The absorption of morphine sulphate, given orally as a controlled release preparation, was studied in 10 patients who had undergone peripheral vascular surgery with a standard opioid-based general anaesthetic technique. Serum morphine concentrations were measured (high pressure liquid chromatography) every 2 h for the first 16 h after surgery and the results were strongly suggestive of a decrease in the rate of absorption of morphine in this situatio

ACHOLA, K. J.

DERBYSHIRE, D. R.

PINNOCK, C. A.

SMITH, G.

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Br. J. Anaesth. (1986), 58, 868-871ABSORPTION OF CONTROLLED RELEASE MORPHINESULPHATE IN THE IMMEDIATE POSTOPERATIVE PERIODC. A. PINNOCK, D. R. DERBYSHIRE, K. J. ACHOLA AND G. SMITHA controlled release formulation of morphinesulphate (MST Continus, Napp Laboratories)has been advocated as a postoperative analgesicagent (Fell, Chmielewski and Smith, 1982;Derbyshire et al., 1984) in those patients for whoman opioid agent is deemed necessary. In a previousstudy MST 20 mg, administered every 4 h, wasshown to provide acceptable analgesia afterhysterectomy or cholecystectomy (Derbyshire etal., 1985). However, the unexpectedly low serummorphine concentrations (mean 1.9 ng ml"1)found 18 h after surgery led to concern that thedecrease in gastric motility, which occurs com-monly after anaesthesia and surgery, might haveled to the accumulation of MST in the stomach.Anaesthetic techniques which use opioids areknown to inhibit gastric emptying temporarily(Nimmo, 1984). Later "dumping"of any accumu-lated drug into the small intestine (from which itis absorbed) would then present a potential hazard.The present study was designed to examine theabsorption of MST immediately after a standardgeneral anaesthetic technique and to compare theresults with those obtained previously in healthynon-anaesthetized volunteers.PATIENTS AND METHODSTen patients (mean age 72 yr (range 54-86 yr);mean weight 69 kg (range 59-84 kg)) undergoingperipheral arterial surgery for which arterialcannulation and intensive postoperative monitor-ing were deemed necessary were studied. PatientsC. A. PlNNOCK, F.F.A.R.C.S.; D . R. DERBYSHIRE,* V.FJLJLC*.;K. J. ACHOLA, M.sc.; G. SMITH, MJ>., F.F_A.R.C.S.; UniversityDepartment of Anaesthesia, Leicester Royal Infirmary,Leicester LEI 5WW.•Present address: South Warwickshire Health Authority.A preliminary report of this study was presented to theEuropean Academy of Anaesthesiology, Basel, September1985.SUMMARYThe absorption of morphine sulphate, given orallyas a controlled release preparation, was studiedin 10 patients who had undergone peripheralvascular surgery with a standard opioid-basedgeneral anaesthetic technique. Serum morphineconcentrations were measured (high pressureliquid chromatography) every 2 h for the first16 h after surgery and the results were stronglysuggestive of a decrease in the rate of absorptionof morphine in this situation.with significant preoperative pain, or who werereceiving opioid therapy or who had a history ofgastrointestinal pathology were excluded from thestudy.All patients received a standard anaesthetictechnique . Following premedication with diaze-pam 10 mg by mouth, sodium thiopentone 3 mgkg"1 was administered. Anaesthesia was main-tained with 66 % nitrous oxide in oxygen. Fentanylwas administered as necessary for the suppressionof reflex responses, and controlled ventilation tonormocapnia was facilitated by the administrationof atracurium. The mean dose of fentanyladministered was 365 ug (range 300-450 ng).After surgery the patients were prescribed MST20 mg 4-hourly by mouth for analgesia. Theywere monitored (continuous ECG and directarterial pressure recording) in the recovery suitefor a period of 18-24 h.Arterial blood was sampled every 2 h for 16 h.Time "zero" (control) was denned (for eachpatient) as the moment immediately before theadministration of the first dose of MST. MST wasadministered once each patient could swallowadequately (in all patients this occurred within30 min of the end of the operative procedure).Blood samples were allowed to clot and centrifugedMST IN THE POSTOPERATIVE PERIOD 869TABLE I. Demographic details of the patients in the studyAge(yr)59706473768654807974Weight (kg)60598480646068747069ProcedureFemoro-popliteal graftFemoro-popliteal graftFemoro-popliteal graftAxillo-bifemoral graftFemoro-popliteal graftFemoro-femoral graftFemoro-popliteal graftFemoro-popliteal graftFemoro-femoral graftFemoro-popliteal graftat 5000 rev min 1 for 15 min. The supernatantserum was extracted and frozen at — 70 °C pend-ing analysis for serum morphine concentration.Serum morphine concentrations were measuredby high pressure liquid chromatography (HPLC)with electrochemical detection (Aitkenhead et al.,1984). The lower limit of detection of this assayis 1 ng ml"1, and the coefficient of variation isless than 5%. The assay is specific to "free"morphine and does not measure the glucuronidesof morphine, which are extracted into aqueoussolution before chromatography.RESULTSDemographic details of the patients and theprocedures undertaken are shown in table I.Figure 1 represents a plot of mean serummorphine concentrations against time for the first16 h after surgery in nine patients. No morphinewas detected in the control samples. Thereafter,serum morphine concentrations increased from amean of l^ngml" 1 at 2h to a mean of12.4 ng ml"1 at 14 h. There is clearly a delay in theincrease in serum concentrations over this periodin comparison with the pattern seen from anotherstudy in volunteers (who had not undergonesurgery and anaesthesia) who received MST20 mg as a single dose (Vater et al., 1984).Each patient was questioned hourly by therecovery suite nursing staff as to whether or not hewas in pain. Although nine patients questionedthus had adequate analgesia, tie respective serummorphine concentrations were considerably lowerthan the 50 ng ml"1 which has been suggested asthe value providing postoperative analgesia(Berkovitz et al., 1975) in studies in whichmorphine was measured by radioimmunoassaytechniques. However, in a study by Dahlstrom and20_ 18g 14I 1 21 8aI 66 8 10Time (h)12 14 16FIG. 1. Serum morphine concentrations in patients given MST20 mg every 4 h by mouth, commencing at time 0 (o O)following peripheral vascular surgery (mean ± SEM, n = 9).For comparison data from Vater and colleagues (1984) are alsoplotted (o o)j showing the profile of serum morphineconcentrations in volunteers following a single dose of MST20 mg (mean ± SEM, n = 11).colleagues (1982) the minimum effective analgesicconcentration for morphine (plasma valuesmeasured by HPLC) was 16 ng ml"1.The single patient who complained of pain hadvomited after each dose of MST and the measuredserum morphine concentrations in this patientwere consistently less than 2 ng ml"1. Analgesiawas supplemented by fentanyl i.v. in thisindividual and the serum morphine concentra-tions have been omitted from the data shown infigure 1.Although the nursing staff received instructionsto omit a scheduled dose of MST if theyconsidered the patient to be excessively sedated,this was not necessary in any patient throughoutthe first 24 h of the postoperative period (whenstrong analgesic drugs are usually required).DISCUSSIONThe pattern, displayed in figure 1, of a slow anddelayed increase in serum morphine concentrationsis strongly indicative of a delay in the absorptionof MST—especially in the period immediatelyafter operation.In the study by Vater and colleagues (1984) inwhich starved volunteers received a single dose of20 mg MST, the mean peak plasma morphine870concentration was 14.8 ng ml"1 and occurredwithin a mean 143 min of administration. Theserum morphine concentration-time data fromthose volunteers have been plotted in figure 1(dashed line) for comparison with the present data.In a more recent study of 29 volunteers givenMST 30 mg the mean peak serum morphineconcentration was 11.6 ng ml"1 and occurred at amean time of 120 min following administration(Pinnock, Derbyshire and Aitkenhead, unpub-lished observations). In both these studies,morphine concentrations were measured using thesame HPLC technique as in the present study(Aitkenhead et al., 1984). Thus the pattern shownfor patients given MST 20 mg every 4 h contrastssharply with the early peak and decay seenfollowing a single dose of MST 20 mg involunteers who had not undergone anaesthesia andsurgery.It is well documented that anaesthesia utilizingopioid drugs may cause a temporary inhibition ofgastric emptying (Nimmo et al., 1975; Nimmo,1976). In contrast, there is little effect on gastricmotility, following anaesthesia for minor pro-cedures, when opioids are not used (Reilly andNimmo, 1984).It seems reasonable to postulate, therefore, thatintestinal motility was decreased in the patientsexamined in the present study following the i.v.administration of fentanyl. In addition, it shouldbe emphasized that the majority of patientsundergoing major surgery will normally receiveopioids i.v. during the course of anaesthesia. Parkand Weir (1984) demonstrated in healthy volun-teers that MST per se has little effect on gastricemptying (whereas morphine i.m. may cause aconsiderable reduction) as assessed by themeasurement of plasma paracetamol concentra-tions. This may be accounted for by the differencein plasma concentrations of morphine producedby the two different routes of administration. Inthe study of Park and Weir (1984) the oral MSTadministered to healthy volunteers was associatedwith a "normal" profile of plasma concentrationsof morphine and a mean peak of around 6 ng ml"1,whereas the i.m. route of administration wasassociated with a peak plasma concentration ofapproximately 30 ng ml"1.In the absence of physical obstruction to thegastric outlet (such as pyloric stenosis) opioidanalgesic drugs are the major cause of delayedgastric emptying in the preoperative period(Nimmo, 1984). The results of the present studyBRITISH JOURNAL OF ANAESTHESIAwould appear to provide evidence supplementaryto that of Derbyshire and colleagues (1985)suggesting that the rate of absorption of MST inthe early postoperative period is reduced followinganaesthesia comprising a nitrous oxide in oxygen—neuromuscular blocker-opioid sequence.A corollary of this statement is that, whennormal gastric activity resumes, passage ofaccumulated MST into the small intestine maylead to excessively high blood concentrations ofmorphine, particularly if the period of gastricstasis is prolonged and oral administration of thedrug is continued. Such a situation may be mostlikely to occur in a patient who has undergoneintra-abdominal surgery following which theincidence of paralytic ileus is high. Whilst manyfactors are of importance in the aetiology of gastricstasis following surgery, the risk of accumulationof MST within the stomach followed by laterabsorption may be seen to be of relevance,independent of the precise mechanism underlyingthe inhibition of gastric transport.The absorption of a substantial amount ofmorphine into the systemic circulation followingregular administration of MST to a patient withgastric stasis is obviously hazardous. Estimates ofthe systemic bioavailability of MST have beenquoted between 18% (Vater et al., 1984) and100% (McQuay et al., 1983) and thus it is difficultto predict for any one individual the dose of MSTwhich would lead to excessive blood concentrationsshould gastric stasis and "dumping" occur.Attention has already been drawn to the death ofa patient following the use of MST for post-operative pain relief (Brahams, 1984). Thus,extreme caution must be advocated in the use ofMST in the early postoperative period. However,it should be noted that, in the present study, thelater postoperative course of these patients wasuneventful. No patient exhibited excessive drowsi-ness as might have been expected if "dumping"of accumulated MST was occurring.Although consideration of the quality ofanalgesia was beyond the scope of this study, it isnoteworthy that in the second 24-h period aftersurgery only two patients required further anal-gesia (this was a single dose of morphine sulphate10 mg i.m.).The intraoperative consumption of fentanyl inall 10 patients was modest (mean 365 ug, range300-450 ng). It is surprising, therefore, thatsatisfactory analgesia was achieved at low serummorphine concentrations and it is tempting toMST IN THE POSTOPERATIVE PERIOD 871speculate that this may be related to thebiotransformation of morphine administered bymouth. All patients had evidence of partialabsorption of MST as shown by detectable serummorphine concentrations from 2 h onwards. Onesignificant breakdown pathway of morphine is byhepatic conjugation. A major metabolite from thispathway is morphine-3-glucuronide, which is notknown to possess any analgesic properties. Asmaller proportion of the administered dose isconjugated to morphine-6-glucuronide (M6G).M6G is thought to be three times as potent as ananalgesic as free morphine and it is possible thatan element of the analgesia seen in these patientsis related to M6G.(NOTE : The revised data sheet for MST Continusfrom Napp Laboratories does not recommend theuse of MST in the early postoperative period.)REFERENCESAitkenhead, A. R., Vater, M., Cooper, C. M., and Smith, G.(1984). Pharmacokinetics of single dose i.v. morphine innormal volunteers and patients with end-stage renal failure.Br.J. Anaetth., 56, 813. <Berkovitz, B. A., Ngai, S. H., Yang, J. C , Hempstead, J., andSpector, S. (1975). The disposition of morphine in surgicalpatients. Clin. Pharmacol. Ther., 17, 629.Brahams, D. (1984). Death of a patient participating in a trialof oral morphine for relief of post operative pain. Lancet, 1,1083.Dahlstrom, B., Tamsen, A., Paalzow, L., and Hartvig, P.(1982). Pharmacokinetics and analgesic plasma concentra-tions of morphine. Clin. Pharmacokinet., 7, 266.Derbyshire, D. R., Bell, A., Parry, P. A., and Smith, G. (1985).Morphine sulphate slow-release. Comparison with i.m.morphine for postoperative analgesia. Br. J. Anaesth., 57,858.Vater, M., Maile, C. J., Larsson, I.-M., Aitkenhead,A. R., and Smith, G. (1984). Non-parenteral postoperativeanalgesia. A comparison of sub-lingual buprenorphine andmorphine sulphate slow-release tablets. Anaesthesia, 39,324.Fell, D. , Chmielewski, A., and Smith, G. (1982) Postoperativeanalgesia with controlled release morphine sulphate: acomparison with i.m. morphine. Br. Med. J., 285, 92.McQuay, H. J., Moore, R. A., Bullingham, R. E. S., Carroll,D., Baldwin, D., Allen, M. C , Glynn, C. J., and Lloyd,J. W. (1983). High Systemic Relative BioavailabiUty of OralMorphine in Both Solution and Sustained-Release Formulation.London: Royal Society of Medicine.Nimmo, W. S. (1976). Drugs, disease and altered gastricemptying. Clin. Pharmacokinet., 1, 189.(1984). Effect of anaesthesia on gastric motility andemptying. Br. J. Anaesth., 56, 29.Heading, R. C , Wilson, J., Tothill, P., and Prescott,L. F. (1975). Inhibition of gastric emptying and drugabsorption by narcotic analgesics. Br. J. Clin. Pharmacol., 2,509.Park, G. W., and Weir, D. (1984). A comparison of the effectsof oral controlled release morphine sulphate and i.m.morphine on gastric emptying. Anaesthesia, 39, 645.Reilly, C. S., and Nimmo, W. S. (1984). Drug absorption aftergeneral anaesthesia for minor surgery. Anaesthesia, 39, 859.Vater, M., Smith, G., Aherne, G. W., Aitkenhead, A.R. (1984).Pharmacokinetics and analgesic effect of slow-release oralmorphine sulphate in volunteers. Br. J. Anaesth., 56, 821.

ABSORPTION OF CONTROLLED RELEASE MORPHINE SULPHATE IN THE IMMEDIATE POSTOPERATIVE PERIOD

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