Treatment of cancer pain with transdermal fentanyl.

Pain is a feature of many cancers, particularly in the advanced stages at which the palliative care approach to symptom control achieves the best outcomes. The holistic approach generally dictates that any treatment of the cancer per se has symptom control as the primary objective at this advanced stage. Pain, which invariably increases with disease progression, is treated with opioids and adjuvant analgesic drugs together with physical therapies. Orally administered opioid drugs are used preferentially because of cost and convenience, but other routes of administration (subcutaneous, rectal, spinal) are also possible. More recently, transdermal fentanyl has been evaluated in the treatment of moderate to severe cancer pain. The rate of fentanyl absorption is constant (after a lag period), and the dose is altered by increasing or decreasing the area of skin covered by the patch (size and/or number of patches). The dosing interval for these systems is generally 3 days. The extent of pain relief provided by transdermal fentanyl and sustained release morphine formulations is similar, with quality-of-life instruments showing no consistent preference for either formulation. Open studies have suggested a lower risk of constipation. Transdermal fentanyl is effective in the treatment of severe cancer pain, particularly when the oral route is unavailable.

Sustained relief of chronic pain. Pharmacokinetics of sustained release morphine.

There are a number of modified release formulations of morphine with recommended dosage intervals of either 12 or 24 hours, including tablets (MS Contin, Oramorph SR), capsules (Kapanol, Skenan), suspension and suppositories. Orally administered solid dosage forms are most popular but significant differences exist in the resultant pharmacokinetics and bioequivalence status of morphine after both single doses and at steady state. Following single doses, the plasma morphine concentrations showed pronounced differences in the 0- to 12-hour period with a 4- to 5-fold difference in the mean peak concentration (Cmax) for morphine and the time to Cmax (tmax) The area under the concentration-time curve (AUC) from 0 to 24 hours for the 4 formulations show greater similarity. None of the formulations were shown to be bioequivalent according to US Food and Drug Administration (FDA) criteria. At steady state, fluctuations in plasma morphine concentrations throughout a 12-hour dosage interval were greatest for MS Contin and least for Kapanol. In fact, the relatively small fluctuations in plasma morphine concentrations following Kapanol administration suggested the same formulation could successfully be used with a 24-hour dosage interval. The pharmacokinetic parameters of morphine following Kapanol once daily were similar to MS Contin (12 hours) with the obvious exception of the longer tmax. There is also another once daily oral morphine preparation (MXL) which has been shown to be bioequivalent to Kapanol under fasting conditions only in a single dose study in volunteers. Food has been shown to have an effect on the pharmacokinetics of morphine following doses of immediate release solution and the modified release preparations. However, bioequivalence is generally maintained between the fed and fasting states for most preparations. MS Contin tablets have been administered rectally, but morphine pharmacokinetic parameters show greater variability compared with oral administration and the 2 routes are not bioequivalent. The results suggest a slower rate but greater extent of morphine adsorption. Somewhat similar results were obtained when Kapanol granules are administered rectally. The morphine pharmacokinetics following administration of a specifically formulated controlled release suppository showed less variability (rectal bioavailability was 42%). The pronounced differences in morphine pharmacokinetics between the various formulations are not translated into measurable differences in the pharmacodynamic effects of pain relief and adverse effects. The lack of bioequivalence between some of the formulations suggests that care should be exercised if physicians change modified release formulations as dosage adjustments may be necessary in some patients.

Interaction between dextromethorphan and norpethidine in rats.

With increasing interest in the application of dextromethorphan in pain control, it is probable that patients will receive this drug in combination with analgesics such as opioids, giving rise to the potential for previously unobserved drug interactions. The interaction between dextromethorphan, and its pharmacologically active metabolite dextrorphan, and norpethidine, a toxic metabolite of pethidine, was examined in rats. Rats were assigned to receive dextromethorphan (0, 20 or 40 mg/kg) or dextrorphan (0, 15 or 30 mg/kg) combined with norpethidine (0, 28 or 42 mg/kg). The occurrence of seizures, myoclonic jerks and shivering was recorded for 60 min after drug administration. Norpethidine produced dose-related increases in the incidence of seizures, myoclonic jerks and shivering. Dextromethorphan, but not dextrorphan, increased the incidence of these behaviours. It is recommended that extreme caution be exercised if dextromethorphan and pethidine are to be used together.

Development of tolerance to antinociceptive effects of an intrathecal morphine/clonidine combination in rats.

Previous animal studies have shown the antinociceptive effects of intrathecal clonidine and intrathecal morphine to be synergistic. This study investigated the intrathecal administration of multiple doses of this drug combination to examine the rate of development of tolerance and to determine whether there was any toxic effect on the spinal cord. Rats with indwelling intrathecal catheters were given saline, morphine (2.5-7.5 micrograms), clonidine (17.5 micrograms), or clonidine (17.5 micrograms) plus morphine (1 microgram) intrathecally twice daily for 4 1/2 days (total of 9 doses). Hot plate and tail flick tests were conducted after the first, fifth and ninth doses. After the ninth dose animals were killed and their spinal cords were removed for histological examination. Tolerance developed to the antinociceptive effects of the drug combination, but at a slower rate than to morphine alone. No evidence of toxicity or injury to the spinal cord was observed other than changes which could be ascribed to the presence of the catheter.

Behavioural effects of norpethidine, a metabolite of pethidine, in rats.

This study investigated behavioural effects of the toxic pethidine metabolite, norpethidine, in rats and its interactions with reserpine, apomorphine and physostigmine. Following intraperitoneal administration, brain concentrations of norpethidine reached a plateau after 20-40 min and remained elevated for 2 h. In the dose range 0.06-0.18 mmol/kg, norpethidine induced myoclonic jerks, a characteristic splayed posture, and episodes of exaggerated shivering. Forward locomotion, grooming, yawning and rearing were suppressed. Seizures and reverse locomotion occurred occasionally. Administration of reserpine 1 h prior to norpethidine, or of apomorphine or physostigmine 15 min after norpethidine, did not alter the norpethidine-induced behaviours; neither did norpethidine block the effects of apomorphine or physostigmine. The characteristic profile of behaviours induced by norpethidine make this toxicant readily amenable to animal studies. Our results indicate that its mechanism of action is unlikely to involve dopaminergic or cholinergic pathways.

Pharmacological management of chronic pain: a clinician's perspective.

Of the currently available mu agonist drugs, the following are relatively contraindicated: 1. Methadone--unpredictable duration of action [5]. 2. Pethidine--unwanted central effects, metabolised to an active metabolite and too short acting. 3. Codeine--too weak and with constipating side-effects. 4. Fentanyl--too short acting. 5. Oxycodone--too short acting although suppositories may overcome some theoretical disadvantages. 6. Dextropropoxyphene--weak agonist which is possibly metabolised to a cardiotoxic metabolite [6]. Morphine remains the drug of choice for chronic pain when administered in a sustained release preparation. MS Contin, a slow release oral formulation of morphine, is available and has a predictable duration of action lasting from 8-12 h, while improved formulations are about to be released in the near future in some countries. Prescribers need to take into account the relatively poor oral bioavailability of morphine when calculating the daily morphine dose.

The reproducibility of bioavailability of oral morphine from solution under fed and fasted conditions.

The reproducibility in bioavailability of orally administered morphine (as a solution) under fed and fasted conditions was studied in 5 patients with chronic pain on three occasions over 1 yr (0, 6, and 12 mo). During each study period (i.e.. 0, 6, and 12 mo), patients received the 50 mg oral dose both in the fasted state (10 hr since food) and immediately after a high fat content breakfast, in randomly determined sequence. Frequent blood samples were collected for 10 hr after the dose. There was no significant difference in the maximum blood morphine concentration (Cmax) or the time to Cmax among the three study periods or between the fed and fasted states. Bioavailability, as assessed by log(AUC), was significantly greater in the fed compared to the fasted state (P less than .01) but did not differ over the three study periods (Two-factor analysis of variance). Intrapatient variability contributed 32% and 54% to total variation in log(AUC) under fed and fasted conditions, respectively.

Assessment of antinociceptive drug effects in the presence of impaired motor performance.

The hot-plate (HP) and tail-flick (TF) tests are widely used to assess analgesic activity of drugs. These tests do not directly measure the intensity of the noxious stimulus perceived by the animal, but only the animal's response to it, and so may be affected by non-analgesic drugs. Sedatives and muscle relaxants, for example, may impair the ability to respond and hence be wrongly considered to have analgesic activity. We examined response of rats in the HP (55 degrees C, cutoff time 25 sec) and TF (cutoff time 5 sec) tests following administration of pentobarbitone, diazepam or pancuronium. These drugs all impaired motor performance as assessed by reduction in mean rotarod performance times to 6-32% of predrug values. However, HP and TF latencies were not appreciably prolonged. We also found that pancuronium did not alter effects of morphine on HP or TF latencies, despite reduction in rotarod performance to 38% of predrug values. Our results support the validity of HP and TF tests as analgesic assays even in the presence of substantial impairment of motor performance.

Stability of fentanyl citrate in glass and plastic containers and in a patient-controlled delivery system.

This study determined the stability of fentanyl citrate stored in glass or polyvinyl chloride containers and the concentrations of fentanyl citrate delivered by the Janssen on-demand analgesic computer (ODAC) system. Solutions containing 500 micrograms of fentanyl citrate (10 mL) were added to 100-mL three glass containers each of 5% dextrose injection or 0.9% sodium chloride injection and to three 100-mL polyvinyl chloride containers of 5% dextrose injection or 0.9% sodium chloride injection. All containers were stored under usual light conditions and at room temperature. Samples were taken immediately and at 0.25, 0.5, 1, 6, 12, 24, 36, and 48 hours. To determine the concentration of fentanyl delivered via the ODAC system, fentanyl citrate injection 2500 micrograms (50 mL) was added to a 500-mL polyvinyl chloride bag containing 5% dextrose injection. The solution was connected to the ODAC system, and samples of bolus demand doses were collected at various times during a 30-hour period. All the samples were assayed by a stability-indicating gas-liquid chromatographic method. For both glass and plastic containers, the mean +/- S.D. recovery of fentanyl after 48 hours was 98.6 +/- 2.3% when the drug was diluted in 5% dextrose injection and 97 +/- 1.5% when the drug was diluted in 0.9% sodium chloride injection. There was no significant difference between the amount of fentanyl recovered from glass containers and the amount recovered from polyvinyl chloride containers. Nor was there any significant difference between the amount of fentanyl recovered from solutions containing 5% dextrose injection and the amount recovered from solutions containing 0.9% sodium chloride injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of a high-fat meal on the absorption of morphine from oral solutions.

The influence of a high-fat meal on blood morphine concentrations after the administration of a morphine solution (50 mg dose) was studied in 12 patients with chronic pain. The oral morphine dose was administered in a total volume of 200 ml to patients either immediately after food intake or while in the fasting state. There was a 34% increase in the area under the curve (AUC) when morphine was administered immediately after food when compared with the fasting state (p less than 0.02). However, there was no significant difference between the maximum blood morphine concentration (Cmax) or the time to maximum concentration (tmax) between the two treatment regimens. The shape of the blood morphine concentration-time curve was consistently altered in the fed patients compared with patients who were in the fasting state, inasmuch as the blood morphine concentrations were maintained at a higher level from 240 to 600 minutes after the dose when the morphine was administered with food (p less than 0.02). It is suggested that morphine concentrations are maintained at higher levels, possibly resulting in more prolonged pain relief, when morphine is administered with food compared with the same dose administered to patients who are in the fasting state.

Halothane induced hepatic necrosis in rats: the role of in vivo lipid peroxidation.

Hepatic damage was induced in phenobarbitone pretreated male Fischer 344 rats by the administration of 1% halothane in 14% oxygen for either 1 or 2 hours. Ethane production during the exposure period was not significantly different between the halothane and non-halothane exposed groups. Animals were sacrificed 1, 2, 6 and 24 hrs from commencement of anaesthesia and the hepatic microsomal fraction analyzed for diene conjugates, lipid hydroperoxides, total lipid content and fatty acid composition. Animals exposed to halothane and sacrificed at 2 and 24 hrs had significantly elevated levels of diene conjugates (P less than 0.05), while lipid hydroperoxide concentration and serum alanine aminotransferase increased in only those animals sacrificed at 24 hrs. Alterations in total lipid content and hepatic microsomal fatty acid composition were not observed in animals sacrificed after 1 and 2 hrs. A significant reduction in total lipid and arachidonic acid content occurred only in those animals sacrificed 24 hrs after exposure, however a concomitant increase in the saturated fatty acid fraction was not observed. It is proposed that alterations in fatty acid composition in vivo and evidence of lipid peroxidation occur as a result of cell death rather than an initiating event in halothane induced hepatic necrosis in rats.

Fentanyl blood concentration-analgesic response relationship in the treatment of postoperative pain.

The inter- and intrasubject variability in blood concentration-analgesic response relationship for fentanyl were investigated using the technique of patient-controlled analgesia (PCA) in 30 consenting patients scheduled for surgical procedures involving an abdominal incision (15 upper and 15 lower abdominal incisions). All patients had a thiopental, nitrous oxide/oxygen, pancuronium anesthetic with 200 microgram fentanyl intraoperatively. Postoperative pain relief was provided with fentanyl from a Janssen On-Demand Analgesic Computer (ODAC) set to provide a basal infusion rate of 20 microgram/hr, a bolus "demand" dose of 20 microgram, and a lockout period of 5 minutes. Frequent blood samples were collected immediately before patients demanded doses, and these were taken as an estimate of the minimum effective concentration (MEC). A mean of 22 samples (range 12 to 45) were collected per patient over a mean study duration of 50 hours (range 24 to 72). The patients required larger hourly fentanyl doses in the first 6-hour period (83.9 +/- 30.1 microgram/hr) than in any other 6-hour period (mean values varied from 37.3 to 63 microgram/hr). The mean (+/- SD) hourly fentanyl dose rate and total cumulative dose were 55.8 +/- 22 microgram/hr (range 28.8 to 136 microgram/hr) and 2739 +/- 1191 microgram (range 900 to 6260 microgram), respectively. The mean (+/- SD) MEC was 0.63 +/- 0.25 ng/ml (five-fold range from 0.23 to 1.18) and the mean intrapatient coefficient of variation in MEC was 30.2% (range 16 to 46%). The MEC values remained relatively constant in all patients over the 48-hour study period.(ABSTRACT TRUNCATED AT 250 WORDS)

Sensitive gas liquid chromatography method for the determination of fentanyl concentrations in blood.

A method for the determination of fentanyl blood concentrations using gas liquid chromatography coupled to a nitrogen phosphorus detector (NPD) is presented. A highly inert fused-silica, megabore column coated with a methyl silicone stationary phase was used for the analysis. The mean coefficient of variation for the range of fentanyl concentrations tested (0.25-10 ng/ml) was 4.65%, ranging from 0.85% at 10 ng/ml to 10.8% at 0.25 ng/ml. The assay was used to quantify blood fentanyl concentrations collected from a 56-year-old woman who was administered fentanyl postoperatively via a patient-controlled on-demand analgesic computer (ODAC). The mean hourly fentanyl dose rate over the 44 hr study period was 41.8 micrograms/hr (range 20-120). The sixfold variation in hourly dose rate was not mirrored by similar fluctuations in the fentanyl blood concentration (mean 0.45 ng/ml, range 0.3-0.7 ng/ml). The patient thus titrated herself to a perceived minimum effective concentration (MEC) of fentanyl.

Halothane hepatitis in an animal model: time course of hepatic damage.

The present study extends previous reports of hepatic damage 24 h after halothane anaesthesia in the phenobarbitone pretreated hypoxic rat model by fully characterizing the lesion during the time course of its onset and recovery. Phenobarbitone treated animals exposed to halothane (1% for 2 h in 14% inspired oxygen) were killed 1, 2, 4, 6, 12 and 24 h and 2, 3, 5, 10, 15 and 30 days after commencement of the anaesthetic period. Blood was collected 1 day before the administration of halothane and at the time of killing for determination of serum alanine aminotransferase (ALT), a biochemical index of hepatic damage. Liver tissue was obtained immediately at post-mortem for histological examination. Serum ALT was increased at the end of the anaesthetic period, i.e. 2 h, with peak levels occurring at 12-24 h and remaining elevated for 3 days after exposure. Minor changes in liver histology were evident at 2 h in 50% of the animals and by 6 h all animals had mild hepatic injury. The extent of the necrosis was maximal at 24 h and this was sustained until 3 days. By 5 days after exposure minimal evidence of liver damage was observed and animals killed at 30 days had morphologically normal livers. Elevation of serum ALT or changes in liver histology were not observed in other treatment groups. The early onset of damage at 2-6 h is in keeping with direct hepatotoxicity associated with the biotransformation of halothane.

A randomized prospective controlled study of the metabolism and hepatotoxicity of halothane in humans.

In a randomized prospective controlled study in humans, the metabolism and hepatic effects of a single administration of halothane were compared with enflurane and meperidine. Pre- and postoperative antipyrine pharmacokinetics, intraoperative indocyanine green clearance, liver histology, and postoperative liver function tests were determined in 24 patients undergoing abdominal surgery who were randomly allocated to receive either halothane (0.5%, group I), enflurane (0.8%, group II), or meperidine (group III) as a supplement to a common basal anesthetic regimen consisting of thiopental, nitrous oxide/oxygen/muscle relaxant. In addition, end-tidal concentrations of the volatile reductive metabolites of halothane, chlorodifluoroethylene (CDF), and chlorotrifluoroethane (CTF) were determined in group I patients and serum and urinary inorganic fluoride were determined in both group I and II patients. Indocyanine green clearance was measured before anesthesia (stage I), during basal anesthesia (stage II), in the presence of surgical stimuli (stage III), and after introduction of the selected anesthetic agent (stage IV). CDF and CTF were detectable within 20 min of the start of halothane anesthesia in every patient receiving halothane. Peak serum fluoride concentrations occurred at 2 and 24 hr in the enflurane and halothane groups, respectively, whereas urinary fluoride excretion was elevated postanesthesia in the enflurane group only. There was no difference between the pre- and postoperative disposition of antipyrine in group II or III, but after anesthesia, antipyrine clearance was significantly decreased (P less than 0.02) and plasma half-life increased (P less than 0.05) in group I patients (halothane). Concentrations of serum alanine aminotransferase (ALT) and bilirubin were significantly elevated (P less than 0.5) postoperatively in groups I and II but unchanged from preoperative values in group III patients. Three of the 24 liver biopsies taken at the end of stage IV showed several foci of acute liver cell necrosis; of these, two patients were from group I and one from group II. There were no significant differences in liver cell morphology (P greater than 0.5) in biopsies taken at the end of stage IV compared with biopsies at the end of stage III, from groups I and II. The results of this study show that reductive metabolism of halothane occurs routinely in patients undergoing halothane anesthesia under conditions of normoxia. This may be the cause of the changes in antipyrine clearance after halothane anesthesia.

Changes in rat hepatic microsomal mixed function oxidase activity following exposure to halothane under various oxygen concentrations.

This study demonstrates that the exposure of phenobarbitone-treated rats to halothane at an oxygen concentration of either 10% or 14% results in marked decreases in cytochrome P-450 content and aminopyrine demethylase activity in animals sacrificed from 1 to 48 hr post-exposure. The alterations observed in the hepatic mixed function oxidase system were accompanied by increases in serum alanine aminotransferase (ALT), ornithine carbamyl transferase (OCT) and changes in liver pathology. However, the minor changes in cytochrome P-450 content and aminopyrine demethylase activity observed following exposure of enzyme-induced rats to halothane under normoxic conditions (i.e. 21% oxygen) were not of a sufficient magnitude to lead to hepatic cell necrosis. Halothane administration in the absence of phenobarbitone pretreatment (i.e. 21% oxygen) or during hypoxia alone (i.e. either 10% or 14% oxygen) did not result in any systematic changes in the parameters assayed. The results suggest that cytochrome P-450 may catalyse its own inactivation by virtue of greater free radical production under conditions which favour the non-oxygen dependent metabolism of halothane. The impairment in microsomal function as evidenced by decreases in cytochrome P-450 and aminopyrine demethylase activity are considered to occur as a primary consequence of the reductive metabolism of halothane. Data are presented which support the concept of the initiation of hepatic damage occurring during the period of anaesthesia with halothane.