PHARMACOKINETICS AND ANALGESIC EFFECT OF SLOW-RELEASE ORAL MORPHINE SULPHATE IN VOLUNTEERS

Sustained-release oral morphine sulphate (MST) 20 mg was administeredto 11 healthy volunteers. Mean peak plasma morphine concentrationwas 14.8 ng ml, and occurred at a mean time of 142.5 min afteringestion. Analgesia by an ischaemic forearm pain test increasedto a maximum 40 min after the calculated peak plasma concentrationof morphine had been achieved, and remained greater than controlvalues as plasma morphine concentration decayed. However, therewas not a significant correlation between analgesia and plasmamorphine concentration. This may result from delay in brainpenetration by morphine. The mean systemic availability of morphinein the first 7 h after administration of MST was 18.3%     

Buccal morphine premedication

Fifty patients were admitted to a double-blind, double-dummy study comparing buccal morphine 10 mg tablets and intramuscular morphine sulphate 13.5 mg as premedication. This investigation was performed on the basis of favourable results obtained in an earlier 25 patient pilot study designed to examine the efficacy, safety and patient acceptability of buccal morphine 10 mg tablets as pre-anaesthetic medication. Both studies and sets of results are presented and show that, whilst buccal morphine is a safe alternative means of delivering opioid premedication, which is acceptable to the majority of patients, an equivalent intramuscular morphine dose is nevertheless a more effective premedicant in terms of anxiolysis and wakefulness, as assessed by linear analogue scores. Pharmacokinetic considerations are advanced both to explain the differing clinical efficacies of the two means of morphine administration and to indicate that improved per- and immediate postoperative analgesia might be obtainable in patients premedicated with buccal morphine.     

Rectal Administration of Morphine Hydrogel: Absorption and Bioavailability in Women

Seven patients undergoing radiological treatment for carcinoma of the uterus were given morphine intramuscularly (0.15 mg X kg-1) and morphine in a starch hydrogel rectally (0.56 mg X kg-1) on two separate occasions. The hydrogel preparation was used to order to improve the contact between the rectal mucosa and thus improve and possibly prolong the absorption of morphine. Plasma concentrations of morphine were followed for 8 h and analysed with a GC/MS technique. It was found that 45-120 min after administration of morphine hydrogel, a mean maximum plasma morphine concentration of 61 ng X ml-1 was obtained. After 8 h, the mean plasma concentration was 10 ng X ml-1. The mean biological availability of morphine hydrogel was 48% (range 31-72%). It is suggested that morphine hydrogel, given rectally, can be clinically useful.     

Effects on gastric emptying of thoracic epidural analgesia with morphine or bupivacaine

The effects of thoracic epidural analgesia on gastric emptying were evaluated in healthy fasting volunteers. In ten volunteers, 4 mg of epidural morphine were injected at the T4 level, and ten volunteers received thoracic epidural analgesia with 0.5% bupivacaine, the latter causing block of the sympathetic innervation to the stomach. Acetaminophen absorption was used as an indirect measure of the rate of gastric emptying. After establishment of the analgesia with bupivacaine, or 160 (110-185) minutes after the administration of epidural morphine, 1.5 g acetaminophen dissolved in water was ingested. Serum samples were taken at 15-minute intervals for 2 hours and serum acetaminophen concentrations were determined by an immunologic method. Control acetaminophen absorption studies without thoracic epidural analgesia were performed in all 20 subjects on another occasion. During epidural analgesia with morphine mean serum acetaminophen concentrations were lower (P less than 0.05), the maximum serum acetaminophen concentration was lower (P less than 0.01), the time taken to reach the maximum concentration was longer (P less than 0.02), and the area under the concentration time curve from 0 to 60 minutes was smaller (P less than 0.01) than in the control study. The corresponding values during epidural analgesia with bupivacaine did not differ from the control values. Four subjects with extremely delayed gastric emptying during epidural analgesia with morphine showed no delay in gastric emptying after receiving 4 mg morphine intramuscularly. Serum morphine concentrations were lower after epidural than after intramuscular morphine. In summary, 4 mg epidural morphine delayed gastric emptying. This was not a systemic effect of morphine. Thoracic epidural analgesia with bupivacaine had no influence on gastric emptying.     

An assessment of prochlorperazine buccal for the prevention of nausea and vomiting during intravenous patient-controlled analgesia with morphine following abdominal hysterectomy.

The effectiveness of prochlorperazine buccal as an anti-emetic for the prevention of post-operative nausea and vomiting in patients using intravenous patient-controlled analgesia with morphine following abdominal hysterectomy has been assessed in a randomized, double-blind, placebo-controlled study. Forty-nine female patients participated with 26 allocated to the prochlorperazine buccal group and the remainder to the placebo group. Each received either placebo or prochlorperazine buccal 6 mg, in each case by the buccal route, 1 h prior to anaesthesia with further doses at 6, 18, 30 and 42 h, respectively. Symptom scores in respect of nausea, pain and sedation, the number without nausea, the number without vomiting and the requirement for rescue anti-emetic therapy were noted for each 4-h period during the 48-h study. Morphine utilization and taste associated with the study material were recorded. Data for 21 patients in the placebo group and 25 patients in the prochlorperazine buccal group were available for analysis. Patients in the prochlorperazine buccal group showed significantly lower mean nausea scores at 4-8 h (placebo group: mean nausea score 0.95; prochlorperazine buccal group: mean nausea score 0.36; P < 0.05) and at 16-20 h (placebo group: mean nausea score 1.24; prochlorperazine buccal group: mean nausea score 0.48; P < 0.05). Furthermore, the prochlorperazine buccal group showed significantly more patients without nausea at 4-8 h (placebo group: 11 patients out of 21; prochlorperazine buccal group: 20 patients out of 25; P < 0.05) and at 16-20 h (placebo group: nine patients out of 21; prochlorperazine buccal group: 18 patients out of 25; P < 0.05). The prochlorperazine buccal group showed a significantly higher number of patients rating the taste as unsatisfactory (placebo group: two patients out of 21; prochlorperazine buccal group: nine patients out of 25; P < 0.05). Intravenous droperidol is the current gold standard prophylactic anti-emetic in post-operative nausea and vomiting associated with intravenous patient controlled analgesia with morphine usage. This study has demonstrated a peri-operative prochlorperazine buccal regimen to be effective in post-operative nausea and vomiting prophylaxis in the use of intravenous patient controlled analgesia with morphine. Prochlorperazine buccal should be considered as an effective, inexpensive option for the prevention of post-operative nausea and vomiting in post-operative intravenous patient controlled analgesia with morphine administration.     

Pharmacokinetics of intravenous, intrathecal and epidural morphine and fentanyl in the goat

Intrathecal and epidural catheters and an intravenous cannula were inserted in 10 goats. After administration of either morphine 4 mg, intravenously, 1 mg intrathecally or 4 and 8 mg epidurally, or fentanyl 0.1 mg intravenously, 0.05 mg intrathecally or 0.1 and 0.2 mg epidurally, venous blood and CSF were sampled at 2, 5, 10, 15, 30 min and 1, 2, 4, 6, 8 and 24 h. The concentrations of the drugs were measured by radioimmunoassay. After administration of intravenous morphine the plasma concentration-time curve fitted a 3-compartment model (body clearance = 84 +/- 23 ml/min/kg, mean +/- s.d., N = 5), while after fentanyl the plasma concentration-time curve was best described by a 2-compartment model (body clearance = 3.9-5.8 ml/min/kg, N = 3]. After intrathecal injection the elimination rates of the opioids from CSF were 0.3 to 2.0 and 0.6 to 2.4 ml/h/kg for morphine and fentanyl, respectively (N = 3). The time to reach maximum CSF concentration after epidural administration was 0.22 +/- 0.14 h for morphine (N = 6) and 0.22 +/- 0.13 h for fentanyl (N = 8). In the same goat the CSF availability was 2.3 and 11.3% for morphine and 0.8 and 3.3% for fentanyl following epidural administration of the low and high doses, respectively. After epidural administration, morphine and fentanyl are absorbed into CSF at the same rate but the relative amount of drug absorbed may be higher for morphine than fentanyl. Bulk flow is supposed to be the principal mechanism of opioid elimination from CSF.     

PLASMA MORPHINE CONCENTRATIONS AND CLINICAL EFFECTS AFTER THORACIC EXTRADURAL MORPHINE OR DIAMORPHINE

Twenty-seven patients undergoing thoracotomy received eithermorphine sulphate 2 mg or diamorphine hydrochloride 2 mg bythoracic extradural injection for postoperative analgesia. Arterialplasma morphine concentrations were measured by specific radkrimmunoassay,and the analgesic, respiratory and biochemical effects noted.The plasma morphine concentrations were significantly graterafter extradural diamorphine than after extradural morphinein the first 30 min after injection. The maximum increase inplasma morphine concentration was significantly (P<0.02)greater after extradural diamorphine, and mean peak values occurredat S and 10 min for diamorphine and morphine, respectively.There were significant decreases in respiratory rate and plasmacortisol concentration with maximum effects between 90 and 180min after the extradural injection. The analgesia produced bythese doses was inadequate. The role of lipophilicity is discussed     

Effect of meptazinol on drug absorption and gastric emptying

The rate of paracetamol absorption after oral administration was used as an indirect estimate of the rate of gastric emptying in 24 patients before minor surgery. Patients who received 10 mg morphine or 100 mg meptazinol i.m. had significantly delayed absorption as shown by a lower peak concentration and a delayed time to peak. The mean AUC at 90 min was 1,590, 642 and 159 micrograms min ml-1 after saline, morphine and meptazinol respectively. Meptazinol delayed paracetamol absorption more than morphine.     

ABSORPTION AND BIOAVAILABILITY OF NEBULIZED MORPHINE

During anaesthesia seven patients received a bolus of morphine10 mg injected into the nebulization reservoir placed betweenthe tracheal tube and the anaesthetic circle (lH). Five daysafter operation the same seven patients received morphine 10mg i.m. On both occasions, venous blood samples were taken beforeand every 15 min after administration over 4.5 h for measurementof free morphine immunoreactivity by radioimmunoassay. Therewas marked individual variation in the serum morphine concentrationsproduced following each route of administration. The maximumserum morphine concentration following inhaled morphine wasapprox. six times lower than that after morphine i.m. and thetime of occurrence differed significantly (P < 0.001). Theindividual relative bioavailabilities of inhaled morphine variedfrom 9% to 35%, with a mean of 17%.     

Rectal administration of morphine in children

Background : There is limited knowledge about the pharmacokinetics of morphine and its metabolites after rectal administration in children. In this study the pharmacokinetics of two different rectal formulations of morphine were examined and compared with intravenous morphine.
Methods : Children undergoing elective surgery received rectal morphine 0.2 mg/kg before start of surgery. Ten children (mean age 14 months) received morphine rectally in a hydro-gel formulation and another 10 children (mean age 16 months) received morphine rectally in a parenteral formulation. For comparison, 6 children (mean age 21 months) were given the same dose intravenously. The plasma concentrations of morphine, morphine-3-glucuronide (M3G) and mor-phine-6-glucuronide (M6G) were measured by HPLC over 6 h after drug administration.
Results : The mean rectal bioavailability of morphine was 35% (range 18–59) after hydrogel administration and 27% (range 6–93) after the solution. Mean values of Cmax were 76 nmol/1 (25–129) and 56 nmol/1 (15–140), respectively. The results showed that morphine gel had a significantly higher bioavailability (P<0.02) than the solution. The ratios of plasma (M3G + M6G) to morphine were higher after rectal administration (mean 7.5–8.7) than after i.v. injection (mean 5.3), indicating the presence of first-pass metabolism using the rectal route.
Conclusions : The rectal morphine hydrogel has pharmacokinetic properties which makes it a useful formulation for premedication and pain alleviation in paediatric patients.     

ANALGESIC EFFICACY OF PERIOPERATIVE BUCCAL MORPHINE

We have studied the effect of regular perioperative administrationof buccal morphine sulphate on postoperative analgesic consumptionin female patients undergoing lower abdominal surgical procedures.Ten matched pairs of women were allocated randomly to receiveeither placebo or buccal morphine before operation and at 12-hintervals up to 44 h after operation. Pain was assessed usinga visual analogue scale and taste assessed using evaluationforms. Postoperative analgesic requirements were compared usinga patient-controlled analgesia system which was set to deliverbolus doses of pethidine without a background infusion. Therewas no significant difference in pain scores between the twogroups. Compared with placebo, buccal morphine did not reducesignificantly post operative pethidine consumption. All patientsreceiving buccal morphine reported a taste which reduced itsacceptability.     

Kinetics of Morphine in Cerebrospinal Fluid After Epidural Administration

Forty patients undergoing arthroscopy were given an epidural dose of 0.05 mg morphine-HCl in 0.1 ml saline/kg body weight to study the disposition of morphine in the cerebrospinal fluid (CSF). In each patient one to three CSF samples were collected (86 samples in total). A mean peak concentration of 13 890 nmol/l was achieved 75 min after morphine administration. The compiled data show an elimination half-life of 162 min (r = 0.98). Individual half-lives in seven patients with three samples ranged from 61-172 min. Large interindividual variations were found in CSF-concentrations of morphine, 9- and 8-fold at 3 and 8 h, respectively, after the dose. However, 16 h after administration no patient had a concentration less than 81 nmol/l. At 8 h after the dose, CSF concentrations of morphine were significantly higher (P less than 0.05) in a group of patients (n = 5) kept uptilted (80 degrees), as compared to those in the supine position (n = 5). Such a difference was not observed 3 h after the dose. The sampling procedure and age also seemed to influence CSF concentrations of morphine. There was no correlation between the dose given in mg and the CSF concentrations achieved. Strict standardization is thus mandatory when studying the disposition of opiates in CSF after epidural or intrathecal administration. Since our calculated half-lives of morphine in CSF were similar to those reported in plasma, the long-lasting effect is probably related to the high initial morphine concentrations in CSF.     

A randomised double-blind study of interpleural analgesia after cholecystectomy

Continuous interpleural analgesia provided by 4 hourly injections of 20 ml bupivacaine 0.5% with adrenaline 5 micrograms/ml was compared with placebo in a randomised, double-blind study after cholecystectomy. All patients self-administered intravenous morphine using a patient-controlled analgesia device. There was a highly significant difference in mean morphine consumption between the groups (72 mg as compared with 22 mg). Visual analogue pain scores tended to be lower in the bupivacaine group throughout and this was significant at 2 hours. Respiratory function measurements were not significantly different between the groups. The mean peak venous plasma bupivacaine concentration after the sixth dose was 3.03 micrograms/ml and no symptoms suggestive of local anaesthetic toxicity occurred. It is concluded that this regimen can provide effective and continuous analgesia after cholecystectomy and that combined administration of interpleural bupivacaine and systemic morphine is more effective than morphine alone in the immediate postoperative period. The doses of bupivacaine required for optimal use of the technique lead to significant total plasma bupivacaine concentrations within 24 hours.     

Excretion of morphine in human breast milk

Five lactating women who underwent surgery and were treated with morphine epidurally or IV/IM in the postoperative phase were included in the study. The morphine concentrations in plasma and breast milk were determined 0, 15, 30, 45, 60, 90, 120, 240, 360 and 480 min after drug administration by means of a specific radioimmunoassay for morphine. The milk-to-plasma ratio was 2.45 +/- 0.8 (mean +/- s.d.). The amount of morphine transferred by nursing is, even at the peak concentration of 500 ng/ml milk, small and will hardly cause respiratory depression or drowsiness in the child.     

Effects of epidural analgesia on gastroduodenal motility Experimental and clinical studies with epidural morphine and epidural bupivacaine

Abstract: These investigations were undertaken to study the effects of epidural analgesia with morphine and bupivacaine on gastrointestinal motility and to evaluate if the effect of morphine after epidural administration is a central or peripheral effect. Comparative studies were performed in volunteers, postoperative patients and pigs. Gastroduodenal motility was evaluated by manometry, electromyography (EMG) and external electro-gastrography (EGG). Gastric emptying was studied by an absorption test (acetaminophen) and orocecal transit time by the hydrogen breath test after ingestion of raffinose. In one study, intrathecal and intramuscular morphine were given simultaneously in an effort to receive plasma concentration of morphine comparable to that after an epidural administration. This combination was compared with intrathecal morphine alone to evaluate if the gastrointestinal effects were mediated by central or peripheral mechanisms. Epidural morphine delayed gastric emptying in healthy volunteers and in postoperative patients. Thoracic epidural bupivacaine with sensory block of the dermatomes T3-T12 did not influence gastric emptying. Orocecal transit time was prolonged after epidural morphine compared to epidural bupivacaine. Duodenal contractile activity was significantly increased in volunteers after epidural morphine compared to epidural bupivacaine. The pressure activity seen after epidural morphine was not always propulsive and retrograde activity occurred frequently. Gastric activity measured by EMG and EGG was significantly disturbed after intrathecal and epidural morphine and tachygastria was frequently seen. Intramuscular administration of morphine during intrathecal morphine resulted in additive effects. These studies have shown that epidural morphine compared to epidural bupivacaine delays gastric emptying and prolongs orocecal transit time. These effects may be explained by the disturbed gastroduodenal motility seen after epidural morphine. The gastroduodenal effects of epidural morphine may be caused by both a central and a systemic effect of morphine.     

Rectally Administered Morphine: Plasma Concentrations in Children Premedicated with Morphine in Hydrogel and in Solution

Seventeen healthy children undergoing eye surgery in general anaesthesia were given morphine rectally for premedication. Six patients (Group I) were given morphine 0.15 mg X kg-1 in a propylene glycol solution also containing diazepam and hyoscine. Eleven patients (Group II) were given morphine 0.5 mg X kg-1 in a starch hydrogel preparation. The plasma concentrations of morphine (Groups I and II) and diazepam (Group I) were studied. After the lower dosage of morphine the plasma concentrations never exceeded 10 ng X ml-1, whereas the mean peak plasma concentration was 25.3 +/- 5.5 ng X ml-1 after the higher dosage. One child in each of Groups I and II needed postoperative analgesics. The simultaneous plasma concentration of morphine was then lower than 5 ng X ml-1. Postoperative nausea occurred to about the same extent in both groups. It is suggested that morphine given rectally in a starch hydrogel may be an alternative to oral and parenteral routes of administration.     

Oral controlled-release morphine and gut function: a study in volunteers

The effects of a single 30-mg tablet of oral controlled-release (OCR) morphine (MST) on gastric emptying and small-intestine transit time (SITT) were compared with placebo in a double-blind, cross-over trial, on ten healthy volunteers. Gastric emptying was measured by paracetamol absorption and SITT by the rise in breath hydrogen after a carbohydrate test meal. There was no alteration in the absorption of paracetamol given 90 min after OCR administration but this was well before peak plasma morphine levels occurred. However, 30% of subjects had nausea after OCR morphine. Mean SITT in controls was 300 min (range 120-460 min) which was significantly prolonged in eight of the 10 subjects (P less than 0.05) and beyond the study period of 480 min in six subjects. Further study is required to determine how this compares with intramuscular morphine. Peak blood levels of morphine occurred at 3 h with a mean plasma concentration of 12.3 micrograms l-1 (SEM 2.0 micrograms l-1).     

PHARMACOKINETICS OF MORPHINE IN PATIENTS FOLLOWING ORTHOTOPIC LIVER TRANSPLANTATION

Plasma and urine concentrations of morphine, morphine-3-glucuronideand morphine-6-glucuronide were measured in seven patients afterorthotopic liver transplantation. After a single i.v. bolusof morphine sulphate 10 mg a biexponential decay was observed.Although the distribution and elimination half-lives for morphinewere similar to those described in previous studies, a greatertotal apparent volume of distribution was observed. This wasreflected in a greater plasma clearance of morphine than hasbeen reported previously. The concentration of morphine glucuronidesremained increased 24 h after administration of morphine; theclinical significance of this remains to be established. Themetabolism of morphine was virtually complete, with 4.5% unchangedmorphine recovered in urine 24 h after drug administration.     

Buccal Absorption of Fentanyl Is pH-Dependent in Dogs

Background: Analgesia and sedation have been achieved noninvasively by fentanyl administration through the oral and nasal mucosa. In theory, the transmucosal bioavailability and absorption of fentanyl could be improved by converting more fentanyl to the unionized form by adjusting the surrounding pH. The authors tested this hypothesis in dogs.

Methods: Under general anesthesia, each of six mongrel dogs was given fentanyl on repeated occasions, first intravenously (once), then by application to the buccal mucosa (six times). Buccal fentanyl administration was accomplished by placement of a pH-buffered solution of fentanyl into a specially constructed cell, which was clamped to the dog's buccal mucosa for 60 min. Fentanyl solutions with pHs of 6.6, 7.2, and 7.7 were studied to span a tenfold difference in the unionized fraction of fentanyl. Femoral arterial blood samples were sampled frequently and analyzed for fentanyl using a radioimmunoassay. Peak plasma concentration and the time of its occurrence for each buccal study were noted from the plasma concentration verses time profile. Terminal elimination half-life, bioavailability, and permeability coefficients were calculated using standard pharmacokinetic techniques.

Results: The variables peak plasma concentration, bioavailability, and permeability coefficient increased three-to fivefold as the pH of the fentanyl buccal solution increased and more fentanyl molecules became unionized. There was no difference in terminal elimination half-life after intravenous fentanyl (244 plus/minus 68 min) or buccal fentanyl administration (pH 7.7, 205 plus/minus 89 min; pH 7.2, 205 plus/minus 65 min; pH 6.6, 196 plus/minus 48 min). In all buccal studies regardless of pH, time to peak plasma concentration occurred within 10 min of removal of the fentanyl solutions from the buccal mucosa.     

Intrathecal morphine and heroin in humans: six-hour drug levels in spinal fluid and plasma

Lumbar spinal fluid and plasma concentrations of morphine were measured by radioimmunoassay after intrathecal administration of 1 mg of morphine (n = 13) or heroin (n = 10). Plasma levels of morphine were measured regardless of 'whether heroin or morphine was injected intrathecally, because of the rapid biotransformation of heroin to morphine in plasma. Significant drug concentrations appeared in plasma after intrathecal heroin (peak concentration 47.8 +/- 9.0 nmol/L, time to peak concentration 10 +/- 2.4 min); after intrathecal morphine plasma drug concentrations were significantly lower (8.1 +/- 1.0 nmol/L; P less than 0.002) and significantly later (216 +/- 39 min; P less than 0.002). Elimination half-life of heroin from spinal fluid (43 +/- 5 min) was significantly shorter than for morphine (73 +/- 5 min; P less than 0.02).