Switching From Morphine to Oral Methadone in Treating
`Cancer Pain: What Is the Equianalgesic Dose Ratio?
`
`By Carla Ripamonti, Liliana Groff, Cinzia Brunelli, Daniela Polastri, Alessandro Stavrakis, and Franco De Conno
`
`Purpose: To define the dose ratio between morphine
`and methadone in relation to the previous morphine
`dose and the number of days needed to achieve the
`same level of analgesia in a group of patients with
`advanced cancer with pain who switched from mor-
`phine to oral methadone.
`Patients and Methods: A cross-sectional prospective
`study of 38 consecutive cancer patients who switched
`from morphine to oral methadone was performed. The
`intensity of pain before, during, and after the switching
`period was assessed through a four-point verbal Likert
`scale. The relationship between previous morphine dose
`and the final equianalgesic methadone dose, dose ratio
`between morphine and methadone, and the number of
`days required to achieve equianalgesia have been ex-
`amined by means of Pearson's correlation coefficient,
`scatter plots, and Cuzick's test for trend respectively.
`Results: Before the switch, the median oral equiva-
`lent daily dose of morphine was 145 mg/d; after the
`switch, the median equianalgesic oral methadone dose
`was 21 mg/d. A median time of 3 days (range, 1 to 7
`
`OPIOIDS, of which morphine is the most commonly
`
`used, are the mainstay of moderate-to-severe cancer
`pain management.' In approximately 80% of the patients
`with advanced cancer-related pain, the type of opioid
`analgesic and/or the route of administration has to be
`changed one or more times 2-4 so the therapy is tailored to
`meet specific clinical circumstances, improve pain con-
`trol,5-7 and/or reduce opioid toxicity.8 The individual re-
`sponses to different opioids are extremely variable and when
`patients fail to obtain adequate pain relief at the maximum-
`tolerated doses of morphine, they may benefit from an
`alternative opioid drug.7
`Among opioids, methadone is considered a good alterna-
`tive to mu-opioid receptor agonist drugs because of its
`excellent oral' and rectal absorption,10 analgesic effi-
`cacy,"'-1 higher potency, lower cost, longer administration
`
`From the Pain Therapy and Palliative Care Division and the
`Psychological Research Division, National Cancer Institute, Milan,
`Italy.
`Submitted March 19, 1998; accepted June 30, 1998.
`Supported in part by grant no. AIRC 198512 from the Italian
`Association for Cancer Research, Milan, Italv.
`Address reprint requests to Carla Ripamonti, MD, Pain Therapy and
`Palliative Care Division, National Cancer Institute of Milan, Via
`Venezian. 1. 20133 Milano, Italy; Email tdpint@tin.it.
`© 1998 by American Society of Clinical Oncology.
`0732-183X/98/1610-0036$3.00/0
`
`days) was necessary to achieve the equianalgesia with
`oral methadone; the lower the preswitching morphine
`dose, the fewer days necessary to achieve equianalge-
`sia with oral methadone (P < .001). Dose ratios ranged
`from 2.5:1 to 14.3:1 (median, 7.75:1), which indicated
`that, in most cases, the dose ratio was much higher than
`that suggested by the published equianalgesic tables. A
`strong linear positive relationship between morphine
`and methadone equianalgesic doses was obtained
`(Pearson's correlation coefficient, 0.91). The dose ratio
`increased with the increase of the previous morphine
`dose with a much higher increase at low morphine
`doses.
`Conclusion: The results of our study confirm that
`methadone is a potent opioid, more potent than be-
`lieved. Caution is recommended when switching from
`any opioid to methadone, especially in patients who are
`tolerant to high doses of opioids.
`J Clin Oncol 16:3216-3221. © 1998 by American
`Society of Clinical Oncology.
`
`intervals,14 no active metabolites that can accumulate in
`patients with renal failure, and the potential to control pain
`no longer responsive to morphine, hydromorphone, and
`fentanyl. 6.,' 5 16 Thus, methadone can have a major role in
`the treatment of cancer pain. Its use, however, is complicated
`by limited knowledge of the correct equianalgesic dose/ratio
`versus other opioids when switching in non-opioid-naive
`patients.
`During the switch from one opioid to another, the dose of
`the new drug is titrated according to the indications of the
`published equianalgesic tables, in which dose ratios between
`oral morphine and oral methadone are 1:1,17 3:1 (ie, 3 mg of
`oral morphine: 1 mg of oral methadone),' 8 and 4:1 (ie, 4 mg
`of oral morphine:l mg of oral methadone). 19 The dose
`equivalence reported in these tables is derived from equian-
`algesic studies conducted on opioid-naive subjects treated
`with single-drug doses, in which morphine and methadone
`show approximately the same analgesic potency, 20 whereas
`cancer patients are treated chronically and, during a switch,
`are already tolerant to opioids.
`Because there is an incomplete cross-tolerance among
`these drugs, some investigators recommend the use of a
`lower equianalgesic dose during the switch and retitration
`according to response.19 However, this is a rather vague
`indication and only partially applicable.
`According to other investigators, 21 during the switch from
`morphine to methadone, a reduction in the calculated equi-
`
`3216
`
`Journal of Clinical Oncology, Vol 16, No 10 (October), 1998: pp 3216-3221
`
`Downloaded from jco.ascopubs.org on November 25, 2014. For personal use only. No other uses without permission.
`Copyright © 1998 American Society of Clinical Oncology. All rights reserved.
`
`1
`
`

`
`MORPHINE TO METHADONE FOR PAIN
`
`analgesic dose of 75% or greater has been recommended in
`regard to the opioid previously administered. This indication
`is more definite than the former; however, it still does not
`consider the preswitching morphine dose level.
`According to Morley and Makin,22 the previous opiate
`should be stopped and replaced by a fixed dose of metha-
`done that is one tenth of the actual or calculated equivalent
`oral morphine dose when the 24-hour dose is less than 300
`mg, or a fixed dose of 30 mg of methadone when the 24-hour
`dose is greater than 300 mg. This fixed dose should then be
`administered orally as required, but not more frequently than
`3 hourly for 6 days. On day 6, the amount of methadone
`administered over the previous 2 days is noted and con-
`verted into a regular 12-hourly regimen. In this case, there is
`a wide range of doses, up to 300 mg of equivalent oral
`morphine dose, in which the equianalgesic dose between
`morphine and methadone is always 10:1.
`At the Palliative Care Unit in Edmonton, Canada, the
`switch is performed over 3 days; the morphine dose is
`reduced daily and replaced with oral or rectal methadone
`every 8 hours, using a titration equianalgesic dose ratio of
`10:1. The dose of methadone is increased only if the patient
`experiences moderate-to-severe pain, and transient episodes
`of pain are managed with the administration of short-acting
`opioids, if required.2 3,2 4
`From all the different published indications regarding the
`modalities of the switch and the dose ratios to be used for the
`achievement of equianalgesia, it is obvious that there is no
`standardization in this practice.
`Moreover, the switch is not easy in clinical practice
`because, for patients who are chronically treated for pain,
`there is a relationship between the preswitching morphine
`dose and the postswitching dose of methadone necessary to
`obtain at least the same analgesic effect. Interestingly, the
`dose of methadone required to achieve the equianalgesic
`effect is not only lower, but unexpectedly much lower in
`patients who previously received very high morphine doses.
`The aims of this study were to define the dose ratio
`between morphine and methadone, the variation of the dose
`ratio in relation to the previous morphine dose, and the
`number of days needed to achieve at least the same level of
`analgesia in a group of advanced cancer patients with pain
`who switched from morphine to oral methadone.
`
`PATIENTS AND METHODS
`
`Patients
`In a cross-sectional prospective study performed at the Pain Therapy
`and Palliative Care Division of the National Cancer Institute of Milan
`(Italy) from January to December 1997, we evaluated all consecutive
`cancer patients who switched from morphine administered by oral,
`subcutaneous, or intravenous routes to oral methadone in solution form.
`For the purpose of this study, only the patients who presented the
`
`3217
`
`following criteria were considered: nociceptive pain; collaboration;
`normal liver and kidney function; a stable dose of morphine during the
`week before the switch and a stable dose of methadone in the first week
`after the end of the switching period; no radiotherapy, chemotherapy, or
`any change in hormone therapy for at least 2 weeks before the switch,
`during the switching period, and for the first week after the end of the
`switching period.
`
`Data Collection
`
`The following data were collected for each patient: age; sex; primary
`tumor sites; intensity of pain before, during, and after the switch; the
`dosage (in milligrams daily) and route of morphine administration
`before the switch; the final equianalgesic dose of oral methadone (in
`milligrams daily); the number of days needed to achieve equianalgesia;
`and the reasons for the switch.
`For comparative purposes, all morphine doses were calculated as the
`oral equivalent daily dosage. A conversion ratio of 3:1 was used for oral
`morphine doses versus subcutaneous and intravenous morphine (3 mg
`of oral morphine: mg of morphine administered subcutaneously or
`25.26
`intravenously).
`
`Pain Assessment
`
`The intensity of pain was reported weekly by the patient using a
`Therapy Impact Questionnaire (TIQ). 27.28 The TIQ is a validated tool
`used to evaluate quality of life. It includes 36 items to assess the degree
`of discomfort experienced and evaluated subjectively by the cancer
`patient through a verbal Likert scale, with four possible answers (not at
`all, 1; slight, 2; a lot, 3; or very much, 4). The period of reference is the
`previous week. Of the 36 items on the TIQ, answers with regard to pain
`were included in this study. In regard to symptoms other than pain,
`morphine or methadone-related adverse effects were considered when
`the patient reported a direct association of the symptoms with opioid
`administration.
`During the switching period, the pain intensity and the opioid-related
`adverse effects were assessed daily. This evaluation was only performed
`for a continuous assessment of pain and other symptoms, with the aim
`of modifying the daily dose of methadone, and it was not included in
`data analysis.
`
`Switching Modality
`
`The switch was performed empirically; based on our clinical
`experience, we reduced the daily morphine dose by at least 30% over
`the first 24 hours and replaced it with oral methadone in solution form
`administered every 8 hours, using a dose ratio of 4:1 for patients who
`received 30 to 90 mg daily of morphine, a dose ratio of 6:1 for patients
`who received 90 to 300 mg daily, and a dose ratio of 8:1 for those who
`received 300 mg daily or more. During the second day, if pain control
`was good, the patient underwent a further decrease in the morphine
`dose. The methadone dose was only increased if the patient experienced
`moderate-to-severe pain. Transient episodes of pain were managed with
`intermittent rescue doses of short-acting opioids. During day 3,
`morphine was discontinued and the patient was maintained on metha-
`done administered every 8 hours plus 10% of the daily methadone dose
`as an extra oral dose for breakthrough pain. The methadone dosage was
`titrated day by day until pain relief was achieved.
`
`Data Analysis
`Results are presented in medians, lower-upper quartiles (Ql to Q3),
`and the ranges observed for the following data: age, previous morphine
`dose, final oral methadone dose at equianalgesia, pre- and postswitching
`
`Downloaded from jco.ascopubs.org on November 25, 2014. For personal use only. No other uses without permission.
`Copyright © 1998 American Society of Clinical Oncology. All rights reserved.
`
`2
`
`

`
`3218
`
`pain intensity, number of days to achieve equianalgesia with oral
`methadone, and dose ratio between morphine and methadone.
`Scatterplots have been used to show
`the relationship between
`previous morphine dose and final equianalgesic methadone dose: in a
`the first plot, the values obtained were compared with those indicated in
`the literature at ratios of 1:1,17 3:1,18 and 4:1.19 A second scatterplot of
`the dose ratio of morphine/methadone versus the previous morphine
`dose was used to better describe the relationship between the equianal-
`gesic doses of the two opioids, also evaluated by Pearson's correlation
`coefficient.
`Cuzick's nonparametric test for trend 29 was performed to study the
`association between previous morphine doses and number of days
`required to reach equianalgesia.
`
`RESULTS
`From January to December 1997, 49 patients switched
`from morphine to methadone. Eleven of these patients were
`excluded from the study because they were not able to
`maintain a stable morphine dose in the week before the
`switch (six patients) or they were undergoing radiotherapy
`(three patients), chemotherapy (one patient), or a new
`hormone therapy (one patient) during the switching period.
`Table 1 lists the age, sex, primary tumor sites, routes of
`morphine administration, and reasons for switching for the
`38 patients on the study.
`
`Table 1. Patient Characteristics
`
`No.
`
`%
`
`55.26
`44.74
`
`10.5
`23.7
`31.9
`5.2
`5.2
`10.5
`5.2
`2.6
`2.6
`2.63
`
`Sex
`Female
`Male
`Age, years
`Median
`Q1-Q3
`Primary tumor sites
`Head and neck
`Lung
`Breast
`Female genitourinary
`Sarcoma
`Colon, rectum
`Pancreas
`Bladder
`Prostate
`Lymphoma
`Morphine administration routes before the switch
`Oral slow-release formulation
`Continuous subcutaneous infusion
`Continuous intravenous infusion
`Reasons for the switch
`Poor pain control at dose-limiting toxicity of
`morphine
`Difficulty swallowing tablets
`Placement of an NGT for feeding
`Mild confusion or drowsiness
`Change from parenteral morphine
`
`21
`17
`
`60.5
`55-66
`
`4
`9
`12
`2
`2
`4
`2
`1
`1
`1
`
`28
`9
`1
`
`6
`7*
`5'
`10
`10
`
`Abbreviation: NGT, nasogostric tube.
`*Methadone is the only opioid available in solution form in Italy.
`
`RIPAMONTI ET AL
`
`Before the switch, 28 patients were receiving oral mor-
`phine and 10 patients were receiving parenteral morphine.
`All the patients who received parenteral morphine could be
`treated again by oral route and methadone was chosen to
`reduce the opioid dose, Because of difficulty swallowing
`tablets or because they had a nasogastric tube for feeding, 12
`patients had to receive an opioid in solution form, and
`methadone is the only one available in Italy. Ten patients
`switched to methadone because they presented mild but
`uncomfortable morphine-related adverse effects, such as
`confusion and drowsiness. Six patients switched because of
`poor pain control at dose-limiting toxicity of morphine
`(Table 1).
`Median pain intensity during the week before the switch
`was equal to the median of the first postswitching week
`(Table 2). Before the switch, the oral equivalent daily dose
`of morphine ranged from 30 to 800 mg daily (median, 145
`mg daily). After the switch, the equianalgesic oral metha-
`done dose ranged from 9 to 60 mg daily (median, 21 mg
`daily). A median time of 3 days (range, 1 to 7 days) was
`necessary to achieve equianalgesia with oral methadone.
`The median dose ratio between morphine and methadone
`was 7.75 (range, 2.5 to 14.3).
`No patients discontinued methadone treatment because of
`unwanted adverse effects. The patients with constipation
`during morphine treatment continued to report this symptom
`during methadone treatment. The patients who presented
`uncomfortable confusion or drowsiness during morphine
`treatment had a downward trend of symptoms during meth-
`adone treatment. This improvement may have been caused
`by an appropriate hydration therapy.
`Figure I shows the final methadone doses required to
`achieve equianalgesia versus the morphine doses previously
`administered, in comparison with the three equianalgesic
`dose ratios reported in the literature: 1:1,14 3:1,15 and 4:1
`ratio,' 6 represented by three straight lines. Note that no
`patient on the study underwent a dose ratio of 1:1, and that
`the dose ratio ranged from 2.5:1 to 14.3:1 (14.3 mg of
`morphine:l mg of methadone), with a median of 7.75:1,
`
`Table 2. Pre- and Postswitching Clinical Results
`
`Median 01-Q3
`
`Range
`
`Previous morphine dose, mg/d (oral equivalent
`daily dose)
`Final oral methadone dose, mg/d (at the equion-
`algesia)
`Preswitching pain intensity
`Postswitching pain intensity
`No. of days to achieve equianalgesia with oral
`methadone dose
`Equianalgesic dose ratio between morphine and
`methadone
`
`145
`
`80-240 30-800
`
`21
`2
`2
`
`15-30
`2-2
`2-2
`
`9-60
`1-3
`1-3
`
`3
`
`2-4
`
`1-7
`
`7.75 5-10 2.5-14.3
`
`Downloaded from jco.ascopubs.org on November 25, 2014. For personal use only. No other uses without permission.
`Copyright © 1998 American Society of Clinical Oncology. All rights reserved.
`
`3
`
`

`
`MORPHINE TO METHADONE FOR PAIN
`
`3219
`
`Table 3. Equianalgesic Dose Ratios at Different Previous Morphine Doses
`
`Preswitching Morphine Dose (mg/d)
`
`30-90
`
`90-300
`
`z 300
`
`No. of patients
`Dose ratio used during the switch
`Dose ratio achieved after the switch
`Median
`Range
`No. of days to achieve equianalgesia
`Median
`Range
`
`10
`4:1
`
`3.7
`2.5-8.8
`
`2
`1-3
`
`20
`6:1
`
`7.75
`4-10
`
`3
`1-7
`
`8
`8:1
`
`12.25
`10-14.3
`
`5.5
`2-7
`
`received 90 to 300 mg daily (our dose ratio was 6:1), and
`12.25:1 for patients who received greater than 300 mg daily
`(our dose ratio was 8:1). The last row shows that the lower
`the morphine dose previously administered, the fewer days
`it took to achieve equianalgesia with methadone, also
`confirmed by Cuzick's test for trend (P < .001).
`
`DISCUSSION
`
`The results of our prospective study of 38 patients
`chronically treated with various morphine dosages confirm
`that the equianalgesic dose ratio between morphine and
`methadone is significantly higher (ie, methadone is much
`more potent) in patients tolerant to higher morphine doses.
`These results agree with those of Lawlor et al, 23 who
`retrospectively evaluated 14 patients with advanced cancer
`who switched from morphine to oral methadone and were
`treated with a median morphine daily dose eight times
`greater than
`that used in our study. The investigators
`reported that the median dose ratio obtained was 11.36,
`which shows that methadone is much more potent than
`expected and the dose ratio correlates with the previous
`administered morphine dose.
`In respect to the equianalgesic tables, no patient in our
`study presented an equianalgesic dose ratio of 1:1, whereas
`the dose ratios of 3:1 and 4:1 approached those obtained in
`patients previously treated with low daily doses of morphine
`that ranged from 30 to 90 mg.
`Recent data in the literature show that although the dose
`ratio between morphine and hydromorphone is equal to that
`expected, 24,30 the hydromorphone/methadone ratio is 5 to 10
`times greater and varies significantly according
`to the
`previously administered dose of hydromorphone. 24,31
`It is not clearly understood why this occurs during the
`switch from morphine or hydromorphone to methadone.
`These findings can be partially explained by the incomplete
`cross-tolerance of methadone in respect to the other opioid
`analgesics. Methadone is a mu-delta opioid agonist and
`morphine is a mu-agonist and, therefore, the doses of
`methadone would be smaller than expected in patients who
`were at least partly tolerant to morphine by escalation of the
`dose to very high levels.
`
`360
`
`300
`
`200
`
`100,
`
`50'
`
`9-
`
`1:1
`
`3:1
`
`!
`
`·
`·
`% * * s
`
`a
`
`WS
`
`00
`
`az0 0I
`
`-
`
`Li.
`
`30
`
`100
`
`200
`
`00
`
`400
`
`50
`
`660oo
`
`760
`
`860
`
`PREVIOUS MORPHINE DOSE (mgfd)
`
`Fig 1. Final doses of methadone required to achieve equianalgesia
`versus the morphine dose administered before the switch compared with the
`three equianalgesic dose ratios reported in the literature (1:1, 3:1, and 4:1),
`represented by three straight lines.
`
`which indicated that, in most cases, the dose ratio was much
`higher than that suggested by the published equianalgesic
`tables. The strong linear positive relationship between
`morphine and methadone equianalgesic doses seen in Fig 1
`and also confirmed by a Pearson's correlation coefficient of
`0.91 can be examined more deeply in Fig 2. In this figure,
`the plot shows that the dose ratio increases at the increase of
`the previous morphine dose and that the increase is much
`higher at low morphine dosages (30 to 300 mg), whereas the
`dose ratio increases more slowly with doses of morphine
`greater than 300 mg. This finding is not compatible with the
`hypothesis of a constant dose ratio in relation to the previous
`morphine dose.
`Table 3 shows that in respect to the dose ratio between
`morphine and methadone empirically used during the switch-
`ing phase, the final median dose ratio of methadone obtained
`was 3.7:1 for patients who received 30 to 90 mg daily of
`morphine (our dose ratio was 4:1), 7.75:1 for those who
`
`So
`
`14-
`
`12-
`
`10-
`
`ooo
`
`oo
`
`a
`0
`
`0
`
`o
`
`o
`
`a
`
`oo
`
`0
`
`0
`
`o o
`
`o
`
` o o
`
`4"
`
`2.5
`
`W z00 zI
`
`-
`
`002
`
`a.
`
`3o
`
`16o
`
`260
`
`360
`
`40
`
`560
`
`60oo
`
`7600
`
`860
`
`PREVIOUS MORPHINE DOSE (mg/d)
`
`Fig 2. Equianalgesic dose ratio between morphine and methadone
`versus previous morphine dose (in milligrams daily).
`
`Downloaded from jco.ascopubs.org on November 25, 2014. For personal use only. No other uses without permission.
`Copyright © 1998 American Society of Clinical Oncology. All rights reserved.
`
`4
`
`

`
`3220
`
`Moreover, in the rat, methadone has been shown to differ
`from morphine and hydromorphone because it has noncom-
`petitive antagonist activity at the N-methyl-D-aspartate
`(NMDA) receptors.32,33 Because NMDA receptors have
`been associated with the development of opioid tolerance in
`animals34-38 and humans, 39 the nonopioid NMDA receptor
`antagonism of methadone may reduce the development of
`tolerance in patients who switch from morphine or hydromor-
`phone to methadone.
`According to Lawlor et al, 23 the median period of 5 days
`to reach equianalgesia during the switch from morphine to
`methadone could allow the elimination of morphine-3-
`glucuronide, which is a metabolite of morphine with proalge-
`sic activity in rodents and, possibly, in humans. 40,41 The
`eventual elimination of this metabolite could reduce pain
`intensity and therefore require a lower postswitching dose of
`methadone to achieve analgesia.
`From the pharmacokinetic aspect, differently from mor-
`phine, methadone is characterized by a slow elimination
`phase (beta half-life of 15 to 60 hours) that causes an
`accumulation of the drug. 14 However, similar to morphine,
`the plasmatic level of methadone does not correlate with the
`analgesic level. 42,43 Because of one or more of the previ-
`ously mentioned reasons, methadone is more potent than
`believed and even more potent in patients tolerant to high
`morphine doses and should be investigated further.
`Whatever the reason for this major potency of methadone,
`a clinical problem remains for the doctors who treat patients
`with cancer pain and who find it necessary to switch from
`morphine to methadone for various reasons. The first
`question concerns the best switching modality and the
`second concerns the dose ratio to be used during the switch.
`Our experience shows that a switch over a period of 3
`days, with a daily reduction of the morphine and replace-
`
`RIPAMONTI ET AL
`
`ment with oral methadone every 8 hours, as described
`previously, 23,24 is a simple and safe modality. Furthermore,
`we believe the different median dose ratios and the relative
`ranges obtained in respect to the preswitching morphine
`dose could be used as an indication in clinical practice for
`methadone dose titration, instead of the use of a constant
`dose ratio of 10:1, In fact, not all patients who require opioid
`switching take high doses of morphine. For example, many
`of the outpatients of our Palliative Care Unit are opioid naive
`at the first visit. They begin morphine treatment and,
`therefore, if they require a switch, the morphine dose is very
`low, even less than 90 mg daily. For these patients, a dose
`ratio of 10:1 is not indicated, as our results show.
`Moreover, our findings have very important clinical
`implications because they confirm that the published equian-
`algesic dose ratios of 3:1 and 4:118,19 can only be relied on
`for patients who are treated with low morphine doses and, at
`the same time, show that the dose ratio of 1:117 is not
`applicable, even in patients tolerant to very low oral
`morphine dosages, such as 30 mg daily.
`We stress that caution is recommended during a switch
`from any opioid to methadone, especially in patients tolerant
`to high doses of opioids. These patients may be at risk for
`toxicity and, therefore, the switch to methadone must be
`performed gradually and personalized. In fact, because of
`the high potency of methadone and its long elimination
`half-life, its inappropriate administration could be life-
`threatening.
`Our study provided safety data and preliminary clinical
`indications that can be used in daily practice. However,
`future prospective, properly designed studies should be
`performed to evaluate the equianalgesia between morphine
`and methadone and to review the current equianalgesic
`tables.
`
`REFERENCES
`1. World Health Organization: Cancer Pain Relief (ed 2) Geneva,
`the response to different opioids: Report of five cases. Pain 49:87-91,
`Switzerland, World Health Organization, 1996
`1992
`2. Cherny NJ, Chang V, Frager G, et al: Opioid pharmacotherapy in
`8. Ripamonti C, Bruera E: CNS adverse effects of opioids in cancer
`the management of cancer pain: A survey of strategies used by pain
`patients: Guidelines for drug treatment. CNS Drugs 8:21-37, 1997
`physicians for the selection of analgesic drugs and routes of administra-
`9. Gourlay GK, Cherry DA, Cousin MJ: A comparative study of the
`tion. Cancer 76:1283-1293. 1995
`efficacy and pharmacokinetics of oral methadone and morphine in the
`3. Bruera E, MacMillan K, Hanson J: Palliative care in a cancer
`treatment of severe pain in patients with cancer. Pain 25:297-312, 1986
`center: Results in 1984 versus 1987. J Pain Symptom Manage 5:1-5, 1990
`10. Ripamonti C, Zecca E, Brunelli C, et al: Rectal methadone in
`4. Coyle N, Adelhart J, Foley KM, et al: Character of terminal illness
`cancer patients with pain. A preliminary clinical and pharmacokinetic
`in the advanced cancer patient: Pain and other symptoms during the last
`study. Ann Oncol 6:841-843, 1995
`four weeks of life. J Pain Symptom Manage 5:83-93, 1990
`11. Ventafridda V, Ripamonti C, Bianchi M, et al: A randomized
`5. Kalso E, Heiskanen T, Rantio M, et al: Epidural and subcutaneous
`study on oral administration of morphine and methadone
`in the
`morphine in the management of cancer pain: A double-blind cross-over
`treatment of cancer pain. J Pain Symptom Manage 1:203-207, 1986
`study. Pain 67:443-449, 1996
`12. Bruera E, Watanabe S, Fainsinger RL, et al: Custom-made
`6. Morley JS, Watt JWG, Wells JC, et al: Methadone in pain
`capsules and suppositories of methadone for patients on high-dose
`uncontrolled by morphine. Lancet 342:1243-1244, 1993
`opioids for cancer pain. Pain 62:141-146, 1995
`7. Galer BS, Coyle N, Pasternak GW, et al: Individual variability in
`13. De Conno F, Groff L, Brunelli C. et al: Clinical experience with
`
`Downloaded from jco.ascopubs.org on November 25, 2014. For personal use only. No other uses without permission.
`Copyright © 1998 American Society of Clinical Oncology. All rights reserved.
`
`5
`
`

`
`MORPHINE TO METHADONE FOR PAIN
`
`oral methadone administration in the treatment of pain in 196 advanced
`cancer patients. J Clin Oncol 14:2836-2842, 1996
`14. Ripamonti C, Zecca E, Bruera E: An update on the clinical use of
`methadone for cancer pain. Pain 70:109-115, 1997
`15. Crews JC, Sweeney NJ, Denson DD: Clinical efficacy of
`methadone in patients refractory to other mu-opioid receptor agonist
`analgesics for management of terminal cancer pain. Cancer 72:2266-
`2272, 1993
`16. Manfredi PL, Borsook D, Chandler SW, et al: Intravenous
`methadone for cancer pain unrelieved by morphine and hydromor-
`phone: Clinical observations. Pain 70:99-101, 1997
`17. Health and Welfare Canada: Cancer Pain: A Monograph on the
`Management of Cancer Pain. Ottawa, Canada, Health & Welfare
`Canada, Minister of Supply and Services, H42-2/5, 1984E
`18. Levy MH: Pharmacological treatment of cancer pain. N Engl J
`Med 335:1124-1132, 1996
`19. Agency for Health Care Policy Research: Management of
`Cancer Pain. Clinical Practice Guidelines. Rockville, MD, US Depart-
`ment of Health and Human Services. AHCPR Publications no. 94-0592,
`March 1994, p 52
`20. Houde RE: Misinformation: Side effects and drug interactions, in
`Hill CS, Fields WS (eds): Advances in Pain Research and Therapy. New
`York, NY, Raven, 1989, pp 145-161
`21. Portenoy RK, Coyle N: Controversies in the long-term manage-
`ment of analgesic therapy in patients with advanced cancer. J Pain
`Symptom Manage 5:307-319, 1990
`22. Morley JS, Makin MK: Letter to the Editor. Pain 70:109-115,
`1997
`23. Lawlor PG, Turner K, Hanson J, et al: Dose ratio between
`morphine and methadone in patients with cancer pain: A retrospective
`study. Cancer 82:1167-1173, 1998
`24. Bruera E, Pereira J, Watanabe S, et al: Opioid rotation in patients
`with cancer pain. A retrospective comparison of dose ratios between
`methadone, hydromorphone, and morphine. Cancer 78:852-857, 1996
`25. Hanks GW, De Conno F, Ripamonti C, et al: Morphine in cancer
`pain: Modes of administration. BMJ 312:823-826, 1996
`26. Kalso E, Vainio A: Morphine and oxycodone hydrochloride in
`the management of cancer pain. Clin Pharmacol Ther 47:639-646, 1990
`27. Ventafridda V, De Conno F, Ripamonti C, et al: Quality-of-life
`assessment during a palliative care program. Ann Oncol 1:415-420,
`1990
`28. Tamburini M, Rosso S, Gamba A, et al: A therapy impact
`questionnaire for quality-of-life assessment in advanced cancer re-
`search. Ann Oncol 3:565-570, 1992
`29. Cuzick J: A Wilcoxon-type test for trend. Stat Med 4:87-90, 1985
`
`3221
`
`30. Lawlor PG, Turner K, Hanson J, et al: Dose ratio between
`morphine and hydromorphone in patients with cancer pain: A retrospec-
`tive study. Pain 72:79-85, 1997
`31. Ripamonti C, De Conno F, Groff L, et al: Equianalgesic
`dose/ratio between methadone and other opioid agonists in cancer pain:
`Comparison of two clinical experiences. Ann Oncol 9:79-83, 1998
`32. Ebert B, Andersen S, Krogsgaard-Larsen P: Ketobemidone,
`methadone and pethidine are noncompetitive N-methyl-D-aspartate
`(NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett
`187:165-168, 1995
`33. Gorman AL, Elliott KJ, Inturrisi CE: The d- and 1-isomers of
`methadone bind to the noncompetitive site on the N-methyl-D-aspartate
`(NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett
`223:5-8, 1997
`34. Elliot K, Kest B, Man A, et al: N-methyl-d-aspartate (NMDA)
`receptors, mu and kappa opioid tolerance and perspectives on new
`analgesic drug development. Neuropsychopharmacology 13:347-356,
`1995
`35. Trujillo K: Effects of noncompetitive N-methyl-d-aspartate recep-
`tor antagonists on opiate tolerance and physical dependence. Neuropsy-
`chopharmacology 13:301-307, 1995
`36. Yamamoto T, Yaksh TL: Studies on the spinal interaction of
`morphine and the NMDA antagonist Mk-801 on the hyperaesthesia
`observed in a rat model of sciatic mononeuropathy. Neurosci Lett
`135:67-70, 1992
`37. Tiseo PJ, Inturrisi CE: Attenuation and reversal of morphine
`tolerance by competitive N-methyl-D-aspartate receptor antagonist LY
`274614. J Pharmacol Exp Ther 264:1090-1096, 1993
`38. Elliott K, Minami N, Kohesnidov Y, et al: The NMDA receptor
`antagonist LY 274614 and Mk-801 and the nitric oxide synthase
`inhibitor NG-nitro-L-arginine attenuate analgesic
`tolerance
`to the
`mu-opioid morphine. Pain 56:69-75, 1994
`39. Clark JK, Kalen GE: Effective treatment of severe cancer pain of
`the head using low-dose ketamine in an opioid-tolerant patient. J Pain
`Symptom Manage 10:310-314; 1995
`40. Smith MJ, Watt JA, Cramond T: Morphine-3-glucuronide: A
`potent antagonist of morphine analgesia. Life Sci 47:579-585, 1990
`41. Morley J, Miles JB, Wells JC, et al: Paradoxical pain. Lancet
`340:1045, 1992
`42. Nilsson MI, Meresaar U, Anggard E, et al: Clinical pharmacoki-
`netics of methadone. Acta Anaesth Scand 74:66-69, 1982
`43. Jaffe JH, Martin WR: Opioid analgesics and antagonists, in
`Goodman Gilman A, Goodman LS (eds): Goodman and Gilman's The
`Pharmacological Basis of Therapeutics. New York, NY, Pergamon,
`1990, p 508
`
`Downloaded from jco.ascopubs.org on November 25, 2014. For personal use only. No other uses without permission.
`Copyright © 1998 American Society of Clinical Oncology. All rights reserved.
`
`6