RELATIVE BIOAVAILABILITY OF CONTROLLED RELEASE MORPHINE TABLETS (MST CONTINUS) IN CANCER PATIENTS

Br. J. Anaesth. (1988), 61, 569-574

RELATIVE BIOAVAILABILITY OF CONTROLLED RELEASE MORPHINE TABLETS (MST CONTINUS) IN CANCER PATIENTS P. POULAIN, P. J. HOSKIN, G. W. HANKS, O. A-OMAR, V. A. WALKER, A. JOHNSTON, P. TURNER AND G. W. AHERNE

JOHNSTON, B.SC. ; P. TURNER, B.SC, M.D., F.R.C.P. ; Department

and 3.25 h with MST. A secondary peak of unconjugated morphine, which may represent enterohepatic circulation, was seen in several patients 2-4 h after administration of elixir and 4-6 h after administration of MST.

of Clinical Pharmacology, St Bartholomew's Hospital Medical College, London. G. W. AHERNE, B.SC, PH.D. ; Department of Biochemistry, University of Surrey, Guildford, Surrey. Accepted for Publication: April 14, 1988. Present addresses: *Institut Gustave-Roussy, rue Camille Desmoulins, 94805 Villejuif Cedex, France. "Leeds General Infirmary, Leeds LSI 3EX. Correspondence to G. W. Hanks.

glucuronide and morphine-6-glucuronide. The RIA used in the second study does not have the same specificity [8] and has been shown to crossreact with morphine-6-glucuronide [9]. An investigation of the steady state kinetics of MST in healthy volunteers (using an HPLC

P. POULAIN,* M.D.; P. J. HOSKIN, B.SC, M.B., M.R.C.P., F.R.C.R. J G. W. HANKS, B.SC, M.B., M.R.C.P. ; V. A. WALKER,** B.SC,

R.G.N.; Continuing Care Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ. O. A-OMAR, B.PHARM.; A.

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Controlled release morphine tablets (MST Continus, MS Contin, MOS Contin) are used SUMMARY widely in the treatment of cancer pain. Controlled The bioavailability of oral controlled release clinical trial data are limited [1, 2] but suggest morphine tablets (MST, Napp Laboratories) and that, for the majority of patients, twice daily oral morphine sulphate in aqueous solution administration of MST is equivalent to a 4-hourly (MSS) was compared in 10 patients with regimen of aqueous morphine. This is supported advanced cancer. Serum samples were analysed by empirical clinical experience. for morphine, morphine-3-glucuronide (M3G) Investigations of the absolute bioavailability of and morphine-6-glucuronide (M6G) using a MST in single dose studies have produced specific HPLC assay. The relative bioavailability conflicting results. In one study in healthy of morphine with MST was significantly less volunteers, the mean systemic availability of than that with MSS (mean 80%. range 50MST in the first 7 h after administration was 110%) although there was no difference between 18.3% [3]. In contrast, in a study in patients, the the formulations in the relative availability of bioavailability of MST was calculated to be 122 % M3G and M6G. There was no significant differ[4]. ence between the formulations in the serum An important difference in the methodology concentration of morphine at 12 h. The mean used in the two studies is that the first utilized a ratios morphine: M6G :M3G (comparing areas high performance liquid chromatography under the serum concentration-time curves) (HPLC) assay to measure plasma concentrations were 1:9:56. There was a highly significant of unconjugated morphine [5, 6], whereas the linear relationship between the dose adminissecond used a radioimmunoassay (RIA) utilizing tered and AUC for morphine, M3G and M6G antibodies raised to 6-succinylmorphine BSA [7]. after MSS; and for morphine after MST. Median The HPLC assay is a specific and sensitive W for morphine was 0.5 h with MSS and method enabling the quantitative measurement of 2.5 h with MST; for M3G 1.5 h with MSS and morphine and its main metabolites morphine-3- 3.0 h with MST; and for M6G 1.5 h with MSS

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PATIENTS AND METHODS

Patients with advanced cancer who were inpatients in the Continuing Care (palliative care) Unit at the Royal Marsden Hospital and who had pain requiring oral morphine were studied if their pain was controlled on a 4-hourly regimen of oral morphine sulphate (MSS) in the same dose for at least 5 consecutive days. The MSS was morphine sulphate in chloroform water with ethylene diamine tetracetic acid and benzoic acid as preservative. The concentration of MSS varied, according to the dose being administered, between the limits of 10-60 mg in 10 ml. Patients whose clinical condition was poor or whose pain was not stable were excluded, as were patients receiving high daily doses of morphine (> 1 g) who would require a large number of tablets. Full explanation of the aims of the study and the procedures involved was given before consent to participate was obtained from patients. The study was approved by the Ethics Committee of the Royal Marsden Hospital. A cannula was inserted into a convenient forearm vein and the study was extended over a period of 3 days. On the first study day, patients continued their usual 4-hourly doses of MSS and blood samples were taken over a 12-h period from the 8 a.m. dose. Sampling was performed at time zero and at 30-min intervals for 5 h, and at 7, 8, 11 and 12 h. On each occasion 10 ml of venous blood was taken, rolled in glass bottles without anticoagulant for at least 20 min, centrifuged at 3500 rev min"1 and the serum separated and frozen immediately at — 20 °C. On the second day MSS was changed to MST, maintaining the same total daily dose in two equal

parts. The final dose of MSS was given at 4 a.m. and the first dose of MST at 8 a.m. No blood samples were taken. On the third day, blood samples were taken for a 12-h period following the 8 a.m. dose of MST, at the same times as on day 1. On days 1 and 3, patients completed 10-cm visual analogue scales for pain intensity and pain relief at 8 a.m. and 8 p.m. and a four-point verbal rating scale for morphine-related side effects was completed each day. Analytical method Analysis of the samples was performed using an HPLC assay developed from the method of Svensson [5]. Extraction of serum samples was performed before analysis using multiple washings through two C18 SEP-PAK cartridges with a Vac-elute system. The chromatography used a 500-ul sample injected by autosampler. Detection of M3G was by u.v.fluorescenceat 210 nm using an FS 970 LC Flurometer, and of morphine and M6G was by electrochemical detection using a two-channel detector and an additional guard cell. The intra-assay coefficient of variation using this assay was < 8% for morphine, < 6% for M3G and < 13% for M6G. Statistical analysis The area under the serum concentration-time curve (AUC) was calculated using STRIPE, an interactive curve stripping program [14]. Student's paired t test was used to compare assay techniques, AUC from the different preparations and visual analogue scale scores. RESULTS

Ten patients were studied: six females (aged 60-79 yr, weights 35-90 kg) with cancer of the breast (three), lung (two) and colon (one); and four males (aged 44-72 yr, weights 65-102 kg) with cancer of the lung (two), kidney (one), and a soft-tissue sarcoma (one). The dose range of morphine was 40-360 mg day"1 (0.7-5.5 mg kg"1). All patients had normal renal and hepatic function. The blood samples were timed to give an accurate estimate of a 4-h period of administration for morphine elixir and of a 12-h-period of administration for MST. In calculating the AUC for MST, therefore, the 12-h data were used, but for morphine elixir the AUC for only the first 4 h

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assay) indicated a bioavailability of 86 % relative to morphine sulphate in aqueous solution [10]. This figure is consistent with data from our earlier study in postoperative patients [11]. There is increasing evidence to suggest that the clinical effects of morphine, in particular its analgesic action, may result from not only the action of morphine itself, but also that of active metabolites, in particular morphine-6-glucuronide (M6G) [12, 13]. We have investigated the relative bioavailability of MST in patients with advanced cancer stabilized on oral morphine sulphate in aqueous solution (MSS), using an HPLC assay to measure both morphine and its principal metabolites.

RELATIVE BIOAVAILABILITY OF MST

571

TABLE I. Twelve-hour cumulative area under the serum concentration-time curve (AUCllk) for morphine. ^95% Confidence interval 0.64-0.98. * Significant difference AUC MST v. AUC MSS (P = 0.05) 1

AUC (ng h ml" ) Patient No.

MSS

MST

Relative Bioavailability (MST/MSS)

20 30 30 30 30 90 120 120 180 180

154 143 288 177 181 357 440 758 930 951

149 72 145 180 144 338 478 623 898 572

1.0 0.5 0.5 1.0 0.8 0.9 1.1 0.8 1.0 0.6

15

.1

Morphine elixir MST

.

II •''• '"

60

ill ' f\'-

50

!

io|V V\ A 5-

w

I/'

30

-

10 0

45 -i

130- 7

35-

100-

E

E

70-!

-

40-

0.8*t

12

4

10

a

12

6

was calculated and multiplied by three for the purpose of comparison (table I). There was a highly significant relationship between dose and AUC with both formulations: r = 0.95, p< 0.001 MSS; r = 0.91, P < 0.001 MST. However, the mean relative bioavailability of MST compared with MSS of 80% (range 50-110%) is significantly lower (t = 2.5, P < 0.05). There was no significant difference in serum concentrations of morphine produced by MSS and MST at 12 h. The individual serum concentration-time curves for the 10 patients are shown in figure 1. A secondary peak in the concentration of unconjugated morphine is seen 2—4 h after administration of morphine elixir in patients Nos 1, 2, 3, 5, 6, 7 and 10. Similarly in the MST curves for patients Nos 3, 5, 8, 9 and 10 there appears to be a secondary peak 4-8 h after dosing. Attenuation of the peak serum concentration (Csmax) for morphine was seen after MST. The ratio of Csmax after MST to Csmax after MSS was 1.32 (SEM 0.13), while the dose ratio MST: MSS was 3. A similar effect was seen with the two metabolites, the mean ratio Csmax MST:Cs max MSS being 1.47 (0.26) for M3G and 1.25 (0.10) for M6G (table II). Peak serum concentrations of morphine were achieved between 0.5 and 2 h after administration of morphine elixir (median 0.5 h) and at 0.5-4 h (median 2.5 h) after MST (table III). For MSS there was a significant correlation between the AUC for both metabolites and dose of morphine (M3G: r = 0.74, P < 0.01; M6G: r = 0.79, P < 0.001) but this was not so for MST

70

160-]

80-

g 4 °H S

45n 40-

2

30-

g

12

o

c 260-, g E & 180-

20-

1001020 12 30-i 2520-

10-

4

8

Time (h)

12

4

8

12

Time (h)

FIG. 1. Serum concentrations of unconjugated morphine in each patient. Morphine elixir; — MST.

(M3G: r = 0.32; M6G: r = 0.46) (table IV). No significant difference between the formulations was seen in the relative bioavailability of either metabolite, although there was wide interindividual variation.

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1 2 3 4 5 6 7 8 9 10 Mean

12-h dose (mg)

20-

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572 TABLE II. Peak serum concentrations (Csmax) ing ml'1) for morphine, morphine-3-glucuronide (M3G) and morphine-6glucuronide (M6G) Patient No.

20 30 30 30 30 90 120 120 180 180

477 426 728 1871 827 2477 2886 3549 3073 3252

19 19 37 20 26 50 51 97 122 115

72 59 61 440 145 491 473 574 558 617

MST

AUC 12b (ng h ml"1)

26 15 52 39 28 67 104 128 136 88

855 1414 1139 3395 782 4481 3300 4498 2080 1409

114 74 77 527 189 718 539 907 649 336

TABLE III. Time (h) to peak serum concentration (tmax) for morphine, morphine-3-glucuronide (M3G) and morphine-6glucuronide (M6G) MSS Patient No. 1 2 3 4 5 6 7 8 9 10 Median Range

Morphine M3G 0.5 0.5 2.0 0.5 1.0 0.5 1.0 1.0 0.5 0.5

1.5 1.0 2.0 1.0 2.5 1.5 1.0 1.5 1.5 1.5

12-h dose (mg)

MSS

MST

Relative Bioavailability (MST/MSS)

M3G M6G

M3G M6G

M3G M6G

20 30 30 30 30 90 120 120 180 180

4695 4041 6890 20784 7503 13589 31963 36771 33181 32791

5786 9438 8271 32069 5185 40828 30700 35314 18973 6888

1.2 2.3 1.2 1.5 0.7 3.0 1.0 1.0 0.6 0.2 1.3 0.3

Morphine M3GM6G Patient No. 1 2 3 4 5 6 7 8 9 10 Mean SEM

701 456 546 4757 1475 3670 4975 5922 5664 6006

871 433 430 4983 1330 6848 4444 6208 5676 1530

1.2 0.9 0.8 1.0 0.9 1.9 0.9 1.0 1.0 0.3 1.0 0.1

MST M6G Morphine M3G

M6G

2.5 2.0 2.5 3.0 2.5 4.0 2.5 0.5 3.0 2.5

4.0 3.0 3.0 4.5 3.0 4.0 3.5 2.5 3.5 3.0

2.5 1.0 2.0 2.0 1.0 1.5 1.5 1.5 1.0 1.5

0.5 1.5 1.5 0.5-2.0 1.0-3.5 1.0-2.5

3.0 3.0 3.0 4.5 3.5 4.0 3.0 2.0 4.0 3.0

2.5 3.0 3.25 0.5-4.0 2.0-4.5 2.5-4.5

The values for the AUC corrected to a standard dose of morphine 100 mg are shown in table V. The mean ratios morphine: M6G: M3G were 1:9:56. Analysis of the VAS ratings for pain and pain relief (table VI) showed no difference between the two study days, and there was no difference in the incidence or severity of adverse effects.

TABLE V. Twelve-hour cumulative area (ng h ml ') under the serum concentration-time curve (AUClih) for morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) after dose correction to morphine 100 mg administered MSS Patient No.

MST

Morphine M3G

M6G

Morphine M3G M6G

1 2 3 4 5 6 7 8 9 10

770 477 960 590 603 397 367 632 517 528

23475 3505 13470 1520 22967 1820 69280 15857 25010 4917 15099 4078 26636 4146 30642 4935 18434 3147 18217 3337

745 240 483 600 480 376 398 519 499 318

28930 31460 27570 106897 17283 45364 25583 29433 10540 3827

4355 1433 1433 16610 4433 7609 3703 5174 4730 850

Mean SEM

584 56

26323 5064

466 45

32689 9026

5033 1441

4726 1289

TABLE VI. Visual analogue scales for pain (0 = no pain; 100 = worst possible pain) and pain relief (JO = no relief; 100 = complete pain relief). Mean (SEM) (mm) Pain

Pain relief

DISCUSSION

This study was primarily a pharmacokinetic investigation and was not blinded, so the ratings of pain intensity and pain relief should be interpreted in this light. However, MST appeared to provide equally good pain relief, as has been shown previously in both open and controlled

8 a.m. Aqueous 12.3(3.0) morphine MST 10.3 (2.7) t 1.220 P >0.2

8 p.m.

8 a.m.

8 p.m.

14.8(3.7)

87.3(4.2)

79.5(6.5)

14.1 (4.1) 0.498 >0.5

86.8 (7.2) 0.064 >0.5

81.4(6.9) 1.032 >0.2

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1 2 3 4 5 6 7 8 9 10

12-h MSS dose (mg) Morphine M3GM6G

TABLE IV. Twelve-hour cumulative area under the serum concentration-time curve (AUCnil) and relative bioavailability for morphine-3-glucuronide (M3G) and morphine-6glucuronide (M6G)

RELATIVE BIOAVAILABILITY OF MST

We have shown a similar attenuation of peak serum concentrations following MST. The secondary peak in the serum concentrations of unconjugated morphine in several patients is of considerable interest. It may represent enterohepatic circulation of morphine. This has been demonstrated clearly in rodents [21, 22] and we have recently shown high biliary concentrations of morphine, M3G and M6G in man [23]. A previous study (in healthy volunteers) showed a secondary peak in plasma concentrations of morphine 4-5 h after administration of MST [24]. In our data the secondary peak is seen most clearly in MSS curves between 2 and 4 h after dosing. We have suggested that enterohepatic circulation may be part of the explanation for the greater efficacy of repeated doses or oral morphine compared with single doses [12].

ACKNOWLEDGEMENTS P. P. was supported by the Association pour la Recherche sur le Cancer, P. J. H. by the Cancer Research Campaign and V. A. W. by the Sir Halley Stewart Trust. This work was also supported by grants from the Royal Marsden Hospital Clinical Research Committee, and Napp Laboratories Ltd.

REFERENCES 1. Knudsen J, Mortensen SM, Eikard B, Henriksen H. Morfin-depottabletter og knoventionelle mortintabletter ved cancersmerter. Ugeskrift fur Laeger 1985; 147: 780-784. 2. Hanks GW, Twycross RG, Bliss JM. Controlled-release morphine tablets: a double-blind trial in patients with advanced cancer. Anaesthesia 1987; 42: 840-844. 3. Vater M, Smith G, Aherne GW, Aitkenhead AR. Pharmacokinetics and analgesic effect of slow-release oral morphine sulphate in volunteers. British Journal of Anaesthesia 1984; 56: 821-827. 4. McQuay HJ, Moore RA, Bullingham RES, Carroll D, Baldwin D, Allen MC, Glynn CJ, Lloyd JW. High systemic relative bioavailability of oral morphine in both solution and sustained-release formulation. Royal Society of Medicine International Congress and Symposium Series

1984; 64: 149-154. 5. Svensson J-O. Determination of morphine, morphine-6glucuronide and normorphine in plasma and urine with high-performance liquid chromatography and electrochemical detection. Journal of Chromatography 1986; 375: 174-178. 6. Svensson J-O, Rane A, Sawe J, Sjoquist F. Determination of morphine, morphine-3-glucuronide and (tentatively) morphine-6-glucuronide in plasma and urine using ionpair high-performance liquid chromatography. Journal of Chromatography 1982; 230: 427^132.

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studies [I, 2, 15, 16] in cancer patients. Similarly, there was no difference in side-effects. The relative bioavailability of MST was measured 24 h after changing to this formulation. The time to achieve steady state is influenced by the absorption half-life, in addition to the elimination half-life, although the latter is the major determinant. We believe most patients will have achieved steady state by this time if they have already been stabilized on morphine elixir, as the elimination of morphine is not changed by this formulation. Our pharmacokinetic data indicate that MST has a slightly lower systemic availability for morphine compared with MSS, although the relative amounts of the metabolites M6G and M3G produced by the two formulations was similar. These data, our clinical trial data [2] and those of others [1], refute the suggestion that MST may be more bioavailable [4, 17] and, therefore, relatively more potent than morphine in solution [18]. The results for M3G and M6G are of particular interest, since there are few comparable data in the literature. Sawe and her colleagues have demonstrated ratios of 1:24.4 for morphine: M3G and 1:2.5 for morphine :M6G after small single doses in cancer patients [19] and ratios of 1:34 and 1:3.9, respectively, in four patients after chronic use [20]. The corresponding ratios in this larger study were 1:56 and 1:9, which are considerably higher. We have suggested that M6G may contribute significantly to the analgesic activity of chronically administered oral morphine [12]. In our study similar amounts of M6G were produced by both MSS and MST. This may account for the equal efficacy of MST, although its bioavailability for unconjugated morphine appears to be slightly lower than that of MSS. The median rmax for MST in the present study (2.5 h) is similar to figures obtained in healthy volunteers after single (2.4 h-2.7 h) [3] and repeated doses (2.3 h) [10]. Similarly, the median tmax for the solution of 0.5 h (range 0.5-2.0 h) is close to that found in healthy volunteers (0.8 h) [10] and in cancer patients (0.8 h) [19]. A recent investigation of the steady state pharmacokinetics of MST in healthy volunteers found a bioavailability of 86 % relative to MSS [10]. The authors also found an "attenuation by 50 % of the peak plasma morphine concentrations obtainable with controlled release morphine".

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7. Aherne GW, Piall EM, Robinson JD, Morris BA, Marks V. Two applications of a radioimmunoassay for morphine. In: Pasternak CA, ed. Radioimmunoassay in Clinical Biochemistry. London: Heyden and Sons, 1975; 81-90. 8. Hanks, GW, Aherne GW. Morphine metabolism: does the renal hypothesis hold water? Lancet 1985; 1: 221-222. 9. Aherne GW, Littleton P. Morphine-6-glucuronide, an important factor in interpreting morphine radioimmunoassays. Lancet 1985; 2: 210-211. 10. Savarese JJ, Goldenheim PD, Thomas GB, Kaiko RF. Steady-state pharmacokinetics of controlled release oral morphine sulphate in healthy subjects. Clinical Pharmacokinetics 1986; 11: 505-510. 11. Hanks GW, Rose NM, Aherne GW, Piall EM, Fairfield S, Trueman T. Controlled-release morphine tablets. A double-blind trial in dental surgery patients. British Journal of Anaesthesia 1981; 53: 1259-1264. 12. Hanks GW, Hoskin PJ, Aherne GW, Turner P, Poulain P. Explanation for potency of repeated oral doses of morphine. Lancet 1987; 2: 723-725. 13. Shimomura K, Kamato O, Veki S, Ida S, Oguri K, Yoshimura H, Tsukamoto H. Analgesic effect of morphine glucuronides. Tohoku Journal of Experimental Medicine 1971; 105: 45-52. 14. Johnston A, Woollard RC. STRIPE: an interactive computer program for the analysis of drug pharmacokinetics. Journal of Pharmacological Methods 1983; 9: 193-200. 15. Meed SD, Kleinman PM, Kantor TG, Blum RH, Savarese JJ. Management of cancer pain with oral controlled-release morphine sulfate. Journal of Clinical Pharmacology 1987; 27: 155-161. 16. Homesley, HD, Welander CE, Muss HB, Richards F. Dosage range study of morphine sulfate controlled-

release. American Journal of Clinical Oncology 1987; 9: 449-453. Welsh J, Stuart JFB, Habeshaw T, Blackie R, Whitehill D, Setanoians A, Milsted RAV, Caiman KC. A comparative pharmacokinetic study of morphine sulphate solution and MST Continus 30 mg tablets in conditions expected to allow steady-state drug levels. Royal Society of Medicine International Congress and Symposium Series 1983; 58: 9-13. Regnard CB, Randell F. Controlled-release morphine in advanced cancer pain. Royal Society of Medicine International Congress and Symposium Series 1984; 64: 141-144. Sawe J, Kager L, Svensson J-O, Rane A. Oral morphine in cancer patients: in vivo kinetics and in vitro hepatic glucuronidation. British Journal of Clinical Pharmacology 1985; 19: 495-501. Sawe J, Svensson J-O, Rane A. Morphine metabolism in cancer patients on increasing oral doses—no evidence for autoinduction or dose-dependence. British Journal of Clinical Pharmacology 1983; 16: 85-93. Dahlstrom BE, Paalzow LK. Pharmacokinetic interpretation of the enterohepatic recirculation and first pass elimination of morphine in the rat. Journal of Pharmacokinetics and Biopharmaceutics 1978; 6: 505-519. Walsh CT, Levine RR. Studies of the enterohepatic circulation of morphine in the rat. Journal of Pharmacology and Experimental Therapeutics 1975; 195: 303-310. Hanks GW, Hoskin PJ, Aherne GW, Turner P, Poulain P. Enterohepatic circulation of morphine. Lancet 1988; 1: 469. Leslie ST, Rhodes A, Black FM. Controlled release morphine sulphate tablets—a study in normal volunteers. British Journal of Clinical Pharmacology 1980;9: 531-534.

17.

18.

19.

20.

21.

22. 23. 24.

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