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Opioids - Clinical Pharmacology




G. Andersen*. L L Christrup', P. Sjogrcn, S H Hansen*', N-H. Jensen, Miiltidisciplinary Pain Centre, Herlev Univ Hospital, 2730 Herlev, DK. ' The Royal Danish School of Pharmacy, Copenhagen, DK

Aim of study: To evaluate a possible relationship between the level of morphine (M), its metabolites morphinc-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) and pharmacodynamics such as pain score and sedation.

Material and methods: Twenty-eight cancer patients with advanced cancer, normal renal function and in continuous treatment with stable doses of slow-release morphine tablets for at least 3 days participated. Pain and sedation was evaluated by visual analogue scale and along with blood samples obtained on average 304 minutes (range 180-450 min) after the latest ingestion of slow-release morphine. The plasma levels ofM, M-3-G and M-6-G were determined by HPLC.

Results: Daily doses of slow-release morphine ranged from 40 to 660 mg, mean 170mg, median 90 mg and demonstrated a moderate but significant correlation with plasma M (r=0.588, p=0.002) and a highly significant correlation with plasma M-3-G (r=0.902, p<0.001) and M-6-G (r=0.927, pO.001). No linear relationship was found between plasma M, plasma M-6-G and pain score or sedation.

Conclusion: In cancer patients in chronic treatment with stable doses of slow-release morphine no relationship between plasma M, plasma M-6-G and pain score was seen. This could be expected in these patients, who are aimed at being constantly sufficiently palliated and whose dose of slow-release morphine consequently will be changed according to their needs. The cause of sedation is most often multifactorial in cancer patients, and no relationship was found between plasma M, plasma M-6-G and sedation. A significant correlation is shown between daily dose of slow-release morphine and plasma M, M-3-G and M-6-G.


Muhammad Ather*. Wolfgang Hamann, Pierluigi di Vadi8, Fand Salam, GKT Dept of Anaesthetics, Guy's Hospital, London SE1 9RT, UK and ^Dept of Anaesthetics, Univ Hospital Lewisham, London SE13 7HL, UK

Aim of Investigation: To test the hypothesis that the ultra-short acting opioid remifentanil permits discrimination between µ;-receptor sensitive and insensitive pain.

Methods: Patient A suffered from phantom-limb pain partially controlled by gabapentin and stump pain following below elbow amputation. Patient B experienced pain because of severe type 1 complex regional pain syndrome. Both patients received iv infusions of saline for 20 min followed by remifentanil at the rate of 0.025 mcg/kg/min for 20 min which was doubled every 20 min upto an endpoint of 0.4 mcg/kg/min (total duration 1 hr 40 min). Intensity of rest and evoked pain and distress were rated by patients using the visual analogue scale (VAS range 0: no pain; 10: worst pain). Patients' monitoring consisted of ECG, pulse oximetry, blood pressure (NIBP), respiratory rate and level ofdrowsiness on VAS (0: fully alert; 10: asleep).

Results: Seventy of stump pain in patient A decreased directly in proportion to the amount infused from level 8 down to 1, whilst the phantom limb pain was not affected at all, staying constant at VAS3. Similarly there was no effect on pain scores of patient B, which remained at level 9. Both patients became drowsy at higher dosage rate and their respiratory rate decreased. There was no change in heart rate or NIBP. Both patients recovered fully within 30 min.

Conclusions: In a safe, fast and convenient way, infusion with remifentanil discriminates between opioid sensitivity in neuro-pathic and nociceptive pain conditions in a way previously observed with oral morphine.


Iwona W. Beczkowska. and Robert F. Kaiko, Purdue Pharma, LP, CT,USA

Aim of Investigation: OxyContin* and MS Contin* are two con-trolled-release oral opioid analgesics formulated in two different release matrices, AcroContin and Contin, respectively. There are no direct comparative pharmacokmctic studies examining the differences and similarities between these two products. The aim of this analysis was to compare pharmacokinetic profiles ofOxyCon-tin (20 mg) and MS Contin (30 mg) tablets.

Methods: Data from six independent studies performed in fasting, normal, healthy, male volunteers who were administered either a single 20-mg dose ofOxyContin (total N=97) or a single 30-mg dose of MS Contin (total N=50) were analyzed. Serial blood samples were collected before and after dosing. Plasma oxycodonc and morphine concentrations were measured by gas chromatogra-phy/negative ion mass spectrometry technique. Apparent half-lives of absorption and elimination as well as C,max;, Tmax and AUCs were used to determine the pharmacokinetic profiles of the drugs.

Results: Average Tmax ofOxyContin was 2.73 (1.45) hours with an apparent half-life of absorption of 1.08 (0.73) hours and a half-life of elimination of 6.38 (1.93) hours. In contrast, average Tmax, of MS Contin was 2.06 (1.09) hours with a half-life of absorption of 0.87 (0.48) hours and a half-life of elimination of 2,80 (1.14) hours. Average Cmax ofOxyContin and MS Contin were 20.33 (6.34) and 15.05 (6.93) ng/mL respectively. The AUG(0, inf)of OxyContin and MS Contin were 198.18 (64.31) and 100.29 (37.83) h-ng/mL, and the AUC,o,ino w^e 20()-8 (67.63) and 103.81 (13.72) h-ng/mL, respectively.

Conclusions: The OxyContin release matrix compared favorably to the MS Contin matrix with OxyContin presenting more sustained plasma opioid concentrations.

Acknowledgments: Studies were sponsored by Purdue Pharma L.P.; the authors are employees of Purdue Pharma L.P.


A Bhattacharya. Anand Arora*, Ashok Kumar*, 0 P Tandon* (SPON: Dr. Swar Bal B), Depts of Pain Therapy & Physiology, Univ College of Medical Sciences, Delhi, India.

Aims of Investigation: To evaluate cognitive effects of morphine through epidural or intramuscular routes using clinicopsychologi-cal & event related evoked potential, to find out correlation between these objective & subjective tests and to determine the efficacy ofP 300 as an objective marker for cognitive effect of morphine.

Methods: 40 adults divided into two groups of 20 each. Group A received 2-mg morphine in 10 ml of .9% saline through lumber epidural catheter. Group B patients received .15 mg/Kg morphine IM. Clinicopsychological tests used -Vigilance score, sedation index, digit forward & digit backward tests (DFT & DBT). Event related potential (P300) recorded using SMP 4100 auditory stimu-lator and MEB 5200 evoked potential recorder. Data analyzed using F test, Tukey test & student's t test. 'p' < 0.05 was taken as significant.

Results: P 300 latency & amplitude - significantly increased in group B. Vigilance score, DFT & DBT scores reduced significantly in group B. Significant correlation between P 300 amplitude & vigilance score, DFT & DBT in group B only.

Conclusions: Extradurally administered morphine had less effect on cognitive functions compared to IM morphine. Subjective tests are not a reliable measure of cognitive state & P 300 wave ofERPS can be an objective marker for cognitive effects of morphine.


Robert G. Buice. Alessandra Cipriano, Joy Andrews (SPON: S. Dawis) Purdue Research Center, 99-101 Saw Mill River Rd, Yonkers.NY, 10701

Aim of Investigation: An ever-increasing interest in pediatric pharmacokinetics is evidenced by several recent regulatory documents, including a draft guidance and current literature indicates that opioid pharmacokinetic profiles in children often differ from those in adults. Accordingly, optimal pediatric use of OxyContin * should be based upon the pharmacokinetics of this drug in children.

Methods: Using a single-dose, two-way crossover approach, the pharmacokinetic metrics [peak and total exposure to oxycodone and two metabolites] of OxyContin* (1x1 Omg) controlled-release tablets were compared with those of oxycodone (lx5mg) immediate-release tablets in 10 pediatric patients (age 5 - 12yr). Following model-independent pharmacokinetic analysis, bioequivalence was assessed by comparison ofCmax (peak exposure) and AUC (total exposure) using analysis of variance. Confidence intervals (90%) were estimated around ratios (test/reference) of least squares means derived from logarithmic-transformed Cmax and AUC values.

Results: Dose-adjusted results indicated a lower Cmax [Ratio = 0.47 (90%CI = 0.38 to 0.57)] and an equivalent AUC [Ratio = 1.02 (90% CI = 0.83 to 1.25)] for OxyContin* While the Cmax and AUC of Ml were slightly lower and those ofM2 were measurably lower than oxycodone, treatment comparisons based upon evalu-able metabolite (Ml) data yielded similar results.

Conclusions: Total exposure to oxycodone was equivalent across treatments, although peak exposure to OxyContin was lower. Longer mean residence times following OxyContin* [8.17 1.62hr vs 4.14 1.33hr] were consistent with a very effective CR product.

Acknowledgments: Study sponsored by Purdue Pharma L.P.;authors are employees of Purdue Pharma L.P.


GE Cawley *, AJ Miller *, TP Nichols *, KA Sinclair * and KJ Smith. (SPON: M Fallon) Napp Pharmaceuticals, Science Park, Cambridge, CB4 4GW, UK

Aim of Investigation: To investigate the pharmacokinetics of oxycodone following administration of two new liquid preparations, 5 mg/5 ml and 10 mg/1 ml.

Methods: Twenty-four healthy volunteers were recruited into a three-part randomised crossover study. Volunteers received a single 10 mg dose of either oxycodone liquid (5 mg/5 ml), oxycodone concentrate (10 mg/1 ml) or a controlled release oxycodone tablet (OxyContin). Following administration, regular blood samples were taken for up to 32 hours and plasma samples were analysed for oxycodone using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were assessed using standard methods.

Results: Both liquid preparations provided an equivalent availability of oxycodone to the OxyContin reference. Mean systemic availabilities of 96% (90% CI 91-101%) and 97% (90% CI 92-103%) were provided by the liquid and concentrate respectively, relative to the OxyContin reference. The two new preparations provided equivalent plasma profiles with the concentrate providing a mean systemic availability of 102% (90% CI 96-108%) and mean C^ ratio of 112% (90% CI 102-122%) relative to the liquid preparation. As anticipated, the OxyContin tablet was associated with typical controlled-release characteristics, a lower Cmax, later t^ and longer apparent half-life than the immediate release preparations.

Conclusions: The provision of an equivalent availability of oxycodone will enable these new liquid preparations to supplement the range of controlled release OxyContin tablets. Where appropriate, they will provide rescue medication for breakthrough pain and enable titration to pain control.


M. Soledad Cepeda. John T. Farrar, Jairo H. Roa*, Ray Boston*, Quig Cheng Ming*, Franklin Ruiz, Daniel B. Carr", Brian Strom*. Depts of Anesthesia and Internal Medicine, Javeriana Univ, Bogota, Colombia and Center for Clinical Epidemiology and Biosta-tistics, Univ of Pennsylvania, Philadelphia; New England Medical Center, Boston.

Aim of the Investigation: To evaluate ethnic differences in response to morphine (M).

Methods: Young, male and healthy subjects from three ethnic groups (Caucasians (n=22). Native Indians (n=22) and Latinos (n=22)) received 0.08mg/kg of IV M followed by a 30 mm infusion of 0.002 mg/kg. To evaluate respiratory response, C02 re-breathing tests were performed before and 25, 95, 180 and 360 min after M administration. Opioid side effects were evaluated and blood sampled for analysis ofM, M3G and M6G at 0, 5, 15, 25, 35, 40, 50, 65, 95, 180, 240, 300 and 360 min after M administration. Analysis for repeated measures, logistic regression and Kruskal-Wallis test were performed.

Results: All ethnic groups had a similar blunted response to hyper-capnia. However, Caucasians were 3.1 times more likely to develop sedation than Latinos (95% CI 1.8- 5.2) and 2.6 times more likely than Native Indians (95% CI 1.6 - 4.3). M6G, and not serum M, was a predictor of sedation. For every ng of M6G the odds of sedation increased 5% (P=0.007). Caucasians had higher plasma levels of M6G. M6G area under the curve were: Native Indi-ans=77835128, Latinos=86393441 and Caucasians= 11914±4958 ng. min/ml (P=0.04, Kruskal-Wallis).

Conclusions: There are ethnic differences in response to morphine. Caucasians are more susceptible to sedation than Native Indians and Latinos. Pharmacodynamic differences can be explained by differences in glucuronidation. Levels of M6G, which is more potent than M, are higher in Caucasians.

Acknowledgment: Supported by USAID grant #5-35682 and N1H K08NS01865.


BA Coda. KL Syrjala, S Dikmen,* B Phillips,* L Risler,* DD Shen, Depts ofAnesthesiology, Rehabilitation Medicine, and Pharmaceutics, Univ of Washington, Seattle, WA 98195; Fred Hutchinson Cancer Research Center, Seattle, WA, 98104 USA

Aim of Investigation: We compared opioid-induced side effects between men and women during sustained equi-analgesic infusions of morphine and hydromorphone.

Methods: Eight normal volunteers (4 men, 4 women) gave informed consent and participated in this double-blind crossover study. A computer-controlled infusion pump used individual phar-macokinctics to achieve pre-selected target plasma concentrations for each opioid. On alternate study days, subjects received 4-hour infusions of morphine (target 35 ng/ml) and hydromorphone (target 4 ng/ml). Our pain model was electrical cutaneous stimulation delivered at an intensity which produced "strong pain" (continuous scale from 0 = no pain to 5 = strong pain). Subjects completed Somatic Side Effect (SSE) and Cognitive Side Effect (CSE) rating scales (each with several reliable subscales), as well as a battery of computer tests for psychomotor function. We measured balance, end-tidal CO;, 0; saturation, and pupil size and exophoria. This entire analgesia and multidimensional side effect test battery was administered before the opioid infusion, at 4 time points during infusion, and after the infusion was stopped. Frequent blood samples were obtained for plasma opioid concentration assay. Once equivalent analgesia with morphine and hydromorphone was confirmed, we pooled side effect data across opioids in order to compare differences between men and women.

Results: Analgesia was equivalent at the selected target morphine and hydromorphone plasma levels. After opioid infusions were stopped, analgesia tended to persist for a longer duration in women. Fine motor coordination was disrupted to a greater extent in women during and after opioid infusion. Women also experienced more opioid-induced nausea (a SSE subscale) and detachment (a CSE subscale), but no difference in sedation, respiratory, or pupil effects compared to men.

Conclusions: Preliminary data reveal striking gender differences in some, but not all, mu opioid-induced somatic, cognitive, and psychomotor side effects.

Acknowledgments; Supported by NCI (CA35582)


J. Desmeules. C. Violand*, V. Piguet, M. Kondo Oestreicher*, & P. Dayer, Multidisciplinary Pain Center, Clinical Pharmacology, Univ Hospital CH-1211 Geneva 14, Switzerland.

Aim of Investigation: The analgesia induced by tramadol (T) race-mate is thought to be related to the synergy of its enantiomers. The (+)-T is mainly responsible for the 4 opioid effect whereas both isomers exert some monoaminergic effects.

Methods: We investigated the effects of repeated ()-, (+)-, and (-)-T(100 mg orally/12h) in a randomized double-blind crossover and placebo (P) controlled study in healthy volunteers. Naloxone (nx 0.8 mg iv) antagonism was assessed. Antinociception was monitored for 36h by objective (R-III reflex) and subjective pain thresholds monitoring (Viking IV, Nicolet, Madison).

Results: After the first dose T gave nse to a significant and long lasting (> 8h) antinociception with a peak effect at ca. 3.5h. A major and cumulative increase in pain thresholds was observed with (+)-T. Racemic T and (-)-T exerted less analgesic effect, both of equal magnitude (p<0.01). nx induced a clear-cut reversal of(+)-T antinociception with signs of acute and shortlasting withdrawal.

Conclusion: These results are consistent with a tramadol opioid antinociceptive effect relying primarily on the contribution of the (+)-isomer. The (-)-tramadol also display antinociceptive effects of lesser magnitude than the (+)-isomer. The fact that 100 mg ()-T is analogue to 100 mg (-)-T suggests some kind of antagonism in these experimental conditions.


MK Erjavec. BA Coda, KL Syrjala, AS Jackson*, B Phillips*, L Risler*, DD Shen, Depts ofAnesthesiology and Pharmaceutics, Univ of Washington, Seattle, WA 98104; Fred Hutchinson Cancer Research Center, Seattle, WA, 98104 USA

Aim of Investigation: We evaluated the potential for paroxetine to modulate morphine's analgesic and side effects during acute, suba-cute and chronic paroxetine treatment.

Methods: Fourteen normal volunteers gave informed consent and participated in this double-blind study. Subjects took either placebo or paroxetine 30mg daily, and underwent 4 morphine infusion test days; once prior to paroxetine or placebo treatment, and again at days 2-3, 7-10, and 23-30 of treatment. Individual pharmacokinet-ics were determined on a pre-study day and used to program a computer-controlled infusion pump to achieve pre-selected morphine target levels. On each study day, subjects received a stepwise morphine infusion, aimed at plasma concentrations of 20 and 50 ng/ml, each maintained for 2 hours. We used electrical cutaneous stimulation of a finger across a range of current intensities to produce "very faint" to "strong" pain, and repeatedly determined stimulus-response curves, i.e., current versus subjective pain report. Subjects completed Somatic Side Effect, Cognitive Side Effect and Modified Profile of Mood States questionnaires for measurement of subjective side effects. Measurements of end-tidal CO;, O; saturation, and pupil size were also obtained. The analgesia and side effect test battery was administered each day before the morphine infusion, at both morphine levels and after the infusion was stopped. Frequent blood samples were obtained to measure morphine and paroxetine plasma concentrations.

Results: The stimulus-response curves were shifted to the right at baseline and at both morphine levels in the paroxetine group on days 7-10 and 23-30. Paroxetine produced minimal change in morphine-induced side effects, and did not affect morphine plasma levels.

Conclusions: Preliminary data suggest that co-administration of paroxetine increases morphine analgesia in the subacute and chronic setting. Paroxetine does not affect morphine pharmacoki-netics.

Acknowledgments: Supported by NIDA (DA05513)


E. Freye. L. Latasch*, Pain Center ofDiisseldorf, Univ Hospital Dusseldorf, Germany, *Inst. ofAnesthesiology, Nordwest Hospital, Frankfurt, Germany

Aim of Investigation: It is generally accepted that long term treatment of painful states with opioids results in constipation. This effect is related to the dose(s) being administered. No studies so far have quantitated whether this side-effect on oro-caecal transit is also seen after administration of controlled release dihydrocodeine (DHC). Additionally, no quantification on the pupillary effect of DHC has been reported and whether this effect is dose-related.

Methods: Following institutional approval by the local ethical committee and informed consent, 12 volunteers were given DHC (60, 120 mg) or placebo orally in a randomized, double-blind cross-over design. Oro-caecal transit time was assessed by means of pulmonary hydrogen based on the measurement of hydrogen that is produced in exhaled air when unabsorbable disaccharid (lactulose) is fermented by colonic bacteria. The time between ingestion of lactulose and a Mold rise in hydrogen in breath (ppm) represented oro-caecal transit time. The response of the pupil to light was quantified using an electronical pupillometer computing the constriction amplitude after light (mm) before and at peak effect of DHC (3 h).

Results: DHC at 60 and 120 mg induced a significant (p< 0.01) prolongation of oro-caecal transit to a mean of 80 and 90 min respectively when compared to placebo (57.9 min). DHC also induced a significant (p< 0.005) depression of the pupillary light reflex to 8.3 and 7.4 min respectively when compared to control (53.9 mm).There was no significant difference of transit times and pupillary reflex between both doses.

Discussion: Constipation is less after controlled release of high dose of DHC when compared to 100 mg of oral non-controlled release tramadol (mean transit 90.8 min), tildine/N (mean transit 129 min) and codeine (mean transit 135 m\n)(Schmerz 10, 254, 1996). The reason is probably due to the lesser amount of slow released DHC which binds to opioid receptors located in the plexus myentericus of the intestine and which block propulsion. This is in rapport with clinical findings where only 24.1% of patients complained of constipation following a 5 week ingestion of DHC.


Robert F. Kaiko and Iwona W. Beczkowska, Purdue Pharma, LP, CT,USA

Aim of Investigation: There are no direct comparative studies designed to determine the relative analgesic potency ofOxyContin and MS Contin tablets following multiple dose regimens. The aim of this analysis was to compare daily dosages of these two products in patients suffering from persistent non-malignant and cancer pain.

Methods: Combined data from independent studies pertaining to the daily dose requirement employing OxyContin to relieve non-malignant pain (four studies, total N=152) and malignant pain (four studies, total N=171) were compared with the combined data from the studies employing MS Contin (one study in non-malignant pain; total N=13; ten studies in malignant pain, total N=214). The non-malignant pain studies included subjects with stable chronic low back pain, osteoarthritis, postherpetic neuralgia, and musculo-skeletal and deafferentiation pain. The malignant pain studies included subjects with advanced cancer of the lung, breast, prostate, gastrointestinal, gynecologic, and other systems. Patients received multiple doses of the respective controlled-release opioid and were titrated to dosages that provided acceptable analgesia without unacceptable side effects.

Results: The average daily dose of OxyContin required to relieve non-malignant pain was 41.25 mg, and 101.5 mg to relieve malignant pain. In contrast, patients receiving MS Contin required a daily dose of 88 mg for relief of non-malignant pain and 216.5 mg for malignant pain.

Conclusions: Consistent with the results of single dose relative potency studies, OxyContin was twice as potent as MS Contin in relieving both non-malignant and malignant pain.

Acknowledgments: Studies were sponsored by Purdue Pharma L.P.; the authors are employees of Purdue Pharma L.P.


Jeffrey Lazar*. Alfred Tonelli*, Robert Kaiko (SPON: Ronald Fitzmartin), Purdue Pharma L.P., Norwalk, CT 06850-3590 USA

Aim of Investigation: To determine whether the 160 mg CR oxy-codone tablet was interchangeable with lower tablet strengths. Methods: The bioequi valence of one 160 mg, two 80 mg, and four 40 mg CR oxycodone (OxyContin) tablets was determined in this single-dose, 3-way crossover study in healthy male volunteers given naltrexone. Bioequivalence was determined from 90% confidence intervals (CI) estimated around the ratio (test/reference) of AUC, (area under the concentration-time curve from time=0 to last quantifiable concentration), AUCo-x, (AUC extrapolated to infinity), and Cmax (maximum plasma concentration).

Results: 26 men aged 23-45 years were enrolled. All 90% CI fell within the range of 80% and 125%, indicating that one 160 mg tablet is bioequivalent to two 80 mg tablets and four 40 mg tablets in terms of both extent of absorption (AUC) and maximum absorption (Cmax):

Ratio (Tex/Reference) and 90% CI

Metric Ratio



Ratio 90%
(%)" CI
















Ratio of least squares means aenveo irom logamnmic iransiormea values. ''90% CI around least squares mean ratio. Adverse events were abdominal pain, headache, and nausea; 1 subject discontinued for headache and flatus.

Conclusions: The 160 mg CR oxycodone tablet can be substituted for multiple tablets of lower strength on a mg-for-mg basis in order to facilitate dosing in opioid-tolerant patients who require daily doses of 320 mg or more.

Acknowledgments: Study sponsored by Purdue Pharma L.P.; the authors are employees of Purdue Pharma L.P.


R.N. Lebcdeva. V.V. Nikoda, Russian Research Centre of Surgery, RAMS, Moscow

Aim of Investigation: To investigate the analgesic efficacy and side effects of tramadol retard (TR) in postoperative patients.

Methods: To evaluate in 30 patients (female/male - 21/9, average -502,5yrs) the pain syndrome moderate or severe intensity, a 10-score VAS has been used before and after the first single 100 mg dose ofTR. A total daily dose was 400 mg. There were registered the patients who required more strong analgesics. Adverse events during pain treatment ofTR (3-10 day) were assessed. Exclusion criteria: hypersensitivity; drug abuse; cardiac or respiratory failure; patients refused to participate in research.

Results: TR 100 mg reduced the pain after single dose in 22 (73%) patients. The average daily dose was 33119 mg. The average time of pain relief was 8,2+0,3 hr. More strong analgesics were required in 10 (34%) patients. The only one patient refused TR by the reason of ineffectiveness. TR was well tolerated in 28 (93%) patients. BP, HR, pulsoxymetry were stable for whole time of investigation. The most frequent adverse effects were nausea and vomiting, which took place in 3 (10%) pts.; two of them has stopped to take it because of the reason.

Conclusion: Tramadol retard provided adequate analgesia in most postoperative patients and was well tolerated by them. Adverse effects were not clinically significant.


Thomas List3. Ake Tegelberg^ Torgny Haraldsson', Goran Isacsson'1, "TMD Unit, Specialist Centre for Oral Rehabilitation, 58185 Linkoping, Sweden.b Dept ofStomatognathic Physiology, 72189 Vasteras, Sweden. 'Dept ofStomatognathic Physiology, 50182 Boras, Sweden. ''Astra Pain Control, 15185 Sodertalje, Sweden

Aim of Investigation: To determine the analgesic effect after a single dose intra-articular injection of 0.1 or 1.0 mg morphine-HCL in patients with TMJ nonspecific arthralgia/osteoarthritis.

Methods: This was a randomized, multicenter, double blind, parallel group study in 54 patients with chronic TMJ pain. The patients were seen on three occasions at the clinic: a first visit comprising screening and diagnosis; a second visit with randomization, assessment, and treatment, and a third visit as a 7-day follow-up. The assessment comprised pain intensity measures using the visual analog scale (VAS) when the jaw was at rest and at maximal opening, consumption of analgesics, pressure pain threshold, man-dibular range of motion, and adverse events. The patients were randomized to receive a 1 ml intra-articular injection of either 1.0 mg morphine-HCl, 0.1 mg morphine-HCL or physiologic saline in the TMJ.

Results: At follow-up the VAS value at maximal opening was significantly lower for the 0.1 mg morphine group compared with both the 1.0 mg morphine group (p<0.04) and placebo group (p<0.02). Although the VAS value difference between the groups was statistically significant the difference was not clinically relevant. With the jaw at rest a significantly lower VAS value was found for the 0.1 mg morphine group compared with the 1.0 mg morphine group, but not compared with the placebo group. No significant difference between the three groups was found in the range ofmandibular movements, i.e., opening with and without pain, laterotrusion, and protrusion. The incidence of adverse events and did not differ between the treatment groups.

Conclusions: A dose ofO.lmg morphine-HCL significantly reduced the pain intensity during maximal opening of the jaw, but this reduction was not clinically relevant.


Gerd Mikus. Oliver von Richter, Ute Hofmann, Michel Eichel-baum, Dr. Margarete Fischer-Bosch (SPON: U Brennscheidt), In-stitut fur Klinische Pharmakologie, 70376 Stuttgart, Germany

Aim of Investigation: To investigate morphine-3-(M3G) and mor-phine-6-glucuronidation (M6G) kinetics in human liver and small intestine and to identify possible inhibitors.

Methods: Liver and isolated enterocyte homogenates from 4 patients were incubated using morphine concentrations from 0.5-20000 u.m. M3G and M6G were determined using a highly sensitive LC/MS method with an LOQ of 1 pmol for M3G and 0.2 pmol for M6G respectively.

Results: M3G data were best fitted with a one enzyme model in liver and intestine (liver: km: 1,95 mM 0,19; Cljn^ 26,3 ul/mg/h 5, intestine: km: 2,0 mM 0,09; Clin^ I6,3 ul/mg/h 1,4). Formation of M6G in liver exhibited biphasic kinetics with a low affinity component (km: 1,09 mM 0,16; Cljnt: 10,4 ul/mg/h 1,86) and a high affinity component (km: 17 uM 15; Clint: 3,7 ul/mg/h 2,9) whereas M6G formation in the intestine was best fitted as monophasic Michaelis Menten kinetics (km: 1,55 mM 0,09; Cljnt: 2,7 ul/mg/h 0,3). M3G/M6G ratio in liver was 3:1 and in intestine 7:1. Inhibition studies showed strong inhibition of M3- and M6-glucuronidation with propafenone, diclofenac, dex-tromethorphan and naringenin. Ki values for diclo-fenac were (M3G/M6G: 18 uM) and for naringenin (M3G: 5 uM/ M6G: 14 uM). Both inhibitions follow a competitive mechanism. For dex-tro-meth orphan a non-competitive inhibition was observed (Ki:10 uM (M3G)/ 71 uM (M6G). None of the inhibitors tested showed selectivity for either inhibition of M3G or M6G. Conclusions: Morphine is glucuronidated in considerable amounts in the human intestine. The different ratios of M3G/M6G in liver and intestine suggest the involvement of different UDP-glucuronosyl-transferases (UGTs) in the formation of the two me-tabolites in both organs. Further studies to identify the high affinity component for M6-glucuronidation in liver have to be earned out. The data on diclofenac and naringenin inhibition are suggestive for potential drug-drug and drug-food interactions with morphine.

Acknowledgments: This study was supported by the Robert Bosch Foundation, Stuttgart, Germany


TP Nichols*, GE Cawley*, AJ Miller, KJ Smith. KA Sinclair*, (SPON: CJ McDonald), Napp Pharmaceuticals, Science Park, Cambridge, CB4 4GW, UK

Aim of Investigation: Two studies were undertaken to investigate the pharmacokinetics ofoxycodone following administration of three new capsule preparations, 5 mg, 10 mg and 20 mg.

Methods: Twenty-four healthy volunteers were recruited into each randomised crossover study. In Study 1, volunteers received a single dose of each capsule strength or a liquid preparation (5 mg/5 ml, 10 mg) on separate occasions. In Study 2 volunteers received either the 10 mg capsule or a controlled release (OxyContin) tablet 10 mg. Following administration, regular blood samples were taken for up to 32 hours and plasma samples were analysed for oxycodone using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were assessed using standard methods.

Results: In Study 1, each strength of capsule provided dose-proportional plasma profiles. Relative to the 5 mg reference, mean systemic availabilities of 99% (90 CI 95-104%) and 103% (90% CI 98-108%) were provided by the 10 mg and 20 mg capsules respectively. The peak concentrations also increased in line with increasing dosage strength. The 10 mg capsule was bioequivalent to the 10 mg liquid reference with a mean systemic availability of 96% (90% CI 92-101%) and mean Cn,ax ratio of 96% (90% CI 85-109%). In Study 2, the 10 mg capsule provided a mean availability of 94% (90% CI 89-98%) relative to the OxyContin reference which was associated with typical controlled release characteristics of a lower C^, later i^ and a longer apparent half life.

Conclusions: The provision of an equivalent availability ofoxycodone to OxyContin and the dose-proportionality of the range of capsule strengths suggest that these new capsules will supplement the range of controlled release OxyContin tablets. Where appropriate, they will enable titration to pain control with a NR preparation and provide rescue medication for breakthrough pain.


Sue Peat. M Hanna, T Durcan, M Fung*, Pain Relief Research Unit, Kings College Hospital, London SE5 9RS

Aims of Investigation: To investigate the pharmacokinetic and clinical profile of morphine 6 gluciironide (M6G) administered via a patient controlled analgesia (PCA) system.

Methods: M6G was given post hysterectomy at four dosage levels using a single blind, parallel design. Loading and bolus doses were: Group 1: 4mg+lmg. Group 2: 6mg+2mg, Group 3: 7.5mg+3mg, Group 4: 9mg+6mg. Nausea, vomiting, sedation, cardiorespiratory parameters and pain (11 point rating scale) were assessed before and frequently after M6G administration. Pain intensity difference (PID) wrt baseline was calculated. Plasma was sampled for M6G, morphine and morphine 3 glucuronide (M3G) prior to each PCA demand, and the mean minimum and maximum values determined.

Results: Twenty four patients were included, (6 per group). Three patents withdrew (2 inefficacy, 1 on request). The total mean doses demanded were 13.3(9-20)mg, 31.6(24-46)mg, 47.5(34.5-67.5)mg, over 4hrs for groups 1-3 respectively, and 112 (75-153)mg over 6hrs for group 4. Mean PID for groups 1-4 respectively were 0.33, 0, 1.5, and 4.8. In group 4 there was a clear reduction in PID over time. No clinically significant cardiorespiratory depression or sedation occurred. Only two patients reported nausea attributable to M6G. Morphine and M3G were not detected. Minimum and maximum mean (range) ng/ml M6G concentrations found were 492(156-845), and 1,885(334-5,628) respectively.

Conclusions: M6G is well tolerated when given post hysterectomy via PCA in the doses used. The results indicate a dose response relationship for analgesia, a lower than expected incidence of post operative nausea and vomiting and an acceptable safety profile. The dose requirement and plasma levels vary widely, and suggest that the mean minimum plasma level for analgesia in post operative pain is in the order of 500 - 1,800 ng/ml. Acknowledgment: Supported by Nycomed.


J.L. Plummer. K.D. Tran*, G.K. Gourlay, Pain Management Unit, Flinders Medical Centre, Bedford Park, SA 5042, Australia

Aim of Investigation: Our Unit provides a service for measurement of blood norpethidine concentrations to medical practitioners. This study aimed to determine the distribution of blood norpethidine concentrations and the types of toxic systems encountered.

Methods: We reviewed our data files for the period March 1984 to December 1998. Reasons for referral, blood norpethidine concentrations and reported toxic symptoms were recorded.

Results: 405 samples, from 256 patients, were assayed for norpethidine. Referral was typically due to suspected toxicity or high pethidine use. Blood norpethidine concentrations ranged from 0 (85 samples) to over 2100 ng/ml (10 samples). Samples from patients not reported as having toxic symptoms (315 samples, 182 patients) had a median blood norpethidine concentration of 224 (interquartile range 0-577) ng/ml. Those from patients (42 samples, 32 patients) reported as having mild symptoms (eg. myo-clonic jerks, agitation) had a median concentration of 496 (137-840) ng/ml, while samples from patients who had had seizures (48 samples, 42 patients) had a median of 754 (261-1312) ng/ml. Five patients had blood norpethidine concentrations above 2100 ng/ml, but were not reported as having any symptoms of toxicity. In a patient in whom samples were collected over 54 hr, the elimination half-life of norpethidine was 18 hr. In a second patient, who had renal failure and was on dialysis, the half-life was 53 hr.

Conclusions: While these results are consistent with increasing blood norpethidine concentration being associated with more severe symptoms, it is notable that there is great individual variation in response to norpethidine.


Soren H. Sindrup. Claus Madsen*, Kirn Broscn*, Troels Jensen, Depts of Neurology, Odense and Aarhus Univ Hospitals and Dept of Clinical Pharmacology, Odense Univ, DK-5000 Odense C, Denmark

Aim of Investigation: To investigate the relationship between relief of pain and serum concentrations oftramadol and its metabolite Ml in tramadol treatment of painful polyneuropathy.

Methods: In a randomised, double-blind, placebo-controlled trial of slow release tramadol 200-400 mg/day in patients with painful polyneuropathy, blood samples for drug level measurements were obtained in 28 out of 34 patients. Serum concentrations were determined by gas chromatography. On-going and touch-evoked pain was rated daily by the patients by use of 0-10 point numeric rating scales during two 4-week treatment periods. Results: Tramadol significantly reduced both on-going (p = 0.002) and touch-evoked pain (p < 0.001). There was no relation between relief of on-going and touch-evoked pain and serum concentrations of(+)-tramadol,(-)-tramadol,(+)-Ml or(-)-Ml (p = 0.11-0.89). Seventeen of the patients were categorised as responders for on-going pain and 16 for touch-evoked pain, i.e. they had a placebo-corrected reduction in pain score of at least 10%. Responders for on-going pain tended to have higher serum concentrations of (+)-M1 than non-responders (median 27.4 nM vs 16.6 nM, p = 0.08). Isobulograms showed that the fraction of non-responders was higher among patients with low concentrations of both tramadol and (+)-M1 both for on-going (p = 0.009) and touch-evoked (p = 0.02) pain.

Conclusion: The opioid effect of Ml may be of major importance for tramadol relief of on-going neuropathic pain, but in general relief of neuropathic pain seems to depend on both the mono-aminergic effect oftramadol itself and the opioid effect of Ml.


KJ Smith. AJ Miller, TP Nichols*, KA Sinclair* and GE Cawlcy*, Napp Pharmaceuticals, Science Park, Cambridge, CB4 4GW, UK

Aim of Investigation: In 1992 Liao et al. reported the non-linear accumulation oftramadol following regular (qid) administration of a conventional tablet 100 mg. This was believed to be due to saturation of first-pass metabolism. This investigation assessed the influence of the controlled-delivery oftramadol on this phenomenon.

Methods: Two studies were undertaken to investigate the pharma-cokinetics oftramadol following administration of a new once-daily tablet. Two groups of healthy volunteers (25 in Study 1, 24 in Study 2) were recruited into each randomised crossover study. In Study 1, volunteers received a single dose of immediate release (1R) tramadol solution 100 mg or tramadol CR tablet 200 mg after an overnight fast or following a high-fat breakfast. In Study 2 a second group of volunteers received either an immediate release tablet 50 mg qid or the CR tablet 200 mg once-daily for 6 days. Single dose or steady state pharmacokinetics were determined using standard methods.

Results: In the single dose study the CR tablet 200 mg (fasting) provided a mean systemic availability of 94% (90% CI 87-102%) relative to the IR solution. As expected the CR tablet exhibited a significantly lower Cmax and later ^than the IR reference and these properties were maintained following ingestion of food. In the steady state study the mean systemic availability was 74% (90% CI 66-82%) relative to the IR reference. A comparison of the data from the two studies confirmed that the availability oftramadol from the IR tablet was greater following multiple dosing than had been anticipated from the single dose study (Study 1). In contrast, the profile associated with the controlled release tablet was consistent with that predicted from the single dose study (Study 2)

Conclusions: These results appear to confirm earlier findings of a non-linear accumulation oftramadol from immediate release preparations. The controlled delivery oftramadol may reduce the saturation of the hepatic first-pass effect. Ref: Liao S et al. Pharmaceutical Research 1992;9:S-308


K..L. Syrjala. B. Coda, S. Dikmen*, A. Jackson*, T. Atkins*, L. Risler*. T. Schroeder, B. Phillips*, D. Shen, Fred Hutchinson Cancer Research Center & U of Washington School of Medicine, Seattle, WA 98109, USA

Aims: 1) To define reliable measures for assessing opioid side effects [cognitive, somatic, psychomotor] and responses that might associate with addiction liability; 2) to evaluate effects of morphine (MS), hydromorphone (H) and saline (S) under conditions of equianalgesic, sustained plasma concentration of infused opioid. Methods: This was a randomized cross-over laboratory trial. Eighteen healthy volunteers participated in 3 preparation days and 3 infusion days. During infusions, subjects received bolus infusion to achieve target plasma concentration, followed by infusion of drug over 4 hours to maintain steady plasma concentration. Subjects completed subjective and objective multidimensional measures prior to infusion, and at 30, 60, 120, and 180 minutes after starting the infusion. Pain with repeated electrical stimulation to the fingertip was measured on multiple dimensions.

Results: Mean plasma concentrations during infusion were: MS=38.6 ng/ml (SD=9.96), H=4.6 ng/ml (SD=0.73). Mean pain intensities, reported on a scale from 0-10 were: S=5.9 (SD=0.57), MS=4.9 (SD=1.67), and H=4.4 (SD=2.13). Repeated measures ANOVA indicated that the S group remained stable in scores over time, while the MS and H groups increased significantly in somatic symptoms, subjective cognitive symptoms, and objective physiologic and psychomotor function. Little change was measured on MS or H in cognitive measures. Few tests demonstrated even trends for difference in effect between active drugs.

Conclusions: The measures demonstrated reliability for evaluating side effects ofopioids in repeated measures designs. Subjects differed significantly from saline to opioids in subjective and objective tests. However, cognitive function did not change on opioids. Acknowledgment: Supported by a grant from the National Cancer Institute CA 68139.


Nina Trekova. Armen Bunatian*, Natalia Zolicheva*, Dept. of Anaesthesiology, Russian Research Centre of Surgery, Moscow, 119874, Russia.

Aim of Investigation: To evaluate the clinical efficacy of opioid tramadol hydrochloride (Tramal, Grunenthal GMBH) in the treatment of postoperative shivering.

Methods: 100 adult patients, ASA physical status II-IV who had postoperative shivering after different kinds of surgery were studied. 50 patients 1 group were treated with tramal (0.7-2.5 mg/kg) i.v. within 10 minutes after shivering appearance. 50 patients of 2 group received placebo. Clinical effects, BP, HR, respiratory variables, side effects were recorded during 1 hour.

Results: Gender, age, weight, ASA physical status, duration of surgery, kind of anaesthesia, body temperature were not significantly different between the two groups. The complete sessation or decreasing of intensity of shivering was seen in group with tramal in 98% of patients in comparison with 16% of patients with placebo (p<0.05). There was evident relationship between efficacy and tramal dose: the shivering completely disappeared in tramal dose 0.7-lmg/kg in 68% of patients. Tramadol efficacy shivering treatment reached 100 % when dose increased up to 2-2.5 mg/kg. The recurrence of shivering was seen in 1 patient 30 minutes after successful treatment. There were next side effects: weak sedation in 17 patients, respiratory depression in 1 patient, nausea - in 1 patient.

Conclusions: The results show that the opioid tramadol is highly effective in the treatment of postoperative shivering with minimal side effects. The dose of drug must be individualized. The possible mechanism oftramadol in blocking shivering response is inhibition of the reuptake ofserotonin and norepinephrine in the spinal cord. Our experience permits us to recommend the tramadol as a drug of choice for treatment postoperative shivering.

Acknowledgments: Supported financially by company Grunenthal GMBH.


Ramani Vijayan. Zahurin Mohamed, Lucy Chan, Mustafa Ali Mohd, Gracie Ong, Alex Delilkan, Depts of Anaesthesiology and Pharmacology, Univ of Malaya, 59100 Kuala Lumpur, Malaysia.

Aim of Investigation: To study the plasma concentration - time profile of 50 mg oftramadol administered subcutaneously in the postoperative period.

Methods: Patients in ASA 1 and II, undergoing elective surgery were recruited. The study was initiated in the recovery room following surgery, when patients were alert and haemodynamically stable. Postoperative pain relief was either patient controlled anal-gesia, NSAIDs or intermittent SC morphine. Fifty mg oftramadol was administered subcutaneously over the upper arm as a single dose. 2 ml of venous blood was drawn via an indwelling venous cannula at the following intervals: Time 0 - before and at 5, 10, 15, 30, 60, 120 min., 3, 6, 12 and 24 hours following administration of tramadol. Plasma tramadol levels were estimated using the gas chromatography - mass spectrometric method using amitriptyline as an internal standard.

Results: The results of 8 patients in whom sampling was complete are presented. The mean and SEM of the plasma concentration peak (Cmax) was 966 +/- 251 ng/ml. The time to achieve peak concentration (Tmax) was 1.3 +/- 0.4 hr. and the biological half life in the terminal phase was 6.6 +/- 0.5 hr.

Conclusion: The above results show that there is a wide in-ter-patient variability in Cmax oftramadol, a variability that has been noted with other opioids.

Acknowledgment: This study was sponsored by a research grant from the Univ of Malaya. Our thanks to Mr. Voo for his technical assistance.


BA Otulana*. RJ Morishige*. RA Beckman^, ET Johansson*, JK Okikawa*, MD Fiore*, RM Rubsamen*. (SPON: L Eitherington), Aradigm Corporation, Hayward, CA 94545, USA ^mithKline Beecham, Collegeville, PA 19426, USA

Introduction: Previous trials have concluded that nebulized morphine for the treatment of pain and dyspnea in cancer patients is an inefficient method of drug delivery. (Masood, Br J Clin Pharmacol 1996; 41: 250). However, an efficient delivery system could enhance the value of inhaled morphine sulfate (MS) as a non-invasive pain management tool. The AERx Pain Management System (AERx PMS) being developed by Aradigm and SmithKline Beecham is a novel drug/device product that uses disposable liquid dosage forms and a hand-held device to produce fine aerosol particles capable of deep lung deposition for systemic delivery of MS via oral inhalation.

Aim of Investigation: To compare the PK profile of inhaled MS using the AERx PMS to IV MS in healthy volunteers.

Methods: Ten healthy adult subjects were studied in an open-label, crossover trial. On separate days, the subjects received 4 mg IV MS or 4 inhalations of AERx MS (total 8.8 mg loaded dose). Blood samples for plasma morphine levels were drawn predose and at specified intervals for 4 hours postdose.

Results: The dose-corrected relative bioavailability for inhaled morphine was 75%. The mean ratio of the least-squares means for AUC(o-inf) for the comparison of inhaled to IV morphine was 163.8%. Both treatments reached peak concentrations in less than 2 minutes. Inter subject variability was also similar between the two routes. The table below shows selected mean PK parametersfor both treatment arms of the study.



AERx morphine IV


Mean Ratio
CmaX (ng/mL) 79.531.7 101.8152.3 78.0
TmaX (n,m) 1.80.6 1.20.6 135.9
AUC (o.inf) 52.4 12.3 32.09.8 163.8


Conclusions: Compared to IV, the bioavailability of morphine from the AERx PMS was 75%, a substantial improvement over the 5% reported using a nebulizer by Masood. We conclude that the AERx PMS provides an efficient delivery system for inhaled morphine with a similar PK profile to IV administration. Acknowledgments: Drs. Otulana and Rubsamen and Messrs. Morishige, Johansson, Okikawa and Fiore are employed by Aradigm Corporation. Dr. Beckman is employed by SmithKline Beecham.


Lucy Robertson*. Peter Drummond, GeoffHammond*, Psychology Dept, Univ of Western Australia, Nedlands, 6907 WA, Australia

Aim of Investigation: Local administration ofopioids may induce analgesia without the side effects of tolerance produced by higher doses. In inflamed skin, locally-administered opioids induce analgesia by activating opioid receptors on peripheral nerves. In the uninflamed skin of rats, opioids reduce pain sensitivity when administered with mannitol. Mannitol, like inflammation, disrupts the perineurial sheath allowing opioids access to opioid receptors. We investigated the effect of local injections into uninflamed human skin offentanyl with mannitol on pain sensitivity. It was hypothesised that mannitol would disrupt the perineurium, increasing the accessibility offentanyl to opioid receptors, thus decreasing pain sensitivity.

Methods: Participants (n=16) received a subcutaneous injection of 0.1 mL (50 mg/mL) fentanyl with 0.1 mL (20% w/v) mannitol into the ventral aspect of the forearm, and a control injection of 0.1 mL normal saline with 0.1 mL mannitol into the contralateral forearm. Pain sensitivity measures included ratings of mechanical-pain induced by von Frey filaments, ratings of heat-pain induced by a probe at 43, 45 and 47 C and the threshold of heat-pain induced by radiant heat which increased from 33 C at 0.75C/sec.

Results: Local injection offentanyl and mannitol significantly reduced sensitivity to mechanical pain F357=4.42, p<01), but had no significant effect on heat-pain threshold or suprathreshold heat pain sensitivity.

Conclusions: In uninflamed human skin, fentanyl injected with mannitol appears to access opioid receptors on mechanical pain fibres, but not heat-pain fibres.

9th WORLD CONGRESS ON PAIN, 1999, Vienna, Austria, p.331 338


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