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PubMed1978

Differentiation of drugs acting centrally upon the cardiovascular system by means of sympathetic and vagal responses.

The response pattern of the autonomic nervous system was investigated after central administration (intra-cisternal, vertebral artery) of amphetamine, morphine, fentanyl, dextromoramide and the substance R 28935, chemically related to the neuroleptic agent pimozide. Effects on the sympathetic system were measured by recording electrical discharges of fibres of the (preganglionic) major splanchnic nerve in anaesthetized cats; those on the vagal system by recording the heart rate in anaesthetized dogs under beta-adrenoceptor blockade; the baroreceptor reflex was elicited by the blood pressure increase of i.v. injected angiotensin. All substances decreased the spontaneous discharge rate of the splanchnic nerve. Amphetamine facilitated the vagally mediated reflex bradycardia and this was antagonized by the alpha-adrenoceptor blocking agent piperoxan. Amphetamine did not affect the resting heart rate, as has already been shown for clonidine and related substances. The narcotic analgesics lowered the resting heart rate but did not facilitate the baroreceptor reflex response. R 28935 neither influenced resting heart rate nor the baroreceptor reflex response in beta-blocked dogs. On the basis of the vagal response pattern it was therefore possible to distinguish between 3 groups of central hypotensive drugs.

Amphetamine↗

PubMed1976

[Neuroleptanalgesia as the anesthesia in pediatric surgery].

In work carried out over a period of two years in the department of anesthetics and intensive care of the Saint-Etienne University Hospital, the authors report their experience of neuroleptanalgesia using droperidol-dextromoramide in children in 104 cases. The observations may be divided up into 2 groups: - 1 group of children below the age of 2 years; - 1 group of children from 2 to 10 years. This study showed the side-effects and complications common to both groups, in particular, the extrapyramidal syndrome. Furthermore, the authors present their technique of administration.

Anesthesia↗

PubMed1976

[Current place of neuroleptics in cardiac surgery under extracorporeal circulation. Cardiovascular effects of different combinations].

We have been using narconeuroleptanalgesia for anesthesia in cardiac surgery under extra-corporeal circulation since 1969, and we have carried out about 3,500 anesthetics of this type on the 1st of October 1975. For all these anesthetics, the neuroleptic used was droperidol. The other components were: - in the case of the narcotic, penthiobarbital, then more recently Alfatesine; - in the case of the analgesic, either dextromoramide or phenoperidine or Fentanyl; in the case of the curare derivative, D, tubocurarine, and above all, pancuronium dibromide. The advantages of neuroleptanalgesia for such surgery seemed to us mainly: - greater cardio-vascular stability in patients with a heart lesion; - the possibility of better control of cardiac output, i.e. by fillingor by inotropic drugs, thanks to the relative vasoplegia produced by the neuroleptic. Finally, in a recent study, we attempted to determine the hemodynamic effect of droperidol and its association on various analgesic drugs measuring in a few patients the cardiac output, the peripheral resistances the the circulating blood volume. We will report the preliminary results of this study.

Adolescent↗

PubMed1987

[Propofol and thoracic surgery].

20 patients undergoing thoracic surgery were studied. Before anaesthesia either a catheter was placed in the intercostal space, at the same level as the thoracotomy (16 patients) or an epidural catheter was inserted if there was a contraindication of intercostal blockade (4 patients). Marcaine 0.5--was injected. Anaesthesia was induced with propofol 2.5 mg.kg-1, vecuronium 0.1 mg.kg-1, dextromoramide 50 mcg.kg-1. It was maintained with propofol 9 mg.kg-1.h-1 for 30 mn, then 4.5 mg.kg-1.h-1 for following hours (by a syringe pump) and vecuronium 0.1 mg.kg-1.h-1. Cardio vascular effects were studied only in the 16 patients with intercostal blockade: during induction bradycardia in 3 patients, and systolic arterial pressure (S.A.P.) decrease of 30% in 8 patients were observed. After the incision, heart rate and S.A.P. became steady. The average duration of anaesthesia was 214 min +/- 74. The time from the end of propofol infusion to the moment of extubation was 15.4 min +/- 33 and the time to recover all mental faculties was 46 mn +/- 11. 30 min after the end of anaesthesia the maxima minute ventilation was equal to the post operative value at 48 H. Propofol anaesthesia allows a fast awakening, without cumulative effects.

Anesthesia Recovery Period↗

PubMedDate not supplied

[Abortion and the use of anaesthesia. Observations after two years' experience (author's transl)].

The authors give an account of their experience of anaesthesia in 380 abortion cases. Two kinds of technique were used: --paracervical block: 10.2 p. cent of the cases, only one complication; --narco-analgesia: considered to be essential. Dextromoramide was the principal analgesic used, chosen for its pharmacodynamic properties. Three narcotic drugs used successively in conjunction with this were: propanidine, with this drug per-anaesthetic complications and post-operative vomiting proved excessive, C.T. 1341 considerably reduced the frequency of these complications, disodic penthiobarbital did not give rise to any problems.

Abortion, Therapeutic↗

PubMed1981

[Modification, by lithium, of catalepsy induced by central cholinergic stimulants and morphine-like drugs].

After unique injection LiCl enhances, in albino rat, catalepsy induced by arecoline and oxotremorine perhaps by adenylcyclase inhibition and/or decrease of acetylcholine synthesis. After repetitive injection of LiCl during 5 days, this phenomenon is not observable, probably owing to increase of acetylcholine synthesis. After unique injection of LiCl enhances catalepsy induced by dextromoramide, probably on account of cholinergic properties of this drug. In contrast catalepsy induced by morphine or pethidine is suppressed. This constatation would depend on opposite influence upon cerebral neuromediators : lithium diminishing cerebral serotonin and striatal acetylcholine levels and morphine increasing them. After repetitive injections these phenomenons are not observable.

Animals↗

PubMed1975

[Constant outflow anesthesia with the combination of alfatesine and fentanyl].

In a previous work, the authors showed the value of administering Alfatesine, in interventions of long duration, at a constant rate by using an automatic syringe, and by combining it with destromoramide. In this new work the authors present an analagous study carried out in 47 subjects, in which dextromoramide was replaced by fentanyl. The automatic syringe used was the Braun Perfusor IV equipped with a 50 ml syringe containing 0.3 ml. of CT 13.41 and 0.006 mg. of fentanyl per ml. Induction was achieved at graduation 10, 14 ml of the mixture having been injected in approximately 60 seconds. Maintenance of anesthesia was ensured at graduation 6 corresponding to an hourly administration of 27 to 30 ml of the mixture (9 ml of CT 13.41 and 0.18 mg of fentanyl). The patients were adults of average weight 64 kg., who had undergone sometimes major orthopedic surgery, of an average duration of 161 mn. The results are looked at from the angle of quality of the anesthesia and of the awakening and of the side effects. They confirm the non-accumulation under these conditions of use and these doses of CT 13.41 used and reveals an analagous behaviour of fentanyl. Reserves are however made owing to the mode of elimination of fentanyl, on the use of such a technique in anuric patients or in renal insufficiency.

Adolescent↗

PubMed2004

Methadone for cancer pain.

BACKGROUND: Methadone is an opioid used in the management of cancer pain both in opioid naïve patients and in rotation from other opioids. A particular role in neuropathic pain has been suggested. The quest for evidence based palliative care prompted a formal appraisal of methadone in comparison with other analgesics. OBJECTIVES: To determine the effectiveness and safety of methadone analgesia in cancer pain patients. SEARCH STRATEGY: MEDLINE (1966 to August 2002), EMBASE (1980 to August 2002), CancerLit (1993 to August 2002), CINAHL (1982 to August 2002) and Cochrane databases were searched using a strategy developed with the Cochrane Pain, Palliative and Supportive Care Group. Assiduous efforts were made to identify unpublished or current trial work. SELECTION CRITERIA: Randomised controlled trials of methadone against active or placebo comparator in patients with cancer pain were included. Outcome measures sought were reduction in pain intensity measured by an appropriate scale, adverse effects, attrition, patient satisfaction and quality of life. There were no language restrictions. Absence of patient reported data was an exclusion criterion. DATA COLLECTION AND ANALYSIS: Eligible studies were selected with independent collaboration from a colleague in Bristol (AND). Full text was retrieved if any uncertainty about eligibility remained. Non-English texts were screened by Cochrane contacts aware of the eligibility criteria. Quality assessment and data extraction were conducted using standardised data forms. Drug and placebo dose, titration, route and formulation were compared and detail of all outcome measures (if available) recorded. MAIN RESULTS: Eight randomised controlled trials (five double blinded, two crossover) with 356 recruits and 326 completing patients were included. All involved active placebo (five morphine, one dextromoramide or pethidine, one diamorphine with cocaine mixture). All employed different starting doses, titration regimens and pain scoring scales. Few presented complete pain data sets and no meta-analysis has been possible. No differentiation by cancer pain syndrome was made. Complete adverse events data were recorded in every study, and were similar in incidence and severity to those experienced with morphine. REVIEWERS' CONCLUSIONS: There is evidence to suggest that methadone is an analgesic with similar efficacy to morphine and a comparable side effect profile. However, the majority of studies involved single dose comparisons or short term use. This methodology fails to reproduce clinical practice. Therefore there is a very significant danger that the effects of methadone accumulation leading to delayed onset of adverse effects which occurs with chronic administration has not been represented. Fixed interval dosing schedules conducted over several days are associated with a high risk of serious morbidity and mortality. There is no trial evidence to support the proposal that methadone has a particular role in neuropathic pain of malignant origin. Conclusions have been limited by the variations in trial design, dosing regimens and limited presentation of primary outcome data. The complex and highly individual pharmacokinetics of methadone require that experienced clinicians take responsibility for initiating, titrating and monitoring this drug.

Analgesics, Opioid↗

PubMed1993

Displacement of thiopental from human serum albumin by associated drugs.

Displacement of thiopental from its binding sites to 4% human serum albumin solution was studied in vitro. Experimental conditions were selected to reproduce a physiological situation. Associations were studied according to the therapeutic conditions of use of the substances (drug and protein concentrations). The unbound fraction of thiopental was obtained by equilibrium dialysis at 37 degrees C and pH 7.4. Eleven drugs were associated with thiopental in 50 combinations of drugs and molar ratios. Bromhexine, citocoline, dextromoramide, dexamethasone, and methotrimeprazine had no effect on thiopental binding. The unbound fraction of thiopental significantly increased with cefamandole, cefazolin, diazepam, desmethyldiazepam, furosemide, and fentanyl. At usual therapeutic drug concentrations, the unbound fraction increase was < 5%. Higher values, however still < 10%, were found with associated drugs that were added at maximal concentrations observed in therapy. The displacement of thiopental from its albumin binding by drugs that are normally associated with the treatment of intracranial hypertension does not modify the pharmacokinetic parameters or pharmacological effect of thiopental.

Binding, Competitive↗

PubMed1987

Potentiation by acetylcholine of the effects of a calcium channel activator, Bay k 8644, on dog atria in situ.

The effects of Bay k 8644 were studied in the canine in situ heart under vagal influence and out of this influence on sinus rate and sinus recovery time, conduction time and effective refractory period (ERP) in the atrioventricular (AV) node and ERP of the atrial muscle. Bay k 8644, intravenously infused at the 2 micrograms X kg-1 X min-1 rate for 30 min, enhanced the inhibition of the atrial specialized tissue as well as the shortening of the atrial muscle ERP during vagal activity, elicited by the injection of dextromoramide into the cisterna magna. It did not develop any atrial action in the absence of vagal activity, suppressed by atropine. The reflex increase of vagal tone, in response to a small increase in blood pressure produced by Bay k 8644, is not the only cause of the phenomena observed in the former case. The observations can be explained primarily in terms of an interaction between Bay k 8644 and acetylcholine (ACh):ACh intraaortically injected near the coronary ostia, in a dose just sufficient to slow down sinus rate before Bay k 8644, reduced the rate by 50% at the end of a 60 min infusion of Bay k 8644 and the ACh threshold dose necessary to elicit a short third degree AV block before Bay k 8644 was reduced by 50% at the end of a 30 min infusion of Bay k 8644. Therefore, ACh appeared to be capable of enhancing the effects of a calcium channel activator as well as the effects of hypercalcaemia, as earlier reported.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1999

Assessment of analgesia in human chronic pain. Randomized double-blind crossover study of once daily repro-dose morphine versus MST continus.

OBJECTIVE: This study evaluated Repro-Dose morphine (RDM; Reliadol from Nycomed Pharma), a new once daily controlled-release morphine formulation, against twice daily MST Continuous (MST) at steady state in patients with chronic opioid responsive pain. METHODS: A randomized double-blind two-way crossover design was used to evaluate the efficacy and adverse effects of RDM once daily or MST twice daily, at the same total daily doses, in patients with chronic stable pain (dose range 20-120 mg per day). During the RDM limb of the study active drug was administered in the evening and placebo in the morning. Dextromoramide was provided as escape analgesia throughout the study. Following a 5-day screening period, during which stability of oral opioid dose was verified, patients underwent two 5-day treatment periods, (one MST, one RDM) in random sequence. Pain scores, escape analgesia requirements and side-effects were compared using data from days 3, 4 and 5 of each treatment period. Any events or medication changes occurring during the study period thought liable to influence analgesia were regarded as protocol violations. Overall assessment and period preference was assessed by direct questioning. RDM treatment was regarded as successful if the amount of escape medication required during the RDM period was equal to or less than that required during the MST period. RESULTS: Forty-seven patients were included in the study, of whom 40 completed both periods [the intention to treat (ITT) population], 31 in strict accordance with the protocol [the per protocol (PP) population]. Results were similar for both populations. There was no significant difference in pain scores or incidence of adverse events occurring during the MST and RDM periods. For the ITT population, requirements for escape medication during the RDM period were less than, equal to or greater than those recorded during the MST period for 14, 15, and 11 patients, respectively. Twenty-nine of 40 patients (72.5%) were therefore RDM treatment successes (95% confidence interval 56.1-85.4%). The percentage of patients preferring RDM (45%) combined with those with no preference (32.5%) was significantly higher than those preferring MST (22.5%; P = 0. 0003). CONCLUSIONS: Oral morphine administered as RDM once daily is at least as effective and well tolerated as MST twice daily, with over 70% of patients in this double-blind crossover study reporting that RDM was equal or superior to MST.

Administration, Oral↗

PubMed1983

[3H]Sufentanil, a superior ligand for mu-opiate receptors: binding properties and regional distribution in rat brain and spinal cord.

Stereospecific [3H]sufentanil binding, inhibited by dextromoramide, represents 90% of the total binding in membrane preparations of rat brain and spinal cord. Scatchard plots of the binding in the forebrain, at 37 degrees C in Tris-HCl buffer without and with 120 mM NaCl, were rectilinear; KD = 0.13 nM and 0.31 nM, Bmax = 13 fmol/mg tissue and 9.9 fmol/mg tissue in the absence and the presence of sodium ions respectively. The reduction in binding affinity in the presence of sodium ions was found to be due to a 9.7 fold enhancement of the initial dissociation rate from t1/2 = 2.1 min in the absence to 13 s in the presence of sodium ions. The [3H]sufentanil binding properties were superior to those of [3H]fentanyl, [3H]dihydromorphine and [3H]naloxone; [3H]sufentanil showed an unmatched favourable ratio of stereospecific versus non-specific binding; it had a 7.7, 20 and 40 fold binding affinity than the above ligands respectively. Due to its relatively slow dissociation rate, a more accurate estimation of the Bmax value was obtained with [3H]sufentanil than with the other, fast dissociating 3H-ligands (t1/2 less than 10 s). A total of 37 narcotic analgesic agonists and antagonists belonging to 5 different major structural classes all inhibited stereospecific [3H]sufentanil binding in a competitive way. There was no relationship between binding affinities and lipophilicity and degree of ionization of the compounds. Binding affinities correlated highly significantly with the analgesic potency measured in vivo, demonstrating that [3H]sufentanil labels mu-opiate receptor sites which mediate narcotic analgesia. Moreover, the binding affinity of sufentanil for delta-type binding sites labelled by [3H] [D-Ala2,D-Leu5]enkephalin was found to be 100 times lower than its binding affinity for the mu-receptor sites. [3H]Sufentanil was used for a detailed investigation of the regional distribution of mu-opiate receptor sites in the brain; Bmax and KD values were measured in the dorsal and ventral spinal cord.

Analgesics, Opioid↗

PubMed1990

Normalization of small intestinal propulsion with loperamide-like antidiarrheals in rats.

Gastrointestinal propulsion and the presence of diarrhea were assessed in rats pretreated with various opioids and challenged orally with either castor or paraffin oil, which both contained phenol red as a marker of gastrointestinal propulsion. In solvent-pretreated rats, diarrhea was always observed within 90 min after castor oil, reflecting a state of hyperpropulsive activity of the gut, but never (up to 8 h) after paraffin oil, reflecting normal intestinal propulsion (which amounted to an average distance of 91% of the total length of the small intestine in 90 min). Paraffin oil propulsion was blocked (to values less than 60%) by all opioids tested with the exception of the gut-selective compounds loperamide, loperamide oxide and fluperamide oxide (ED50s: greater than or equal to 160 mg/kg). Castor oil diarrhea was antagonized by all opioids tested and, at comparable but slightly (1.3-2.6 times) higher doses, propulsion was normalized to values (less than 100%) comparable to those measured in paraffin oil-challenged control rats. Castor oil propulsion was further reduced to subnormal values (less than 60%) by still higher doses of the opioids, comparable to those that blocked propulsion after paraffin oil. However, the required dose increment varied consistently among the opioids tested and ranged, depending on gut selectivity, from a factor 2.3 times the antidiarrheal dose for narcotic analgesics such as pethidine and dextromoramide to greater than 300 for antidiarrheals such as loperamide, loperamide oxide and fluperamide oxide. Protection from diarrhea and normalization of propulsion showed a close correlation; both failed to correlate with central analgesic activity and are thought to be mediated via peripheral opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗

PubMed1987

Role of calcium in the rate-dependent depression of atrioventricular nodal conduction in the dog heart under vagal influence.

Increase in heart rate may be detrimental to atrioventricular conduction. The effects of such an increase were investigated in the paced intact dog heart, by measuring the conduction time in the atrioventricular node (obtained from the His bundle potential recording) and the effective refractory period in this node as determined by the extrastimulus method. Investigations on atrioventricular nodal conduction were performed with and without vagal influence. After central restoration of vagal tone by dextromoramide in anesthetized animals, both parameters appeared to lengthen as the heart rate rose. This lengthening became considerable at the highest rates. After blockade of cholinergic receptors by atropine, no significant change occurred when the heart rate was raised. The prolongation observed under vagal tone was enhanced by the rise in the plasma calcium concentration to 3.10 mmol X l-1 and reduced by a calcium influx inhibitor, verapamil, in 0.2 mg X kg-1 dose. These effects are related to the calcium intracellular concentration, since the rise in this concentration beyond an optimum has been demonstrated to inhibit the calcium and potassium channel.

Animals↗

PubMed1976

5-Hydroxytryptamine and narcotic-analgesics interactions in the intestine.

The effects of 5-hydroxytriptamine (5-HT), 5-HT blocking agents, morphine, narcotic-antagonists and ganglionic blocking agents were tested in the dog intestine by close intra-arterial injection. Morphine, as 5-HT, induced an immediate increase in the intestinal tonus followed by phasic contractions. When 5-HT was injected immediately after cessation of morphine induced phasic contractions, a significant potentiation of the 5-HT induced intestinal contraction could be observed. The potentiation could be demonstrated for other narcotic-analgesics like dextromoramide and it is specific for 5-HT. 5-HT blocking agents like LSD, BOL, and cyproheptadine did not block either 5-HT or morphine. However, bufotenidine, a neural tryptaminergic blocking agent, blocked the effects of both 5-HT and morphine. The effects of 5-HT and morphine upon intestinal motility were also diminished by ganglionic depolarizing agents such as nicotine and DMPP. This effect could, however, be prevented by the pretreatment with hexamethonium. These results seem to confirm the hypothesis of a 5-HT mediator role in the intestinal contractile effect induced by the narcotic-analgesics. On the other hand, narcotic-antagonists such as nalorphine and cyclazocine, not only lacked the 5-HT potentiation effect but also prevented the 5-HT potentiation induced by morphine. Cyclazocine also showed a long lasting 5-HT blocking effect. These results seem to show that the 5-HT potentiating effect of morphine in vivo is very specific and characteristic of the narcotics and thus could be implicated in some of their central effects.

Analgesics, Opioid↗

PubMed2004

Evaluation of the One-Step ELISA kit for the detection of buprenorphine in urine, blood, and hair specimens.

A solid-phase enzyme immunoassay involving microtiter plates was recently proposed by International Diagnostic Systems corporation (IDS) to screen for buprenorphine in human serum. The performance of the kit led us to investigate its applicability in other biological matrices such as urine or blood, and also hair specimens. Low concentrations of buprenorphine were detected with the ELISA test and confirmed by HPLC/MS (buprenorphine concentrations measured by HPLC/MS: 0.3 ng/mL in urine, 0.2 ng/mL in blood, and 40 pg/mg in hair). The intra-assay precision values were 8.7% at 1 ng/mL of urine (n = 8), 11.5% at 2 ng/mL in serum (n = 8), and 11.5% at 250 pg/mg of hair (n = 8), respectively. The immunoassay had no cross-reactivity with dihydrocodeine, ethylmorphine, 6-monoacetylmorphine, pholcodine, propoxyphene, dextromoramide, dextrometorphan at 1 and 10 mg/L, or codeine, morphine, methadone, and its metabolite EDDP. A 1% cross-reactivity was measured for a norbuprenorphine concentration of 50 ng/mL. Finally, the immunoassay was validated by comparing authentic specimens results with those of a validated HPLC/MS method. From the 136 urine samples tested, 93 were positive (68.4%) after the ELISA screening test (cutoff: 0.5 ng/mL) and confirmed by HPLC/MS (buprenorphine concentrations: 0.3-2036 ng/mL). From the 108 blood or serum samples screened, 27 were positive (25%) after the ELISA test with a cutoff value of 0.5 ng/mL (buprenorphine concentrations: 0.2-13.3 ng/mL). Eighteen hair specimens were positive (72%) after the screening (cutoff: 10 pg/mg) and confirmed by LC/MS (buprenorphine concentrations: 40-360 pg/mg). The ELISA method produced false positive results in less than 21% of the cases, but no false negative results were observed with the immunological test. Four potential adulterants (hypochloride 50 mL/L, sodium nitrite 50 g/L, liquid soap 50 mL/L, and sodium chloride 50 g/L) that were added to 10 positive urine specimens (buprenorphine concentrations in the range 5.3-15.6 ng/mL), did not cause a false negative response by the immunoassay.

Buprenorphine↗

PubMed2004

[Tribute to Paul Janssen (1926-2003): two discoveries per year"].

Paul Janssen (1926-2003) performed during fifty Years an intense pharmaceutical research activity. From 1953 to 2003, he discovered numerous new drugs in various fields of pharmacology. He widened the neuroleptic spectrum with haloperidol and risperidone, the opioid one with dextromoramide, fentanyl and its short-life derivates, constipating agents like loperamide, hypnotics, anaesthetics. In the field of anti-infectious agents, he discovered azole antifungals, parasiticides among which levamisole and mebendazole. Other therapeutic classes have been enriched by JANSSEN's works: vasodilatating agents, antihypertensive and anti-allergic drugs, etc. More recently, his research was oriented towards virology namely anti-HIV drugs. When Paul JANSSEN's life ended, his scientific production seemed to be one of the most eminent in the XXth century.

France↗

PubMed1997

Pharmacokinetics and pharmacodynamics of twenty-four-hourly Kapanol compared to twelve-hourly MS Contin in the treatment of severe cancer pain.

Twenty-four patients with severe pain related to cancer completed a randomised, double-blind, double-dummy, crossover study examining morphine pharmacokinetics and pharmacodynamics when the same 24-h morphine dose was administered using two modified release oral morphine formulations; either one dose of Kapanol (a new sustained release polymer coated pellet formulation administered in capsule form, Glaxo Wellcome group of companies) per 24 h, or MS Contin (Purdue Frederick Company, Connecticut, USA) administered at 12-h intervals. The morphine dose was optimised for each patient using an immediate release morphine solution in the lead-in period to provide the most favourable balance between pain relief and side-effects. Patients were then randomly allocated to receive their 24-h morphine dose as either Kapanol or MS Contin in period 1. Patients recorded daily measures of pain relief and morphine related side-effects (morphine pharmacodynamics) in a diary. Patients were admitted to the Pain Management Unit on the morning of day 7 (+/- 1 day) and frequent blood samples were collected for 24 h following the 10:00 h dose to fully characterise the pharmacokinetic profile for morphine and its metabolites at steady state. Morphine pharmacodynamics and the amount and timing of rescue medication (dextromoramide) were also recorded during this time. Period 2, which commenced at 10:00 h on day 8, was identical to period 1 except the modified release formulations were changed. The pharmacokinetic profile of Kapanol exhibited a significantly higher Cmin (minimum plasma morphine concentration), less fluctuation in plasma morphine concentration throughout the dosing interval, a longer Tmax (time associated with the maximum morphine concentration) and a greater time that the plasma morphine concentration was > or = 75% of Cmax (an index of the control the formulation exerts over the morphine release rate) compared to that of MS Contin. Some of these pharmacokinetic differences (e.g., Cmin and fluctuation in plasma morphine concentration) were surprising given that the dosing interval for Kapanol (24 h) was double that of MS Contin (12 h). There was no significant difference between the Kapanol and MS Contin treatment phases in any of the pharmacodynamic parameters, morphine related side-effects, the percentage of patients taking rescue medication as well as the amount or time to the first dose of rescue analgesia on day 7 in periods 1 and 2, patient or investigator assessments of global efficacy at the end of periods 1 and 2, or patient treatment preference at the end of the study. Once a day Kapanol provided the same degree of pain relief and morphine related side-effects as 12-h MS Contin.

Adult↗