Pharmacokinetics and Clinical Efficacy of Oral Morphine
`Solution and Controlled-Release Morphine
`Tablets in Cancer Patients
`
`MICHAEL P. THIRLWELL, MD,* PAUL A. SLOAN, MD,t JEAN A. MAROUN, MD,* GERRY J. BOOS, MD,*
`JEAN-GUY BESNER, P H D , ~ JOHN H. STEWART, MSc,ll AND BALFOUR M. MOUNT, MDt
`
`Twenty-three adult patients with chronic pain due to cancer completed a double-blind, randomized, two-
`phase crossover trial comparing plasma morphine concentrations and analgesic efficacy of oral morphine
`sulfate solution (MSS) and controlled-release morphine sulfate tablets (MS Contin [MSq, Purdue Fred-
`erick, Inc., Toronto, Ontario, Canada). MS Contin was given every 12 hours to all patients except those
`whose daily morphine dose could not be equally divided into two 12-hour doses with the tablet strengths
`available. MSS was given every 4 hours. Patients received both of the test drugs for at least 5 days, and,
`on the final day of each phase, peripheral venous blood samples for morphine analysis were obtained.
`Eighteen patients received MSC every 12 hours, and five received it every 8 hours. The same total daily
`morphine dose was given in both phases. In the 18 patients who received MSC every 12 hours, the daily
`morphine dose was 183.9 k 140.0 mg (mean k SD). In this group, the mean area under the curve (AUC)
`with MSC was 443.6 f 348.4 ng/ml/hour, compared with 406.8 f 259.7 ng/ml/hour for MSS (P
`> 0.20). Mean maximum morphine concentrations (Cmm) for MSC and MSS were 67.9 k 42.1 and 58.8
`? 30.3 ng/ml, respectively (P > 0.05). Mean minimum morphine concentrations (Cmi,,) were 17.0 f 17.7
`and 18.3 k 15.0, respectively (P > 0.30). There was a significant difference (P < 0.001) between the two
`drugs in time required to reach maximum morphine concentration (T-). Mean T,,
`after MSC occurred
`at 3.6 t 2.3 hours. After MSS, it occurred at 1.3 k 0.4 hours. In the five patients who received MSC
`every 8 hours, the findings paralleled those in the principal group, with no significant differences between
`and a highly significant difference between the two in Tmx. However, in
`MSC and MSS in C,,
`or C,,
`this small group of patients, the AUC with MSC was significantly (P = 0.04) greater than that with
`MSS. All patients had very good pain control throughout the study and both formulations were well
`tolerated. There were no significant differences between MSC and MSS in pain scores or side effects.
`Under the conditions of this study there was no clinically significant difference in bioavailability between
`MSC and oral MSS. When given on a 12-hourly basis in individually titrated doses, the MSC provided
`therapeutic plasma morphine concentrations throughout the dosing interval.
`Cancer 63:2275-2283, 1989.
`
`From the *Division of Medical Oncology, Montreal General Hospital,
`McGill University, Montrkal, Qukbec, Canada; the ?Palliative Care Ser-
`vice, Royal Victoria Hospital, McGill University, Montrkal, Qukbec,
`Canada; the $Division of Medical Oncology, Ottawa General Hospital,
`Ottawa Regional Cancer Centre, Ottawa, Ontario, Canada; the §De-
`partment of Pharmacy, Universitk de Montrkal, Montrkal, Qukbec,
`Canada; and the 11 Scientific Department, Purdue Frederick, Inc., Toronto,
`Ontario, Canada.
`Supported by a grant from Purdue Frederick, Inc., Toronto, Ontario,
`Canada.
`The authors thank Dr. Ina Ajemian, Dr. Reina Bendayen, Dr. Marcel
`Boisvert, Ms. Michelle Deschamps, Ms. Faye Edwards, Mr. Nathan Fox,
`Ms. Lois Hollingsworth, Ms. Jane Nelson, Mme. Marie Pineau, Mr.
`Francois Shubert, Ms. Pat Sproule, and Dr. David Stewart for assistance
`with the design and conduct of the study.
`Address for reprints: Michael P. Thirlwell, MD, Department of Med-
`icine, Montreal General Hospital, 1650 Cedar Avenue, Montrkal, Qukbec,
`Canada H3G 1A4.
`Accepted for publication January 27, 1989.
`
`I morphine had approximately one sixth the potency
`
`N 1965, Houde and colleagues' reported that oral
`
`of intramuscular morphine. Later, Brunk and Delle' noted
`that, although oral morphine is well absorbed from the
`gastrointestinal tract, it is so rapidly metabolized in the
`intestinal mucosa and liver that only a fraction of the
`dose reaches the systemic circulation. These observations
`led to the incorrect conclusion, particularly in North
`America, that morphine is not an effective analgesic when
`given orally. However, studies by Saunders3 and
`Twycross4 in the United Kingdom and, later, by Melzack
`et aZ.596 in Canada demonstrated that oral morphine given
`in regularly scheduled individually titrated doses is highly
`effective in controlling pain in a large majority of cancer
`patients. These apparently conflicting views have now
`
`2275
`
`1
`
`

`

`2276
`
`CANCER June 1 Supplement 1989
`
`Vol. 63
`
`largely been resolved by our understanding (I) that the
`reduced oral bioavailability of morphine requires the ad-
`ministration of larger oral morphine doses to achieve the
`same effect as parenterally administered dose^,^,^ and (2)
`that, with repeated administration to patients with cancer
`pain, the parenteral/oral potency ratio of morphine is 1 :
`2 or 1:3 rather than 1:6.9
`In recent years, oral morphine has become recognized
`as a mainstay in the treatment of severe cancer
`Because the goal of analgesic therapy is to anticipate and
`prevent pain, not to treat it only as it reappears, each dose
`of oral morphine must be given before the effect of the
`previous dose has subsided. Because morphine has a short
`elimination half-life (2 to 3 hours), it must be administered
`every 4 hours if an optimal degree of efficacy and freedom
`from side effects are to be maintained. Unfortunately, a
`4-hourly regimen is inconvenient for patients because it
`requires dosing during the night. Moreover, compliance
`is known to decrease as the required frequency of dosing
`increases,13 and noncompliance adds to the risk of sub-
`optimal pain control.
`To overcome the difficulties associated with a 4-hour
`dosing regimen, controlled-release morphine sulfate tab-
`lets (MS Contin [MSC], Purdue Frederick, Inc., Toronto,
`Ontario, Canada) have been formulated using the Contin
`release system, which has been used successfully with a
`wide range of drugs.14 The system consists of a matrix of
`aliphatic alcohols and alkyl cellulose. The rate of release
`of active drug from the matrix depends on the drug's par-
`tition coefficient between the components of the matrix
`and the aqueous phase within the gastrointestinal tract.
`Contin formulations control the rate of release of active
`drug within the gastrointestinal tract, with the result that
`the drug is delivered to the body at a specific, planned
`rate. The potential advantages of controlled-release for-
`mulations include extended duration of action, more
`constant plasma concentrations and clinical effects, re-
`duced dosing frequency, increased compliance, and fewer
`side effects.
`With drugs other than morphine, most notably the-
`ophylline,15 controlled-release formulations have been
`found to be more effective than conventional formulations
`and better accepted by patients. However, these formu-
`lations also have some potential disadvantages. The release
`of active drug may be incomplete, resulting in reduced
`bioavailability, or the drug may be released too rapidly,
`producing toxic plasma concentrations. Also, because
`more drug is contained in controlled-release formulations,
`tablet size may increase, which, in turn, may lead to dif-
`ficulty in swallowing.
`MS Contin tablets have been in clinical use for several
`years, and studies have demonstrated excellent analgesic
`efficacy and a 12-hour duration of action in most pa-
`tients. 16,17 However, only limited pharmacokinetic data
`
`are available, and no controlled pharmacokinetic study
`has been conducted in cancer patients. This study was
`undertaken to compare the pharmacokinetics and clinical
`efficacy of MSC tablets with those of oral morphine so-
`lution in patients with cancer pain.
`
`Materials and Methods
`
`Patients
`Adult patients with cancer-related pain requiring oral
`opioid therapy participated in the study. All were mentally
`and physically competent to provide consent, answer
`questions, and comply with the therapeutic protocol, and
`all had serum creatinine levels of < 130 pmol/l and serum
`bilirubin levels of <26 pmol/l. Patients with hepatic or
`renal impairment were excluded from the study, as were
`patients with severe nausea and/or vomiting or uncon-
`trolled pain requiring frequent parenteral morphine and
`patients who were scheduled to receive a course of che-
`motherapy or radiotherapy in the 7 days before or at any
`time during the trial.
`Patients provided written informed consent before par-
`ticipation. The study was approved by the Research and
`Ethics Committees of the Royal Victoria Hospital, Mon-
`trkal, the Montreal General Hospital, the Ottawa General
`Hospital, and the Bureau of Human Prescription Drugs,
`Department of National Health and Welfare, Canada.
`
`Test Medications
`The test medications were MSC tablets in 30, 60, and
`100 mg strengths and oral morphine sulfate solution
`(MSS) in 1 and 5 mg/ml concentrations. The MSS used
`at the Royal Victoria Hospital was prepared by the hos-
`pital's Department of Pharmacy and that used at the other
`centers was obtained commercially (Statex Pharmasci-
`ence, Inc., Montrkal). The MSC was administered every
`12 hours, except to patients who required 90 mg/day.
`These patients received MSC 30 mg every 8 hours because
`90 mg could not be given in two equally divided 12-hour
`doses with the tablet strengths available at the time of the
`study. The MSS was administered every 4 hours to all
`patients. Each patient's daily morphine dose was the same
`during both the MSC and MSS treatment periods. For
`example, a patient receiving 20 mg of morphine sulfate
`solution every 4 hours during MSS administration re-
`ceived 60 mg of morphine every 12 hours during MSC.
`Breakthrough pain was controlled by the use of separate,
`open-label doses of MSS. The date, time, and amount of
`MSS used for breakthrough pain was recorded.
`
`Concomitant Medications
`No opioids other than the test medications and the
`open-label MSS for breakthrough pain were given during
`
`2
`
`

`

`No. I 1
`
`PHARMACOKINETICS AND EFFICACY OF MSS AND MSC
`
`Thirlwell et d.
`
`*
`
`2217
`
`the trial. Nonopioid analgesics and other medications (e.g.,
`laxatives) that had been taken routinely by the patients
`before the trial were continued at stable doses during the
`trial.
`Antiemetics, including prochlorperazine ( 10 mg three
`times daily), metoclopramide (10 mg three times daily),
`haloperidol (1-2 mg twice daily), and cyclizine (50 mg
`three times daily), were prescribed, as necessary, during
`the trial.
`Study Design
`The study was a double-blind, randomized, two-phase
`crossover comparison of the steady-state pharmacokinet-
`ics and analgesic efficacy of MSC and MSS. Each phase
`was at least 5 days long, and the order in which the patients
`received MSC and MSS was determined by a randomly
`generated allocation sequence. Blindness was maintained
`using the double-dummy technique, i.e., each day patients
`received both tablet (every 12 hours or every 8 hours) and
`solution (every 4 hours) formulations, one active and the
`other a placebo.
`Procedure
`Initial doses: Patients who had been receiving oral
`morphine began taking test medication at the total daily
`morphine dose they had been taking before the trial. Pa-
`tients who had not been receiving morphine before the
`trial started with a daily morphine dose calculated from
`a standard analgesic equivalency chart."
`Phase 1; Patients received the test medications at a
`constant daily dose for a minimum of 5 days to ensure
`that steady state had been reached. On the pharmacoki-
`netic assessment day, a peripheral intravenous minicath-
`eter was inserted just before the morning dose, and a blood
`sample was collected for morphine analysis. Patients then
`received their morning dose, and blood samples were col-
`lected every 30 minutes for the next 12 hours. Patients
`received their scheduled doses of MSS 4 and 8 hours after
`the morning dose, and, if they were receiving MSC on an
`8-hourly schedule, they received their scheduled MSC
`dose.
`Pain intensity was measured each day in the morning,
`at noon, at dinner time, and at bedtime using the present
`pain intensity (PPI) scale of the McGill pain question-
`naire.I8 Side effects were recorded once daily, and their
`severity was rated using a four-point scale (0, none; 1,
`mild; 2, moderate; 3, severe). All extra doses of MSS used
`for breakthrough pain were also recorded. To avoid con-
`founding the results of the pharmacokinetic comparison,
`a minimum of 24 hours elapsed between any use of extra
`morphine for breakthrough pain and blood sampling for
`pharmacokinetic assessment.
`Phase 2: Patients crossed over to the other test medi-
`cation on the day after the Phase 1 pharmacokinetic as-
`
`sessment. There was no washout period between the
`phases, and the daily morphine dose taken during Phase
`1 was continued throughout Phase 2. Thus, with the ex-
`ception of any extra morphine used for breakthrough pain,
`each patient's total daily morphine dose was the same
`during the MSC and MSS phases. Patients received the
`Phase 2 medication for at least 5 days, and the pharma-
`cokinetic assessment was the same as in Phase 1.
`Plasma Morphine Analysis
`Plasma morphine concentrations were determined us-
`ing a high-performance liquid chromatography tech-
`nique.I9 Successful analyses were performed in 98% of
`the samples. In the remaining 2%, analysis could not be
`performed due to failure to obtain sufficient plasma or
`breakage of tubes in transport. Missing values were esti-
`mated by interpolation from neighboring concentrations.
`
`Statistical Analysis
`Model
`independent pharmacokinetic parameters,
`maximum plasma morphine concentration (C,,,), min-
`imum plasma morphine concentration (Cmin), and time
`after administration at which the maximum plasma mor-
`phine concentration occurred (Tmax) were determined for
`each patient directly from the raw data. The area under
`the curve (AUC) during MSC and MSS administration
`was calculated for each patient using the trapezoidal rule.
`For patients who received MSC every 12 hours, the AUC
`was calculated from zero to 12 hours postdose, i. e., one
`12-hour MSC interval and three 4-hour MSS dose inter-
`vals. For patients who received MSC every 8 hours, the
`AUC was calculated from 0 to 8 hours postdose, i.e., one
`8-hour MSC interval and two 4-hour MSS intervals.
`Pharmacokinetic parameters were compared using Stu-
`dent's t test.
`Analysis of variance for repeated measures was used to
`compare the mean plasma morphine concentrations dur-
`ing MSC and MSS. Morphine concentrations at each time
`of sampling were compared by t tests. Because of the large
`number of comparisons (25 over the 12-hour sampling
`period), a nominal significance level of 0.002 was used to
`give an overall alpha error rate of approximately 0.05 (25
`X 0.002 = 0.05). In this context, an overall error rate of
`0.05 means that the probability of erroneously declaring
`a significant difference between one or more pairs of
`means over the whole set of 25 comparisons is not greater
`than 0.05.
`Wilcoxon's sign rank test was used to determine the
`significance of differences between the two medications
`in pain and side effect scores.
`Linear regression analysis was performed to determine
`the relationship between plasma morphine concentrations
`and daily morphine dose (mg/kg) using a method that
`required the regression line to pass through the origin.
`
`3
`
`

`

`2278
`
`CANCER June 1 Supplement 1989
`
`Vol. 63
`
`TABLE 1. Patient Characteristics
`
`Sex (no. of patients)
`Male
`Female
`Age (Yd*
`Weight (kg)*
`Prestudy analgesics (no. of patients)
`Morphine
`Indomethacin + aspirin
`Anileridine
`Primary site of malignancy or type
`(no. of patients)
`Lung
`Colon
`Urinary bladder
`Breast
`Pancreas
`Prostate
`Stomach
`Mediastinal germ cell tumor
`Multiple myeloma
`Osteosarcoma
`Squamous cell carcinoma
`Unknown primary
`
`*(Mean f SD).
`
`13
`10
`58 k 12
`58 f 16
`
`19
`2
`2
`
`I
`3
`3
`2
`1
`1
`I
`1
`1
`1
`1
`1
`
`Results
`Twenty-eight patients enrolled in the study. Two pa-
`tients were removed from the study during Phase l, both
`due to increasing somnolence and disorientation neces-
`sitating withdrawal of morphine. At the time of discon-
`tinuation, one patient was receiving MSC, and the other
`MSS. The trials of two other patients were discontinued
`on the first pharmacokinetic assessment day because of
`difficulty in obtaining blood samples. The data from one
`patient were excluded from analysis because he received
`an extra dose of morphine on one of the pharmacokinetic
`sampling days. The characteristics of the 23 patients in-
`cluded in the analysis are shown in Table 1. Randomiza-
`tion resulted in 1 1 patients receiving MSC in Phase 1 and
`MSS in Phase 2. The other 12 patients received the med-
`ications in the opposite sequence. There were no signifi-
`cant differences between the two groups in mean age,
`weight, or daily morphine dose. The results are expressed
`as mean f standard deviation.
`
`Overall Pharmacokinetic Data
`The daily morphine doses (mean, 163.5 mg) and phar-
`macokinetic values calculated for each patient during the
`two regimens are listed in Table 2. There was no significant
`difference in bioavailability between MSC and MSS. The
`mean AUCs for MSC and MSS were 394.4 and 353.1 ng/
`ml/hour, respectively. The 95% confidence interval for
`the bioavailability of MSC relative to MSS was 98% to
`125%.
`Three patients (Patients 3, 13, and 20) had marked
`differences in plasma morphine concentrations and AUCs
`
`between the two phases. For Patients 3 and 20, the plasma
`concentrations-versus-time profiles for both drugs had the
`expected configuration, but concentrations during one
`phase were approximately twice those of the other. During
`MSC treatment, Patient 13 showed a steady decline in
`concentrations beginning 1 hour after administration and
`continuing to the end of the sampling period, suggesting
`that this patient may not have received the test medication
`or that the dose was administered considerably earlier than
`scheduled. However, a thorough review of the records of
`these three patients revealed no discrepancies, and their
`data therefore were included in the analysis.
`The mean C,,, during MSC administration (62.4 ng/
`ml) was significantly (P < 0.05) greater than that during
`treatment with MSS (54.1 ng/ml). There was no significant
`difference in mean Cmin between the two drugs (16.1 and
`16.5 ng/ml for MSC and MSS, respectively). The C,,,/
`Cmin is a measure of the amplitude of the fluctuation in
`plasma morphine concentrations. The Cmax/Cmin during
`MSC was 4.6 +- 1.8. During MSS it was 3.9 5 1.6 (P
`> 0.20). During MSS administration, fluctuations of this
`amplitude occurred every 4 hours, whereas they occurred
`every 12 or 8 hours while the patients were taking MSC.
`Linear regression analysis revealed a very close corre-
`lation between dose and morphine concentrations during
`both MSC (r = 0.94) and MSS (r = 0.96). Figure 1 shows
`the fitted regression line and each patient’s mean plasma
`morphine concentration during both phases as a function
`of daily morphine dose. The 95% confidence limits for
`the slope of the line are 10.7 and 13.1.
`As would be anticipated in a comparison of controlled-
`release and immediate-release formulations, there was a
`very highly significant (P < 0.001) difference between the
`mean T,,,
`values obtained with the two preparations (3.4
`and 1.2 hours with MSC and MSS, respectively).
`
`MS Contin (Every 12 Hours) Group
`
`The mean MSC and MSS plasma morphine concen-
`tration-versus-time profiles of the 18 patients who received
`MSC on a 12-hourly schedule are compared in Figure 2.
`The mean concentration during treatment with MSC was
`significantly greater than that during MSS at 3.5 and 4.0
`hours. At no time did MSS produce a significantly higher
`mean concentration than MSC, although the difference
`at 9.0 hours approached significance (corrected P = 0.10).
`Inspection of Figure 2 reveals that the highest mean
`concentration during MSC occurred 4.5 hours after ad-
`ministration. The mean concentration at 4.5 hours was
`significantly higher than that at 0 hour and those from
`7.5 to 12 hours. Thus, by virtue of the nonsignificant dif-
`ferences, the period from 0.5 to 7.0 hours must be con-
`sidered the plateau period. Each 4-hourly dose of MSS
`at 1 .O hour, and this concentration was
`produced a C,,,
`
`4
`
`

`

`No. 11
`
`PHARMACOKINETICS AND EFFICACY OF MSS AND MSC
`
`- Thirlwell et a/.
`
`2279
`
`TABLE 2.
`
`Individual Steady-State Pharmacokinetic Parameter Values in 23 Cancer Patients*
`During MS Contin and Oral Morphine Sulfate Solution Treatments
`
`180
`1
`180
`2
`60
`3
`180
`4
`120
`5
`60
`6
`400
`7
`120
`8
`120
`9
`60
`10
`60
`11
`120
`12
`120
`13
`I80
`14
`360
`15
`180
`16
`600
`17
`210
`18
`90
`19
`90
`20
`21
`90
`90
`22
`90
`23
`163.5
`Mean
`129.3
`SD
`Significance of difference
`
`51.5
`68.7
`33.8
`126.6
`24.4
`56.5
`197.3
`34.4
`43.6
`36.0
`62.6
`74.9
`34.3
`75.4
`52.2
`65.7
`114.5
`70.3
`30.2
`40.4
`48.7
`39.5
`53.0
`62.4
`38.7
`P < 0.05
`
`65.9
`71.8
`54.5
`87.8
`32.6
`42.7
`143.1
`25.1
`31.6
`26.0
`24.0
`53.0
`46.1
`74.6
`51.4
`65.7
`100.9
`61.8
`35.0
`36.1
`29.2
`44.6
`39.9
`54.1
`28.3
`
`13.0
`13.4
`8.5
`46.8
`5.0
`7. I
`69.3
`7.2
`8.3
`8.5
`7.3
`18.1
`0
`14.1
`16.8
`7.5
`42.0
`13.0
`8.7
`12.1
`13.2
`14.3
`15.6
`16.1
`15.7
`
`NS
`
`15.2
`16.1
`9.6
`45.3
`9.4
`10.2
`56.8
`8.9
`3.8
`4.3
`9.6
`9.3
`5.3
`20.1
`24.6
`18.7
`41.4
`20.8
`11.3
`5.3
`10.2
`12.8
`11.7
`16.5
`13.7
`
`1 .o
`1.5
`1.5
`4.0
`9.0
`1.3
`4.5
`1.7
`3.5
`0.8
`1.5
`2.2
`1.7
`8.0
`3.0
`0.8
`1.3
`2.5
`2.0
`1.2
`1.2
`1.5
`1 .o
`2.0
`1 .o
`1.8
`1.2
`4.5
`0.8
`5.0
`0.8
`3.0
`2.5
`1.2
`5.5
`0.7
`3.0
`0.5
`1.5
`0.8
`2.5
`0.3
`1.9
`1.2
`5.0
`1.2
`3.4
`1.2
`0.4
`2.1
`P < 0.001
`
`357.5
`482.0
`165.2
`877.5
`178.5
`229.8
`1514.7
`229.7
`26 1.7
`270.7
`219.0
`482.5
`92.2
`548.7
`345.0
`36 I .4
`905.7
`463.2
`172.2
`230.7
`215.0
`234.2
`234.5
`394.4
`32 1 .O
`
`NS
`
`404.2
`439.0
`309.0
`809.0
`203.0
`227.7
`1128.0
`184.7
`166.0
`168.7
`187.5
`332.5
`227.2
`435.2
`460.2
`434.5
`760.0
`445.7
`180.2
`116.2
`153.7
`177.0
`172.0
`353.1
`25 1.2
`
`MSC: MS Contin; MSS: morphine sulfate solution; C,,,: maximum
`plasma morphine concentration; C,,, : minimum plasma morphine
`concentration; AUC area under the curve; T,=: time after administration
`occurred; NS: not significant.
`at which C,,
`* Patients 1 through 18 received MSC every 12 hr in equally divided
`
`doses; Patients 19 through 23 received MSC 30 mg every 8 hr; MSS was
`given every 4 hr to all patients.
`t Calculated from 0 to 12 hr postdose for Patients 1 through 18 and
`from 0 to 8 hr postdose for patients 19 through 23.
`
`usually significantly greater than the concentrations at 0
`hour and between 2.5 and 4.0 hours. There were some
`differences between the three MSS doses. The dose interval
`from 0 to 4 hours had a substantially longer period of
`nonsignificant differences than did that from 8 to 12 hours.
`There were also differences in the AUCs for the three
`consecutive MSS dose intervals. The mean AUCs for the
`first, second, and third intervals were 138.5 f 82.8, 144.2
`f 93.1, and 124.1 f 88.0 ng/ml/hour, respectively. When
`tested by analysis of variance, the AUC for the third in-
`terval (8- 12 hours) was found to be significantly (P < 0.05)
`less than that of the first and second.
`The values for the pharmacokinetic parameters cal-
`culated for the 18 patients in the 12-hourly MSC group
`are given in Table 3.
`
`MS Contin (Every 8 Hours) Group
`The mean MSC and MSS plasma morphine concen-
`tration-versus-time profiles of the five patients who re-
`ceived MSC every 8 hours are compared in Figure 3. Al-
`
`though the mean concentrations were generally greater
`during MSC than during MSS, at no time point did the
`difference between the two reach statistical significance.
`The pharmacokinetic parameter values for these patients
`are given in Table 4.
`
`Pain Scores, Side Eflect Ratings, and Use of
`Extra Morphine
`All 23 patients generally experienced very good pain
`control during both phases of the study, and clinically
`there was no overt difference in pain severity between the
`two phases for any patient. Because five patients failed to
`fully complete their daily diaries, data from only 18 pa-
`tients were used in the detailed comparison of the PPI
`pain scores and side effect ratings of the two treatments.
`The PPI pain score during MSC treatment was 0.55
`f 0.58, and during MSS it was 0.57 f 0.63 (P = 0.85).
`Both medications were very well tolerated throughout
`the study, with only three patients reporting mild nausea
`during MSC and three different patients reporting mild
`
`5
`
`

`

`2280
`
`W
`
`150
`=
`E
`% 125
`E
`E
`.-
`0
`c !? 100
`4- E
`Q) 0 E 8 75
`Q) E r .-
`e
`50
`i!
`v) 2 25 n
`
`0
`
`CANCER June 1 Supplement 1989
`
`Vol. 63
`
`0
`
`0
`
`0
`
`FIG. 1. Mean plasma morphine
`concentration versus daily morphine
`dose in 23 cancer patients during MS
`Contin and oral morphine solution
`administration. Scattergram and
`least-squares linear regression line
`through the origin (Y = 11.9X; r
`= 0.94).
`
`1.0
`
`3.0
`6.0
`4.0
`5.0
`2.0
`Morphine dosage (mg/kg/day)
`
`7.0
`
`8.0
`
`nausea with MSS. The severity scores for nausea during
`MSC and MSS were 0.06 k 0.13 and 0.07 & 0.17, re-
`spectively. Three patients also reported mild dizziness
`
`during the two phases, with no significant difference in
`either incidence or mean seventy between the two drugs.
`The use of extra morphine to control breakthrough pain
`
`FIG. 2. Mean steady-state plasma
`morphine concentration as a func-
`tion of time after administration in
`18 cancer patients after MS Contin
`every 12 hours (0) and oral mor-
`phine solution every 4 hours (0).
`The mean total daily morphine dose
`was 183.9 ? 140.0 mg.
`
`0
`
`1
`
`2
`
`3
`
`0
`1
`9
`8
`7
`6
`5
`4
`Hou rs after administration
`
`1
`
`1
`
`1
`
`2
`
`
`
`6
`
`

`

`No. 11
`
`PHARMACOKINETICS AND EFFICACY OF MSS AND MSC
`
`* Thirlwell et a/.
`
`228 1
`
`was minimal. While taking MSC, three patients each re-
`quired one extra dose. During MSS administration, two
`Datients reauired one dose and a third required two doses.
`$he amount of extra morphine used for breakthrough
`pain represented less than 1% of the morphine adminis-
`tered during the study.
`
`Discussion
`has been marketed for
`MS ‘Ontin
`years’ but
`only limited information on the pharmacokinetics of this
`preparation has been available, particularly information
`on its pharmacokinetics in cancer patients. Difficulties
`with various analytical techniques for measuring mor-
`phine concentrations have been a principal obstacle in
`obtaining such data, and it is now known that the assays
`used in earlier patient studies20-22 were neither sensitive
`nor specific enough to produce unequivocal results. The
`high-performance liquid chromatography method used
`in this study is highly specific and allows the measurement
`of concentrations as low as 1.0 ng/ml with an average
`relative precision of 5.0% over a range of 1 to 200 ng/ml.
`It thus overcomes the problems associated with earlier
`techniques.
`The steady-state plasma concentration-versus-time
`profile obtained in cancer patients taking MSC every 12
`hours (Fig. 2) demonstrates that the prolonged release of
`morphine from the tablets reduces both the rate of ab-
`sorption and the rate of decline of plasma morphine con-
`centration. As a result, doses of MSC that are three times
`those of MSS result in approximately equivalent maxi-
`mum and minimum plasma morphine concentrations
`and a similar amplitude of fluctuation. Inasmuch as clin-
`=
`\ E 100
`0 c
`c
`W .-
`0
`E 50
`w
`c
`Q) 0 c
`0
`0
`c .-
`Q) c
`P E
`E
`10 n
`
`CI
`
`u)
`
`FIG. 3. Mean steady-state plasma
`morphine concentration as a func-
`tion of time after administration in
`five cancer patients during the ad-
`ministration of MS Contin every 8
`hours ( 0 ) and oral morphine solu-
`tion every 4 hours (0). Each patient’s
`total daily morphine dose was 90 mg.
`
`0
`
`1
`
`2
`
`3
`
`TABLE 3. Steady-State Pharmacokinetic Parameter Values
`(Mean f SD) Obtained in 18 Cancer Patients
`Receiving MS Contin Every 12 Hours
`
`MSC
`
`MSS
`
`Significance
`of difference
`
`G a x (ng/ml)
`Cmm (ns/ml)
`Tmax (hr)
`AUC (ng/ml/hr)
`
`58.8 f 30.3
`18.3 f 15.0
`0.4
`1.3 f
`406.8 f 259.7
`
`NS
`NS
`PiO.001
`NS
`
`67.9 f 42.1
`17.0 f 17.7
`443.6 * 348.4
`3.6 f 2.3
`MSC: MS Contin; MSS: morphine sulfate solution; NS: not significant;
`concentration; cmn: mi*mum plasma
`c,a:
`plasma
`morphine concentration; T,=:
`time after administration at which C,,
`Occurred; AUC: area under the curve.
`
`‘
`
`~
`
`‘
`
`~
`
`3
`
`~
`
`~
`
`
`
`ical experience has demonstrated that morphine solution
`most often has optimal efficacy when given every 4
`hours,’
`our pharmacokinetic findings indicate that
`a 12-hourly regimen of MSC should similarly be optimal
`for most patients. The reduction in the frequency with
`which plasma concentrations fluctuate during MSC may
`also be clinically important, although this was not appar-
`ent in the current study.
`These study patients received very good pain control
`throughout both phases of the study. In several other con-
`trolled clinical comparisons, 12-hourly MSC has been
`shown to control cancer pain as effectively as a 4-hourly
`
`morphine s o l ~ t i o n . * ~ - ~ ~ Although plasma morphine con-
`centrations were declining at the end of the dose interval,
`at no time did they fall significantly below the corre-
`sponding concentrations obtained with MSS. A recent
`carefully controlled efficacy study has also documented
`that there is no loss of analgesic efficacy over the last few
`hours of the MSC dose interval.”
`
`0
`1
`9
`8
`7
`6
`5
`4
`Hours after administration
`
`1
`
`1
`
`1
`
`2
`
`
`
`7
`
`

`

`2282
`
`CANCER June 1 Supplement 1989
`
`Vol. 63
`
`TABLE 4. Steady-State Pharmacokinetic Parameter Values
`(Mean f SD) Obtained in Five Cancer Patients
`Receiving MS Contin Every 8 Hours
`
`~~~
`
`~~
`
`MSC
`
`MSS
`
`Cmax (ng/ml)
`Cmm W m l )
`Trnu (hr)
`AUC (ng/ml/hr)
`
`42.4 f 8.9
`12.8 f 2.6
`2.8 -C 1.4
`217.3 f 26.5
`
`37.0 -C 5.7
`10.3 +- 2.9
`0.8 f 0.4
`159.8 f 26.5
`
`Significance
`of difference
`
`NS
`NS
`P < 0.02
`P < 0.05
`
`MSC MS Contin; MSS: morphine sulfate solution; NS: not significant;
`Cmm: maximum plasma morphine concentration; Cmin: minimum plasma
`morphine concentration; Tmax: time after administration at which C,,,
`occurred: AUC: area under the curve.
`
`MSC was administered every 8 hours to five pa-
`tients, all of whom required daily morphine doses of 90
`mg, which could not be administered in two equally di-
`vided doses with the tablet strengths available at the time
`of the study. Since then, a 15-mg tablet has been intro-
`duced in Canada, which allows the administration of doses
`of 45 mg every 12 hours. The pharmacokinetic results in
`the 8-hour MSC group suggest that this regimen produces
`a greater AUC than MSS, but there were no clinically
`significant differences between the formulations. Because
`MSC provides effective plasma morphine concentrations
`for 12 hours, there is little rationale for more frequent
`dosing.
`Overall, the mean AUC (bioavailability) of MSC was
`12% greater than that of MSS, but the difference was not
`statistically significant (P = 0.09). Given that the 95%
`confidence interval for the bioavailability of MSC relative
`to MSS was 98% to 125%, it is unlikely that there is a
`clinically significant difference in bioavailability between
`the two formulations. This conclusion is supported by a
`recent steady-state comparison of MSC and MSS con-
`ducted in healthy volunteer^.^^ The finding that the AUC
`differed significantly among the individual MSS dosing
`intervals may reflect a diurnal variation in morphine ki-
`netics, or the patients' food intake before the third MSS
`dose may have inhibited morphine absorption. A signif-
`icant food effect appears unlikely, however, since, in a
`separate study, food showed no effect on morphine ki-
`netics after MSC admini~tration.~' The variation in AUC
`seen after sequential doses of MSS has implications for
`the design of comparative bioavailability studies, since it
`is apparent that the formulations to be compared must
`be given in equal doses over identical periods of obser-
`vation (as was the case in the current study). An assump-
`tion that the AUC of any MSS dosing interval is repre-
`sentative of the AUC of all dosing intervals could result
`in an in