cancer pain. Cancer 1998;82:1167–73.
q 1998 American Cancer Society.
KEYWORDS: morphine, methadone, dose ratio, equianalgesic tables, opioid rotation,
cancer pain.
O
Address for reprints: Eduardo D. Bruera, M.D.,
Palliative Care Program, Grey Nuns Community
Health Centre, 1100 Youville Drive West, Edmonton, Alberta, Canada T6L 5X8.
Received June 18, 1997; revision received September 5, 1997; accepted September 5, 1997.
pioid analgesics are the principal form for treatment for cancer
pain in ú80% of cancer patients before death.1,2 Both morphine
(M) and methadone (ME) are considered potent opioid agonists and
are recommended for Step 3 (moderate to severe pain) of the World
Health Organization analgesic ladder.2,3 When symptoms of opioid
toxicity such as myoclonus, hyperalgesia, and delirium occur with M
treatment, opioid rotation to a different opioid may be necessary.3 – 6
The accumulation of metabolites such as M-3-glucuronide7 and M6-glucuronide8 and normorphine9 have been suggested as causative
q 1998 American Cancer Society
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W: Cancer
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CANCER March 15, 1998 / Volume 82 / Number 6
factors for opioid toxicity. The elimination of these
metabolites after rotation from M to another opioid
forms the rationale for opioid rotation.6,10
In relatively low doses11 and in higher doses,12 ME
has been shown to be a useful alternative to M and
hydromorphone in the treatment of cancer pain. ME
is a synthetic opioid with excellent oral13 and rectal
absorption14 and is approximately 90% cheaper than
equianalgesic doses of commonly used opioids. However, the large interindividual variation in pharmacokinetics, the slow elimination phase,15 and the consequent potential for severe toxicity due to accumulation13 have limited the use of ME in the treatment of
cancer pain.
In the event of opioid rotation from M to ME,
physicians frequently use guidelines in the form of
equianalgesic tables3,16 – 18 to assist them in dose calculation. These guidelines are based on the results of
single dose studies and, therefore, are potentially inaccurate and misleading for patients who are receiving
chronic opioid treatment. Our group12,19 has highlighted the gross underestimation (by most equianalgesic reference tables) of the potency of ME in switching from hydromorphone to ME, with the consequent
potential for serious or life-threatening toxicity. In addition, the dose ratio between hydromorphone and
ME has been shown to change as a function of the
level of hydromorphone dosage; the dose ratio (hydromorphone/ME) was 60% higher in patients receiving
ú300 mg of parenteral hydromorphone per day.19
Some tables propose a ratio of 1:1 between oral M
and ME (i.e., ME 10 mg is equianalgesic to M 10 mg
orally)18,20,21 and others propose a M-ME ratio of 4:1
for the oral route and 2.7:1 for the parenteral route.17
To our knowledge, there are no reported studies to
date that examine the dose ratio between M and ME
in patients receiving long term treatment such as those
with advanced cancer. To test our hypothesis that the
dose ratio of M to ME might be higher than what is
published in most guidelines and that the dose ratio
between ME and M might vary according to the previous dose of M, we conducted a retrospective study
of consecutive patients admitted to our tertiary level
palliative care unit.
PATIENTS AND METHODS
In this retrospective study of opioid rotations between
M and ME, we reviewed the computerized records of
all patients admitted to our tertiary level palliative care
unit between April 1993 and September 1996. The following selection criteria were applied: 1) patients with
cancer pain who were rotated from M to ME or ME
to M; 2) available computerized data; 3) patients rotated at least 24 hours after admission to allow for
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reliable data collection regarding pain intensity, M
dose, and cognitive status, patients who brought reliable data (transferred from another hospital) concerning these parameters also were included in the study
(2 patients); 4) patients rotated at least 7 days prior to
discharge or death; 5) patients receiving M or ME for
at least 72 hours prior to rotation; 6) patients who
reached a stable dose of ME or M for a selected day
of stabilization (minimum of 4 days after commencement of M-ME rotation or a minimum of 72 hours
after rotation from ME to M, and a minimum of 48
hours prior to death or discharge for either rotation)
followed by 2 total daily opioid dose values that
showed no ú20% difference from the value on the day
of stabilization (standard rescue doses on our palliative care unit are 10% of the total regular daily dose);
and 7) for patients with ú1 rotation (M to ME or ME
to M), an interval of at least 7 days between the 2
separate rotations. After application of selection criteria (1 – 7), 14 M to ME rotations in 13 patients and 6
ME to M rotations in 6 patients were evaluable, selected from an original total of 32 rotations in 27 patients.
All patients admitted to the Palliative Care Unit
were treated using a standard protocol of titrating opioid doses to achieve analgesia. Titration was monitored twice per day during weekdays and once per day
during weekends by one or more of the three full time
specialist palliative medicine physicians. Opioid rotation (M-ME or ME-M) took place only when intolerable side effects occurred during opioid titration, irrespective of the level of analgesia achieved. According
to our Palliative Care Unit policy, inadequate analgesia
per se was not considered a reason for rotation but
rather served as an indication to increase the opioid
dose until analgesia was achieved or dose-limiting toxicity was encountered. This policy is in keeping with
current literature recommendations.3,22,23
Rotation from M to ME usually was performed
over a 3-day period. This phased approach has become standard practice in our unit to diminish the
risk of ME toxicity, particularly because of the long
elimination half-life of ME15 and the consequent risk
of ME accumulation and toxicity.13 On the first day of
rotation, the dose of M was decreased by approximately 30% of the total previous 24-hour dose and
replaced with ME, administered every 8 hours (e.g., a
patient receiving M, 300 mg/day would now receive
M, 200 mg/day and ME, 10 mg/day). A conversion
ratio of 10:1 was used for conversion of oral equivalent
M doses to ME (oral or rectal). On the second day of
rotation, a further 30% (approximate) reduction in M
dosage took place and was replaced with ME (e.g., in
the previous example the patient would now receive
W: Cancer
Methadone Potency in Cancer Pain/Lawlor et al.
M, 100 mg/day and ME, 20 mg/day). Finally, on Day
3 of rotation, the remaining 33% (approximately) of
the original M dose before rotation was discontinued
and replaced with ME. Rotation from ME to M involved an immediate switch on the day of rotation
using a ratio of 10:1 for oral M equivalent to ME (oral
or rectal).
Patient demographics (including age and gender)
in addition to cancer diagnosis were collected. Data
also were collected concerning the Edmonton staging
system24 status of each patient on admission, which
acted as a prognostic indicator for achieving analgesia.
Patients classified as Stage 1 were considered to have
a good prognosis regarding pain control, whereas patients classified as Stage 3 (those with neuropathic
pain, incidental pain, tolerance, severe psychologic
distress manifested as somatization or depression, or
a history of drug or alcohol abuse) were considered to
have a poor prognosis. Those patients classified as
Stage 2 had an intermediate prognosis. The daily original opioid dose (M or ME) for the last day prior to
rotation was established. The dose of newly rotated
opioid for the selected day of stabilization, as defined
in the selection criteria 6 also was established. Mean
pain intensity on a visual analogue scale (VASP) for
the day prior to rotation and for the day of stabilization
on the newly rotated opioid were calculated. The mean
VASP was the mean of 2 daily assessments, performed
at 10:00 a.m. and 6 p.m. The VASP is scored from 0 to
100 with 0 Å no pain and 100 Å worst possible pain.
VASP ratings were performed by patients who were
intact cognitively (Mini-Mental State Examination25
was performed weekly to screen for cognitive impairment). VASP ratings in cognitively impaired patients
were performed by nursing staff or family. In those
patients with advanced cachexia and asthenia, the
nurse assisted the patient with VASP ratings. The total
dose of M or ME for the day before rotation was divided by the dose of newly rotated opioid on the day
of stabilization to give a conversion dose ratio. For
comparative purposes, all M doses were calculated as
the oral equivalent daily dosage. A conversion ratio
of 2:1 was used for M oral doses/M subcutaneous or
intravenous doses. A unified overall dose ratio was
calculated by combining the rotations from M to ME
with those from ME to M. In the latter process, the
ME to M rotation dose ratios were expressed as M/
ME to facilitate comparison and statistical analysis.
Data on dose ratios were expressed as medians (lowerupper quartiles) unless otherwise stated. VASP ratings
were expressed as mean { standard deviation. Parametric data were analyzed using the Student’s t test
for paired data. The Spearman correlation coefficient
was used to assess the level of correlation between
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1169
TABLE 1
Patient Characteristics (20 Rotations in 19 Patients)
Age (yrs) (mean { SD)
Gender: male/female
Primary tumor
Genitourinary
Gastrointestinal
Lung
Head & neck
Breast
Unknown
Hematologic
ESS Stage I (good prognosis)
Stage II (intermediate
prognosis)
Stage III (poor prognosis)
Opioid dose before rotationa
M-ME
(n Å 14)
ME-M
(n Å 6)
62.1 { 14.9
6/7
57.7 { 13.5
6/0
4
1
2
3
1
2
1
4
1
2
1
2
2
—
10
1165 (84–24025)b
—
4
60 (3–240)
M: morphine; ME: methadone; SD: standard deviation; ESS: Edmonton Staging System.
a
Expressed as median (range) in mg.
b
Morphine doses expressed as oral equivalent (ratio of 2:1 used to convert subcutaneous doses to
oral).
previous opioid dose and conversion dose ratio. The
Wilcoxon rank sum test was used to analyze nonparametric data such as dose ratios. Statistical analysis was
performed using the SAS statistical package.26
RESULTS
The restrictive selection criteria (1 – 7) resulted in 20
evaluable rotations in 19 patients (14 rotations from
M to ME and 6 from ME to M), from a total of 32
rotations in 27 patients. For M-ME rotations, the route
of administration of M was solely subcutaneous in six
patients, solely oral in three patients, mixed intravenous and oral in two patients, and mixed subcutaneous and oral in the remaining three patients. Patients
rotated to ME received oral administration of ME, with
the exception of one patient in whom rectal administration was used. For ME to M rotations, all six patients
received oral ME and were rotated to oral M (four
patients) or subcutaneous M (two patients). Patient
characteristics for both types of rotations (M-ME and
ME-M) are summarized in Table 1. In 14 of the 20
rotations (70%), the patient was classified on admission as Stage 3 on the Edmonton staging system24 and
therefore had difficult pain syndromes. The daily oral
equivalent M dose before rotation was relatively high
at a median value of 1165 mg per day with a wide dose
range (85 – 24027 mg/day).
Table 2 summarizes the previous dose, the stable
dose of new opioid, the number of days required to
W: Cancer
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CANCER March 15, 1998 / Volume 82 / Number 6
TABLE 2
Summary of Previous Opioid Dose, Stable Dose of New Opioid, Days
to Reach Stabilization after Rotation, Dose Ratios, and Comparison of
Pain Intensity Pre- and Postrotation, as Measured on a Visual
Analogue Scale (0–100 mm)
Median prerotation opioid dose (mg/day)a
(range)
Median postrotation dose (mg/day)b
(range)
Median days to reach stabilization postrotation
(range)
Median dose ratioc
(lower–upper quartile)
Mean pain intensity on VASP { SDa
(prerotation)
Mean pain intensity on VASP { SD
(postrotation)
P value (VASP pre- vs. postrotation (Student’s t
test for paired data)
M-ME
n Å 14
ME-M
nÅ6
1165 (M)
(84–24025)
100 (ME)
(20–710)
5
(4–13)
11.36
(5.98–16.27)
60 (ME)
(3–240)
265 (M)
(35–1320)
4
(4–5)
8.25
(4.37–11.3)
58.6 { 19.6
72.5 { 21.8
51.1 { 18.6
55 { 27.7
0.28 (NS)
0.08 (NS)
VASP: visual analogue scale; M: morphine; ME: methadone; SD: standard deviation; NS: not significant.
a
Values recorded refer to day prior to opioid rotation.
b
Values recorded refer to day of stabilization after rotation.
c
Derived by expressing previous opioid dose for day prior to rotation/dose of new opioid on day of
stabilization. For comparative purposes, methadone-morphine rotation ratios are expressed as morphine/methadone.
reach stabilization after rotation, the dose ratios, and
comparison of pain intensity pre- and postrotation, as
measured on a VASP (0 – 100 mm). For both types of
rotation, there was a wide dosage range before and
after rotation. The overall median time from rotation
to the day of stabilization was 5 days in the case of
M-ME and 4 days in the case of ME-M, with ranges
of 4 – 13 days and 4 – 5 days, respectively. There was no
significant difference in mean pain intensity ratings
before and after rotation for both types of rotations. In
the case of M-ME rotation, the respective percentage
distribution of pain intensity rates pre- versus postrotation was 43% versus 54% by the patient, 25% versus
17.8% by the nurse, 10% versus 7% by the patient and
nurse combined, 0% versus 3% by the family and patient combined, 10% versus 3% by the family, 3% versus 14% when the rater was not identified, and 7%
versus 3% when no rating took place. In the case of
ME-M rotation, the respective percentage distribution
of pain intensity raters pre- versus postrotation was
42% versus 42% by the patient, 25% versus 25% by the
nurse, 33% versus 0% by the patient and nurse, and
0% versus 33% when no rating was recorded. The median dose ratio for the M-ME rotation was 11.36 (5.98 –
16.27, lower-upper quartiles). For the ME-M rotation,
the median dose ratio was 8.25 (4.37 – 11.3, lower-up-
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FIGURE 1. Correlation between final daily morphine dose before rotation
and dose ratio of morphine-methadone. A conversion ratio of 2:1 was used
for oral morphine:parenteral morphine. M: morphine; ME: methadone.
TABLE 3
Comparison of Dose Ratios (M/ME) in Patients Receiving Lower
Doses versus Those Receiving Higher Doses of Morphine
Morphine dose prerotationa
Dose ratio M/MEb
7 patients receiving õ1165 mg
(range)
7 patients receiving ú1165 mg
(range)
5.42
(2.95–9.09)
16.84
(12.25–87.95)
P valuec
0.007
M: morphine; ME: methadone.
a
Expressed as oral equivalent morphine daily dose for day before rotation (ratio of 2:1 used for oral:subcutaneous routes): median, 1165 (range, 84–24025).
b
Expressed as median (lower-upper quartiles).
c
Using Wilcoxon rank sum test.
per quartiles), when expressed in the direction of
M:ME for comparative purposes.
The correlation between the final daily M dose
before rotation and the dose ratio of M-ME is illustrated graphically in Figure 1. Univariate correlational
analysis revealed a Spearman correlation coefficient
of 0.86, with a corresponding P value of 0.0001, thus
indicating a strongly positive correlation between previous M dose and the conversion dose ratio. Table 3
shows a comparison of dose ratios for those patients
receiving lower doses of M versus those receiving
higher doses. A median prerotation M dose of 1165
mg was used to divide the group into 7 patients who
received less than this dose and 7 patients who received more than this dose. A median dose ratio of
5.42 (2.95 – 9.09, lower-upper quartiles) was calculated
for those receiving lower doses versus a corresponding
value of 16.8 (12.25 – 87.95, lower-upper quartiles) for
those receiving higher doses (P Å 0.007). Table 4 shows
a unified median dose ratio (for all 20 rotations, both
W: Cancer
Methadone Potency in Cancer Pain/Lawlor et al.
TABLE 4
Comparison of Dose Ratios for M-ME and ME-M Rotations
Unified median dose
ratio
(n Å 20)
M-ME (n Å 14)
dose ratio
P valuea
ME-M (n Å 6)
dose ratio
11.2 (5.06–13.24)b
11.36 (5.98–16.27)b
0.23 (NS)
8.25 (4.37–11.3)b
M: morphine; ME: methadone; NS: not significant.
a
Using Wilcoxon rank sum test.
b
All ratios are expressed in the direction of morphine:methadone and as median (lower-upper
quartiles).
M-ME and ME-M). Table 4 also compares the dose
ratios for M-ME and ME-M rotations. Although the
median dose ratio for ME-M rotation was 8.25 (4.37 –
11.3, lower-upper quartiles) and lower than the corresponding values of 11.36 (5.98 – 16.27) for the M-ME
rotation, the difference was not statistically significant
(P Å 0.23).
DISCUSSION
This retrospective study of 14 rotations between MME and 6 rotations between ME-M adds further confirmation of the generally underestimated potency of
ME.12,19 This study established a unified overall (MME and ME-M) median dose ratio of 11.2, suggesting
that ME is approximately 11 times more potent than
M. In a previous study by our group,19 the median
dose ratio for 65 patients rotated from subcutaneous
hydromorphone to ME was found to be 1.14:1. Based
on the latter study, and a dose ratio of 5:1 for M/
hydromorphone, one could estimate a dose ratio of
11.4 for M/ME. Approximately 70% of the rotations
involving ME revealed that the patient was classified
as Stage 3 on the Edmonton staging system, thus indicating that most patients had particularly difficult pain
syndromes. Accordingly, the median prerotation daily
M dose of 1165 mg per day (377 – 1730, lower-upper
quartiles) confirms that most of these patients were
receiving relatively high doses of M and therefore were
at high risk of toxicity. The reason for opioid rotation
in these patients was the development of toxic side
effects, irrespective of the level of analgesia. Although
the reported pain intensities in this study were relatively high (in keeping with Stage 3 on the Edmonton
staging system), there was no significant difference
between mean pain intensities before and after rotation, indicating equianalgesia between the final day
on the previous opioid and the day of stabilization on
the new opioid. Standard clinical practice in patients
with advanced cancer3,21 involves titrating the dose of
opioid to the point of dose-limiting toxicity in an effort
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1171
to achieve analgesia. Therefore, our findings reflect
clinical reality and standard practice in advanced cancer patients, and suggest a need to revisit the equianalgesic dose ratio tables in relation to the potency of
ME. Using many of the standard equianalgesic table
guidelines,16,18,20,21 there is a serious risk of ME toxicity.
The other major finding in this study was the discovery
of a highly significant positive correlation between the
prerotation M dosage and the conversion dose ratio
between M and ME. The median dose ratio for those
patients receiving ú1165 mg per day of M was 16.84,
which was 3 times higher than the median dose ratio
of 5.42 for the 50% of patients who were receiving a
dose of M of õ1165 mg per day. The change in conversion dose ratio as a function of the previous M dose
also has been observed by our group in patients
switched over to ME from hydromorphone.19 This correlation was not observed for rotation between hydromorphone and M and vice versa.27 A possible explanation for this observed correlation is the presence of
partial cross-tolerance between ME and other opioid
agonists. Another explanation could be the observed
effects of ME as a noncompetitive N-methyl-D-asparate (NMDA) receptor antagonist.28 NMDA receptors
have been associated with the development of opioid
tolerance in animals29,30 and humans.31 The observed
correlation between dose ratio and previous M dose,
coupled with the observed wide variation in dose ratio,
suggests the need for a highly individualized approach
in the process of reaching an optimal dose of ME. The
highest quartile of daily M dose before rotation ranged
from 1730 mg/day – 24025 mg/day. Specialist multidimensional assessment of patients receiving such high
doses32 is essential to identify those patients with somatization, severe psychologic distress, and a history
of drug or alcohol abuse. Recognition of these factors
and nonpharmacologic interventions may account for
the large decrease in opioid dose when these patients
were rotated to ME. In addition, the observed median
5-day period for dose stabilization in the process of
rotating from M to ME could allow time for the elimination of metabolites such as M-3-glucuronide, which
has been shown to be proalgesic in rodents33 and possibly also in humans.7 Therefore, the potential elimination of such proalgesic metabolites could lessen
pain intensity and reduce analgesic requirements on
the newly rotated opioid.
Given the major limitation of a small sample size
of 20 patients in this study, we recommend cautious
interpretation of our findings. The lack of a statistically
significant difference between the observed median
M-ME dose ratio (11.36) and the median ME-M dose
ratio (8.25) possibly could be due to the small number
of ME-M rotations (6) in this study. Also, the small
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CANCER March 15, 1998 / Volume 82 / Number 6
number of ME-M rotations provided inadequate statistical power in correlational analysis of dose ratio
and ME dosage before rotation to M. Other limitations
of this study included the retrospective and unblinded
features. However, these features are balanced to some
extent by virtue of the fact that neither the physicians
nor patients were aware that the dose ratio was going
to be studied at the time of opioid rotation. Both observer and patient bias could have influenced the assessment of pain intensity level before rotation could
have been biased due to the patient experiencing toxic
side effects. The advantages of the study includes the
fact that patient assessment was performed by experienced full time palliative medicine specialists and opioid rotation took place because of toxic side effects,
the reason most patients undergo opioid rotation in
clinical practice. Opioid rotation in patients with good
pain control usually is not necessary; hence a prospective study of opioid rotation in such patients would
contribute limited clinically beneficial information,
considering the fact that the most common reason for
opioid rotation is dose-limiting toxicity on the previous opioid. Furthermore, prospective study of ME rotation versus no rotation in patients with M toxicity
would engender obvious ethical and methodologic obstacles.
No complications were observed using the 10:1
conversion, even for patients receiving ú1165 mg of
M. This mostly was because the 3-day conversion allowed us to withdraw M without the third increment
of ME during Day 3 in high dose patients.
This study highlighted the gross underestimation
of the potency of ME by establishing an overall median
dose ratio of 11.2:1 between of M and ME. Second,
the dose ratio for M to ME rotation shows a statistically
significant positive correlation with the M dose prior
to rotation, resulting in a dose ratio approximately 3
times higher in patients receiving ú1165 mg of M/day
than the ratio for those receiving õ1165 mg M/day.
Because the dose ratio (M-ME) is not fixed and
changes as a function of previous M dose, our findings
underscore the need for a highly individualized approach in patients who are undergoing opioid rotation
from M to ME. In patients receiving õ1000 mg of M/
day a ratio of approximately 10:1 appears to be reasonable (e.g., for someone receiving M, 500 mg/day we
should aim for approximately ME, 50 mg/day for Day
3). In patients receiving ú100 mg of M/day an even
lower ratio is required (e.g., for someone receiving
3000 mg of M/day we should aim for approximately
200 mg of ME/day by Day 3). Otherwise, there is a high
risk of ME toxicity, which could be life-threatening.
Finally, because the standard equianalgesic dose ratio
reference tables are based on single dose studies, our
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findings in cancer pain patients who received multiple
doses suggests a need to reassess these standard reference tables.
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