PAIN Pharmacokinetics of controlled release morphine (MST) in patients with liver carcinoma

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1 British Journal of Anaesthesia 94 (1): 95 9 (2005) doi: /bja/aei007 Advance Access publication October 29, 2004 PAIN Pharmacokinetics of controlled release morphine (MST) in patients with liver carcinoma H. I. M. Kotb 1 *, S. A. El-Kady 1, S. E. S. Emara 2, E. A. Fouad 3 and M. Y. El-Kabsh 4 1 Department of Anesthesia, 2 Department of Pharmaceutical Analytical Chemistry, 3 Department of Pharmaceutics and 4 Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt *Corresponding author. kotbhi@yahoo.com Background. There are no studies reported on the pharmacokinetics of controlled release morphine (MST) in patients with hepatocellular carcinoma, the fifth most common cancer in the world. Methods. We have studied the pharmacokinetic profile of MST (30 mg) in 15 patients with liver carcinoma (eight with primary carcinoma on top of chronic hepatitis C, and seven with secondary metastatic liver malignancy as a result of other primary) compared with our previously published data for 10 healthy controls. Plasma morphine concentrations were measured in venous blood samples at intervals up to 12 h by high-pressure liquid chromatography. Total body clearance (Cl) and systemic bioavailability were estimated using a compartmental method. Results. Morphine bioavailability showed a substantial increase in patients with primary liver and secondary metastatic carcinoma than that of controls (64.8, 62.1, and 16.8%, respectively). The area under the serum concentration time curve increased 4-fold in primary carcinoma (416 [SEM 25] mg h 1 litre 1 ) and 3-fold (303 [21] mg h 1 litre 1 ) in metastatic liver patients compared with healthy control (92.5 [3] mg h 1 litre 1 ). No significant difference was found in T max between the two malignant groups but C max was significantly greater in primary liver carcinoma patients. Impaired morphine elimination was noted in primary carcinoma only (t 1/ [0.39] h). Conclusion. Careful administration of morphine is recommended in patients with liver cancer. Br J Anaesth 2005; 94: 95 9 Keywords: analgesics opioid, morphine; drug deliver, oral; liver, disease; pharmocokinetics, morphine; pharmacology, morphine Accepted for publication: July 30, 2004 Morphine is still the gold standard for analgesia and remains the most commonly used opioid because of its relatively low cost and the availability of numerous dosage forms. 1 Morphine is metabolized mainly by the liver and its metabolites are excreted via the kidney. 2 Therefore, it might be expected that there are alterations in morphine disposition in patients with liver disease. Hepatocellular carcinoma (HCC) is increasingly associated worldwide with estimates of hepatitis B and hepatitis C prevalence. A marked increase has been shown in the USA over the last two decades, it has also increased in France and the UK. HCC ranks as the fifth most common cancer in the world. Of all cancers HCC accounts 7.4% for males and 3.2% for females. The highest prevalences are in eastern Asia (including Japan and China) and Sub-Saharan Africa. 3 5 However, secondary hepatic cancer deposits are more common than primary cancer. Therefore, there is a need to investigate the disposition of morphine, in patients with cancer pain as a result of primary and secondary liver carcinoma. Patients and methods Fifteen patients with moderate to severe pain as a result of liver malignancy completed this study to investigate the single dose kinetic profile of 12-h controlled release morphine (MST) 30 mg (MST Continus: Napp Laboratories). All were admitted to the Pain Control Unit of Assiut University Hospital. The dose was administered at 10:00 to allow maximum time for patient observation during daylight hours. It was determined that 15 patients would be sufficient to provide 80% power, at a type I error rate of 0.05 to detect a 1.5-h # The Board of Management and Trustees of the British Journal of Anaesthesia 2004

2 Kotb et al. difference in the time of which blood morphine concentrations were more than/equal to 75% of C max. The inclusion criteria were adult patients with documented (pathological and radiological) evidence of liver cancer requiring the prescription of oral morphine to control moderate to severe pain. Exclusion criteria were, significant abnormalities in hepatic, renal, hematological, or pulmonary function and any gastrointestinal pathology or surgery, which could influence the absorption of morphine. Other exclusion criteria included patients undergoing chemotherapy or radiotherapy, intractable vomiting or patients who could not swallow a tablet and patients with a history of drug seeking behaviour or any other medication that can alter hepatic blood flow/enzyme activity. Study protocol The study protocol was reviewed and approved by The Ethics Committee at Assiut Faculty of Medicine. All patients gave their acceptance to participate in this study and signed informed consent. The protocol included two groups of cancer liver patients. Group I: primary liver cancer associated with cirrhosis (eight patients). Their mean age was 59.3 (50 70) yr; mean weight 66.8 (SD 9.9) kg. All had carcinoma on top of chronic hepatitis C. All had been investigated thoroughly including hepato-renal function, serum albumin, total plasma protein, transaminases and bilirubin, ultrasound, and liver biopsy. Computerized topographic (CT) findings demonstrated the presence of focal lesions in the liver as well as cirrhosis. Group II: secondary metastatic liver malignancy (seven patients). Their mean age was 52 (40 60) yr; mean weight 65 (SD 7) kg. Their inclusion was based upon diagnosis of the primary plus ultrasonographic picture of an enlarged liver with metastasis with no evidence of cirrhosis. CT findings demonstrated enlarged liver with multiple focal lesions. Serum albumin, serum bilirubin, and total protein concentrations were all within the normal range. Both groups were opioid naïve. The study protocol included also 10 healthy control subjects previously given 30 mg (MST) to serve as our study control. They all had normal renal and liver function with negative tests for hepatitis. 6 Administration of morphine was started at 10:00 in all patients. A cannula was inserted into an antecubital vein under local anaesthesia to facilitate sampling of venous blood. Blood was obtained every 30 min for the first 3 h, followed by every hour for the next 3 h, and then every 2 h up to 12 h. Plasma concentrations of morphine were measured by high-pressure liquid chromatography using a fluorescence response. The limit of quantification was 2 ng ml 1, with a coefficient of variation of less than 3%. Morphine concentrations at different times after oral MST 30 mg were fitted to a two-compartment model, where, the total body clearance (Cl) and bioavailability (F) were calculated. The differential equations of the proposed model were analysed using the MULTI (Rung computer) program. 7 The mean residence time MRT was calculated using the following equation: MRT ¼ k 12 þ k 21 þ 1 k 10 k 21 k a where k a is the absorption rate constant. k 12,k 21 are the intercompartmental rate constants. k 10 is the elimination rate constant. The other parameters including maximum concentration in the blood concentration curve (C max ) and the time to reach that concentration (T max ) were obtained graphically. The area under the serum concentration time curve (AUC) was determined using the the trapezoidal rule. The halflife of the elimination phase (T 1/2 ) was calculated using the slope of the elimination phase. T 1=2b ¼ 0:693=b: The total body clearance was calculated using the following equation: Cl ¼ Dose F AUC Data analysis All values shown are mean (SEM) of number of observations. All mean values between groups were analysed by one-way analysis of variance. Differences between groups were considered significant when P<0.05. Pharmacodynamic efficacy variables of oral MST were assessed using verbal rating scale; 0=no pain, 1=mild pain, 2=moderate pain, 3=severe pain. The level of sedation was assessed by using a similar scale; 0=alert and active, 1=awake and calm, 2=drowsy but respond to verbal and tactile stimuli, 3=asleep. All data concerning pain and sedation were collected by a blinded physician observer. Patients were kept in the ICU with continuous monitoring of ECG, arterial blood pressure, pulse oximetry, and ventilatory frequency for 24 h post-drug administration. Results Pharmacokinetics Plasma concentrations of morphine over the 12-h study are shown in Figure 1. Morphine was present in the blood within the first 30 min of the study in both controls and patients. In controls, the curve showed a decreasing trend after 5 h of sustained plasma concentration with no secondary peak. A higher peak was reached in patients with sustained concentration almost above that in controls over the study period. The decay in plasma morphine concentration fitted best to biexponential function in all patients. Kinetic data were derived from the morphine concentration time curve (Fig. 2). 96

3 MST in patients with liver carcinoma Concentration ng ml Time (h) Normal Primary cancer liver Secondary cancer liver (data ±SD) Table 1 The pharmacokinetic values of oral MST 30 mg tablets in the control, primary and secondary liver cancer patients. a,b Significant difference (P<0.05) with the control and between the two cancer groups, respectively. Data are presented as mean (SEM). *These parameters were calculated by using the mean data Parameters Control Primary cancer liver Fig 1 Semi-log plot for serum concentration time profile of morphine after oral administration of one tablet MST 30 mg to normal, primary and secondary liver cancer (data [SD]). Concentration ng ml Time (h) Normal Primary cancer liver Secondary cancer liver (data ±SD) Fig 2 Serum concentration time profile of morphine after single oral administration of MST 30 mg tablet to normal, primary and secondary liver cancer (data [SD]). Secondary cancer liver C max (ng ml 1 ) (0.47) 52.7 (1.93) a (2.80) a,b T max (min) (4.91) 180 (0.00) a 180 (0.00) a AUC (mg h 1 litre 1 ) (3.85) (25.77) a,b (21.69) a MRT (h) 7.03 (0.61) 8.04 (0.45) 7.03 (0.47) T 1/2 (h) 4.01 (0.15) 5.99 (0.39) a,b 4.61 (0.39) F (%)* Cl (litre h 1 kg 1 )* The individual pharmacokinetic parameters for the control, primary, and secondary cancer liver patients after oral administration of MST 30 mg tablets are shown in Table 1. Table 2 shows the liver function test of the patients. C max was significantly higher in the primary cancer group (C max 52.7 [1.93] ng ml 1 ) and in the secondary cancer group (C max [2.80] ng ml 1 ) compared with control (C max [0.47] ng ml 1 )(P<0.05). But still there were also significant differences between the primary and secondary cancer groups. T max was similar in the primary cancer and secondary cancer groups (180 [0.00] min) but there was a significant difference between the two cancer groups and the control group ( [4.9] min). Systemic bioavailability (F%) was significantly higher (4-fold) in the primary group (F 64.8%) than in the control group (F 16.8%) and (3-fold) significantly higher in secondary group (F 62.1%) than the controls (P<0.05). AUC in the patients was significantly increased compared with controls. There was also a significant difference between primary and secondary metastatic groups of patients (P<0.05). There was no significant difference in MRT between the control (7.03 [0.61] h), primary (8.04 [0.45] h) and the secondary groups (7.03 [0.47] h). T 1/2 was significantly higher in the primary group (5.99 [0.39] h) compared with the control (4.01 [0.15] h) and the secondary group (4.61 [0.39] h). The total body clearance was higher in the secondary group (1.01 litre h 1 kg 1 ) compared with the control group (0.73 litre h 1 kg 1 ) and in the primary group (0.70 litre h 1 kg 1 ), all changes were statistically insignificant. Pharmacodynamics After oral morphine administration all the studied patients expressed patient satisfaction and complete pain relief. The side-effects were more pronounced in the primary liver cancer group: two cases of respiratory depression occurred in this group. In both cases it was noted by a gradual decline in oxygen saturation measured by pulse oxymeter, decrease in the ventilatory frequency, and sedation 3 h after morphine administration. They responded to nalbuphine administration and mechanical ventilation was not needed in any of them. Estimated serum morphine levels at that time were 52 and 56 ng ml 1, respectively. In the secondary cancer group the side-effects were sedation (six cases, sedated but arousable) and nausea (one case with cancer pylorus). Discussion We have determined the pharmacokinetics of oral morphine (MST 30 mg) in patients with liver carcinoma associated with cirrhosis or secondary to primary carcinoma. Derived kinetic variables in control healthy volunteers have been published and fitted closely to other reported data. 6 Patients with liver cancer showed a 3 4-fold increase in the peak concentration of morphine presumably as a result of the reduction in first pass metabolism secondary to a reduction in liver cell mass; this led to an increase in total systemic 97

4 Kotb et al. Table 2 Liver function tests Patients Bilirubin Total protein Albumin Globulin A/g 3 17 mmol litre g litre g litre g litre :1 AST (SGOT) ALT (SGPT) 5 20 m litre m litre 1 A. Liver function tests for primary cancer liver group B. Liver function tests for secondary cancer liver group bioavailability of morphine. Approximately 70% of the dose entered the systemic circulation in patients with liver cancer compared with 20% in healthy control. This is reflected in an increase in the AUC. Systemic clearance was maintained in liver cancer patients with a prolonged elimination half-life in patients with primary liver carcinoma as a result of cirrhosis. Early studies produced conflicting evidence on the effect of the liver cancer on hepatic drug metabolism; limited information is available on hepatic drug metabolism in primary and secondary liver cancer. 8 Based on the intact hepatocyte theory Kawasak and co-workers 9 showed that in a group of six patients with liver cancer (three primary and three metastatic) phenazone clearance was unchanged. Clearance of antipyrine was also reported to be unchanged by Robertz-Vaupel and colleagues. 10 In cirrhosis, there is usually marked fibrosis and nodular regeneration resulting in circulating changes of importance expecting a reduced clearance in patients with liver cancer on top of cirrhosis. However, there is evidence of increased hepato-arterial flow that is equal or even above that of normal. 11 Vascular changes as a result of cancer itself may complicate the situation further. 12 These mechanisms can in part explain the maintained clearance of morphine in patients with liver cancer included in this trial. On the other hand, glucuronidation has been shown to be preserved in cirrhosis and even up-regulated. 13 The prolonged half-life in primary liver cancer patients is a result of increased volume of distribution as clearance is maintained in this group of compensated liver patients. Another cause of impaired elimination in patients with liver pathology may be the impaired uptake of the drug across the capillarized endothelium (impaired drug uptake theory). 14 In this trial, there was complete pain control and good patient satisfaction in all liver cancer patients. The sideeffects were more frequent in the primary liver cancer group, especially respiratory depression (two cases). Both had a high serum morphine concentration and were above 65 yr of age with normal renal function. Altered blood brain transport in patients with cirrhotic liver may partly be responsible for this. 15 Acknowledgement We thank Professor Abdel-Hameed H. El-Baz for advice and support. References 1 Kaltenback BL, Becker AJ. Use of opioids in adults with chronic cancer pain. Health Care 2002; 1: Hasselström J, Säwe J. Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin Pharmacokinet 1993; 24: Muir C, Waterhouse J, Mack T, et al. Cancer Incidence in Five Continents, World Health Organization, Vol V. IARC Scientific Publications. Lyon: IARC, 1987; No Rustgi VK. Epidemiology of hepatocellular carcinoma. Gastroenterol Clin North Am 1987; 16: Kubicka S, Rudolph KL, Hanke M, et al. Hepatocellular carcinoma in Germany: a retrospective epidemiological study from a low-endemic area. Liver 2000; 20: Kotb HI, El-Kabsh MY, Emara SE, Fouad EA. Pharmacokinetics of controlled release morphine (MST) in patients with liver cirrhosis. Br J Anaesth 1997; 79: Yamaoka K, Nakagawa T. A non linear least squares program based on differential equations, MULTI (Ruge) for microcomputer. J Pharmacobiol Dynam 1983; 6: Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease: an update. Clin Pharmacokinet 1995; 29: Kawasak S, Imamura H, Bandai Y, et al. Direct evidence for the intact hepatocyte theory in patients with liver cirrhosis. Gastroenterology 1992; 102:

5 MST in patients with liver carcinoma 10 Robertz-Vaupel GM, Lindecken KD, Edeki S, et al. Disposition of antipyrine in patients with extensive metastatic liver disease. Eur J Clin Pharmacol 1992; 42: Neal APS, Datta DV, Wath W, Mathur VS. Enhanced bioavailability and decreased clearance of analgesics in patients with cirrhosis. Gastroenterology 1979; 77: Sherlock S, Dooley J. Malignant liver tumours (31). In: Sherlock S and Dooley J, eds. Diseases of the Liver and Biliary System. Oxford: Blackwell Scientific Publications, 2002; Debinski HS, Lee CS, Danks JA, et al. Localization of 5 0 -diphosphate-glucuronyl-transferase in human liver injury. Gastroenterology 1995; 108: Reichen J. hepatic spaces and transport in the perfused liver. In: Petzinger E, Kinne RK-J, Sies H, eds. Hepatic Transport in Organic Substances. Berlin: Springer-Verlag, 1989; Xie R, Hammar-lund-Udenaes M, de Boer AG, et al. The role of P-glycoprotein in blood brain barrier transport of morphine: transcortical microdialysis studies in mdrla ( / ) and mdrla (+/+) mice. Br J Pharmacol 1999; 128: