[High-dose buprenorphine for outpatient palliative pain therapy]. / Hochdosis-Buprenorphin im Rahmen der ambulant-palliativen Schmerztherapie.

The case of a 78-year-old patient with cancer-related pain and additionally mixed-pain syndrome is presented. Pain therapy with buprenorphine TTS 210 microg/h every 3 days was sufficient in the beginning, later the therapy was changed because of increasing problems of tape fixing during fever periods under chemotherapy to a continuous infusion of buprenorphine intravenously via an external medication pump. During the course of therapy it became necessary to increase the dose to 99.9 mg/day buprenorphine. Under this medication a sufficient pain reduction (median NRS 2-3) over a period of 135 days could be achieved. At the same time the patient was vigilant and cooperative without signs of intoxication until the end of life at home in the presence of his family.If no signs of intoxication occur under extreme opioid therapy and a sufficient pain therapy can be achieved, a rotation to another opioid is not necessary. However, outpatient palliative care requires a frequent adaptation to the individually varying opioid demand of the patient and time-consuming nursing care.

Reflex activity caused by laryngoscopy and intubation is obtunded differently by meptazinol, nalbuphine and fentanyl.

BACKGROUND AND OBJECTIVE: To evaluate the different potencies of several opioids in obtunding reflex mechanisms of laryngoscopy and intubation. METHODS: Three groups of patients (each n = 25, ASA 1-2) undergoing elective plastic surgery were randomly given meptazinol (2.5 mg kg-1), nalbuphine (0.3 mg kg-1) or fentanyl (5 microg kg-1) in a blinded fashion prior to laryngoscopy and intubation. This was followed by a standardized bolus induction of a barbiturate and a muscle relaxant. The response to laryngoscopy and intubation was studied, using blood pressure, heart rate and bispectral index. RESULTS: With fentanyl, there was an increase of heart rate by 17%, and systolic blood pressure by 7% when compared to control. Bispectral index dropped an additional 8% when compared to 1 min after barbiturate induction. In the nalbuphine group there was a 16% increase in systolic blood pressure, and a 16% increase in heart rate when compared to control. Also, bispectral index increased by 18% when compared to 1 min after barbiturate injection. The group receiving meptazinol demonstrated no cardiovascular changes although bispectral index dropped by an additional 19% when compared to 1 min after barbiturate injection. CONCLUSION: Meptazinol, appears to depress cardiovascular stimulatory effects and electroencephalogram arousal induced by laryngoscopy and intubation better than nalbuphine or fentanyl.

[No potentiation of fentanyl by use of transdermal buprenorphine in patients undergoing fast-track anesthesia for open-heart surgery]. / Kein Opioidüberhang bei Patienten mit transdermalem Buprenorphin und Fast-Track-Anästhesie nach Eingriffen am offenen Herzen.

OBJECTIVE: Simultaneous use of opioids with a different pharmacological profile may lead to unexpected prolongation of effects. In an open label study possible overhang in post-operative respiratory effects and vigilance was determined in a group of patients (n = 22) carrying a transdermal buprenorphine patch for at least 2 months for treatment of chronic pain, undergoing a fentanyl-based fast-track enflurane anesthetic technique for open-heart operation. Data was compared with another randomised group (n = 21) undergoing similar open-heart procedures with no other opioid than fentanyl on board. METHODS AND RESULTS: Following induction with fentanyl and a barbiturate, depth of anesthesia with enflurane (Fi 0.5) was guided using the bispectral index (BIS). Additional doses of fentanyl were given when blood pressure and/or heart-rate increased 20% above pre-induction levels. Early postoperative extubation was initiated once the cardiovascular system was stable and there were no signs of respiratory impairment. Following a similar time of operation and anesthesia and a similar total dose of fentanyl (0.69 mg +/- 0.23 SD versus 0.67 mg +/- 0.16 SD), postoperatively, there were no significant differences between the buprenorphine- and the control group regarding the time till extubation (25.2 min +/- 6.1 versus 33.3 min +/- 5.0) and the arterial blood gases under oxygen inhalation (paO2 136 torr +/- 48 SD versus 128 torr +/- 35 SD; paCO2 43.3 torr +/- 3.3 SD versus 41.9 torr +/- 1.2 SD and the post-anesthetic vigilance and recovery score (6.8 +/- 1.0 versus 7.5 +/- 0.8) 60 minutes after end of anesthesia. Contrary to the control group, there was a lower and significant (p < 0.01) incidence of PONV in patients with transdermal buprenorphine. CONCLUSION: Patients using a buprenorphine patch for the relief of chronic pain cannot be regarded as opioid naïve. Due to adaptive mechanisms and the development of tolerance, there is no prolongation of the respiratory depression induced by intraoperative fentanyl. Long-term use of transdermal buprenorphine does not lead to potentiation or prolongation of opioid effects in cardiac surgery patients.

Constitutive opioid receptor activation: a prerequisite mechanism involved in acute opioid withdrawal.

The opioid receptor antagonist naltrexone, which is used in detoxification and rehabilitation programmes in opioid addicts, can precipitate opioid withdrawal symptoms even in patients who have no opioid present. We tested the hypothesis that in order to precipitate withdrawal, opioids need to convert the inactive opioid receptor site via protein kinase C into a constitutively active form on which the antagonist precipitates withdrawal. Acute microg/kg), given for 6 days, which was followed by the antagonist naltrexone (20 microg/kg i.v.) in the awake trained canine (n = 10). Abrupt displacement of opioid binding resulted in acute withdrawal symptoms: increase in blood pressure, heart rate, increase in amplitude height of somatosensory evoked potential, reduced tolerance to colon distention and a significant increase in grading of vegetative variables (restlessness, panting, thrashing of the head, whining, yawning, gnawing, salivation and/or rhinorrhoea, mydriasis, stepping of extremities and vomiting). Following a washout period of 14 days, the same animals were given the highly specific protein kinase C inhibitor H7 (250 microg/kg) prior to the same dosages of sufentanil and naltrexone. Such pretreatment was able to either attenuate or completely abolish the acute withdrawal symptoms. The data suggest that for precipitation of withdrawal, intracellular phosphorylation is a prerequisite in order to activate the opioid mu-receptor. In such a setting, naltrexone acts like an 'inverse agonist' relative to the action of the antagonist on a non-preoccupied receptor site not being exposed previously to a potent opioid agonist.

Increase in delta- and beta-wave activity of the EEG during rapid opiate detoxification (ROD)-reversal by administration of the non-specific NMDA-antagonist S+ ketamine-.

Little is known on effects taking place in the CNS during rapid opioid detoxification (ROD) while the patient is under anesthesia. We therefore measured EEG-power spectra in the beta, alpha, Theta, and delta-band in 36 patients undergoing ROD. Measurements were taken before, during steady-state anesthesia and following administration of the antagonist naltrexone. In addition, the non-specific NMDA-antagonist S+ ketamine was given for reduction of CNS-hyperexcitation, while the efficacy of this adjunct was determined using EEG power spectra analysis. Compared to steady-state anesthesia, EEG power spectra were characterized by a marked decrease of power by 251% in the delta (0.5-3 Hz) and an increase by 209% in the beta- (13-30 Hz) domain when withdrawal was induced with naltrexone. Subsequent administration of S+-ketamine induced a reversal of acute abstinence-related EEG power changes: compared to anesthesia with naltrexone on board, power in the EEG increased by 65% in the delta- and decreased by 723% in the beta-band. While sympathetically induced hemodynamic alterations in anesthesia-assisted opioid detoxification can be attenuated by the alpha2-agonist clonidine and sedation, central nervous sensory activation can be attenuated by the administration of S+-ketamine (1.5 mg/kg). Since EEG alterations during acute withdrawal with naltrexone can be controlled by the non-specific NMDA-antagonist S+-ketamine, this latter presents a useful adjunct during ROD management.

A radio frequency electric current enhances antibiotic efficacy against bacterial biofilms.

Bacterial biofilms are notably resistant to antibiotic prophylaxis. The concentration of antibiotic necessary to significantly reduce the number of bacteria in the biofilm matrix can be several hundred times the MIC for the same bacteria in a planktonic phase. It has been observed that the addition of a weak continuous direct electric current to the liquid surrounding the biofilm can dramatically increase the efficacy of the antibiotic. This phenomenon, known as the bioelectric effect, has only been partially elucidated, and it is not certain that the electrical parameters are optimal. We confirm here the bioelectric effect for Escherichia coli biofilms treated with gentamicin and with oxytetracycline, and we report a new bioelectric effect with a radio frequency alternating electric current (10 MHz) instead of the usual direct current. None of the proposed explanations (transport of ions within the biofilm, production of additional biocides by electrolysis, etc.) of the direct current bioelectric effect are applicable to the radio frequency bioelectric effect. We suggest that this new phenomenon may be due to a specific action of the radio frequency electromagnetic field upon the polar parts of the molecules forming the biofilm matrix.

[Use of opioids in the elderly -- pharmacokinetic and pharmacodynamic considerations]. / Einsatz der Opioide bei alten Patienten -- Pharmakokinetische und pharmakodynamische Uberlegungen.

Perioperative management of geriatric patients is becoming an important component in anaesthetic practice in the 21st century. This phenomenon is due to the fact that people aged 65 and over are the segment with the fastest growing population. Thus, it is estimated that by the year 2025 20 % of the population in the western hemisphere will be > 65 years of age. Currently, elderly patients comprise one-third of all operations, and one out of two patients older than 65 years of age will undergo an operation in their lifetime. The dramatic change in demographics of surgical patients will have a tremendous impact on the use of anaesthetics. Older patients facing surgery can generally be expected to be a more complex case than their younger counterparts. They have more systemic diseases (e. g. cardiac, pulmonary, endocrine), and usually these diseases have advanced to more serious stages. These patients may suffer disability, both physical and mental, and may show differences in the pharmacokinetic as well as the pharmacodynamic of compounds such as opioids. While neuronal numbers, dendrites and synapses decline with age and the ventricular volume triples, cerebral circulation is similar to young adults, although there is a reduction in cerebral blood flow (CBF). This is because of the lower unit weight, lower CBF and CMRO (2), which are tightly coupled in aging where autoregulation is preserved. However, because of a decline in dopaminergic, serotonergic, cholinergic and GABAergic transmitters, anticholinergic compounds (atropine, scopolamine) as well as some anaesthetics such as ketamine, benzodiazepines or even propofol may produce delirium and/or an increase in efficacy when given together with opioids. Therefore it is mandatory to consider a pharmacologic interaction with a potentiation and/or an addition in effects of other drugs when judging the net action of opioids in the elderly. Physicians and nurses treating geriatric patients tend to have an unfounded level of fear of complications associated with treating perioperative pain. Although it is known that inadequate analgesia may delay recovery, the treatment of perioperative pain in the geriatric patient remains inadequate, even relative to younger patients. It is well established that there is increased responsiveness to the effects of opioids in the elderly. This may result in an increased risk of respiratory depression, while especially the elderly female patient demonstrates an increase in the duration of effects, but the risk of nausea is not augmented. Increased sensitivity of older patients to systemic opioids mostly involves pharmacokinetic factors such as a higher proportion of unbound and active substances as well as changes in drug redistribution. Because of a 40 % reduction in stroke volume in the elderly, there is a protracted redistribution of opioids to the liver. This results in a prolonged metabolisation, a lesser inactivation over time followed by an increase in duration of effects, mainly impairment of respiration. To a much lesser extent, pharmacodynamic factors with an increased response at opioid receptor sites have to be considered. Although the mechanisms causing differences of opioid action in the elderly may be complex, the clinical implications are not. They include slow titration of opioids to allow for long circulation times, lower total doses because of increased sensitivity, and anticipation of a longer duration of action because of reduced clearance. Since elderly patients present multimorbidity, therapy of chronic pain has to be considered in the light of multidrug intake, which, due to interaction, results in marked side-effects, and a prolonged duration of action. Those opioids should be used which, due to their pharmacokinetic properties, have a reduced volume of distribution, present a low plasma protein binding and finally result in the formation of no pharmacologically active metabolites.

No difference in electroencephalographic power spectra or sensory-evoked potentials in patients anaesthetized with desflurane or sevoflurane.

BACKGROUND AND OBJECTIVE: Hitherto, neither desflurane nor sevoflurane, with similar physicochemical properties, have been compared with regard to their effects on the central nervous system. We compared the effects of desflurane and sevoflurane on electrical cortical activity and sensory transmission at two anaesthetic concentrations in patients undergoing hysterectomy. METHODS: The 1 and 2 MAC in nitrous oxide/oxygen (55%/45%) of desflurane or sevoflurane were administered while electroencephalographic power spectra and the somatosensory-evoked potentials were measured and correlated with cardiovascular effects. RESULTS: Both volatile agents induced a concentration-related increase of power in the slow delta-band and a concomitant decrease of power in the fast beta-domain. There was a close correlation with regard to the decrease in beta-power and heart rate (r2 = 0.988) and systolic blood pressure (r2 = 0.952) following both agents. Desflurane and sevoflurane had little effect on the early N20-peak, but affected the late N100-peak. There was a concentration-related increase in latency and a depression of amplitude height. Changes were not significantly different between both agents. CONCLUSIONS: Both desflurane and sevoflurane possess a similar profile with regard to their hypnotic effects and a similar outline in depressing propagation within the sensory nervous system. Cortical nervous effects are mirrored closely in heart rate and systolic blood pressure.

Use of gabapentin for attenuation of symptoms following rapid opiate detoxification (ROD)--correlation with neurophysiological parameters--.

Rapid opiate detoxification (ROD) is a technique whereby the opiate-dependent patient is withdrawn acutely, under anesthesia, from the opioid. Following detoxification, patients experience severe back pain and restlessness often accompanied by a restless-leg-syndrome. We evaluated gabapentin given immediately following detoxification to attenuate these symptoms. In addition, we evaluated the use of the somatosensory-evoked potential (SEP) as a parameter to quantitate pain responses. Patients (n=21; mean age 32.5 +/- 7 SD; 12 males, 9 females) underwent ROD with naltrexone (2 x 50 mg) during propofol anesthesia and artificial ventilation (IPPV). Sympathetic overshoot was attenuated by clonidine, and increased bowl movement was managed by continuous i.v. somatostatin. Back pain, restlessness, and restless-leg-syndrome were treated with gabapentin (1200 mg) in the ICU. Efficacy was assessed by the patient's subjective ratings of restlessness (0-4). In addition, measurements of amplitude (microV), latency (ms) of late N100-peak of the somatosensory evoked potential (SEP), and tolerance to an increased electrical nociceptive stimulus (mA) to the forearm were performed. Data were compared to pre-treatment control and to the period shortly after detoxification. From a mean of 8.4 +/- 2.5 microV, N100-peak increased to a mean of 12.3 microV +/- 3.3 (p < 0.005) following opioid detoxification. Gabapentin reduced amplitude height to a mean of 3.5 +/- 1.5 microV. Also, tolerance to nociceptive stimulus, which had dropped to 4.4 mA, increased to 12.5 mA (p < 0.01), while intensity for restlessness and thrashing of limbs dropped from 3.2 to 1.2 (p < 0.05). The sudden displacement of the opiate from its receptor site induced by naltrexone, resulted in a post inhibitory SEP overshoot with an increase in nociceptive afferent volleys, and a lowering in pain threshold. This was associated with back pain, limb thrashing and a restless-leg-syndrome, all of which could be attenuated by gabapentin. The amplitude of late N100-peak parameter appears to be a potential candidate to quantify the increase of nociception in such patients.

[Postoperative routine use of physostigmine on vigilance, cardiovascular parameters and need of analgesics]. / Routinemässige Gabe von Physostigmin hat für die postoperative Phase keine Bedeutung--eine randomisierte Untersuchung zur Vigilanz, zum Kreislaufverhalten, Muskelzittern und Schmerzmittelbedarf.

OBJECTIVE: A central anticholinergic syndrome (CAS) can be related to the majority of anesthetic agents, but is often not recognized as such. Thus, most anesthesiologists seem to miss the occurrence of an anticholinergic syndrome especially when agitation and/or restlessness are the major symptoms. Therefore, the following study was undertaken to test the hypothesis that routine administration of the anticholinergic agent physostigmin is of benefit for patients in regard to vigilance, the cardiovascular system and the need of analgesics easing the time in the post anesthesia care unit (PACU). METHODS: After approval by the local ethics committee and written informed consent, 100 patients undergoing a cholecystectomy or a struma resection, were given either physostigmin (n = 51) or saline 0.9 % (n = 49) in a randomized fashion. The study was conceived to block a possible isoflurane-N2O/O2 (opioid-based plus relaxant) induced central anticholinergic syndrome and to evaluate the effects on the cardiovascular system on vigilance and on postoperative analgesic demand. Following parameters were measured: systolic and diastolic blood pressure, heart rate, respiratory rate, and arterial blood gases. In addition, vigilance was determined and typical anticholinergic symptoms (disorientation, slurred speech, agitation, nausea, emesis, cardiac arrhythmia and muscle shivering) were determined 10, 20, 40 and 60 minutes following the intravenous injection of physostigmin. Also, the need for the postoperative analgesic pethidine was evaluated among the two groups. RESULTS: Except for a significant reduction in the need of analgesics, a reduced diastolic pressure and heart rate and a lower incidence of muscle shivering there was no difference among the two groups. One major side effect following the use of physostigmin was the higher incidence of nausea in the im mediate minutes following injection. This effect may be due to the rapid injection of the anticholinergic compound. Otherwise there were no detrimental effects of physostigmin in patients. CONCLUSION: From the results it can be concluded that routine administration of an anticholinergic agent results in a short term beneficial effect in regard to vigilance, a lesser incidence of muscle shivering and a lesser demand for analgesics. However, because of the low incidence of a classical central anticholinergic syndrome, routine physostigmine is only indicated when agitation is diagnosed.

[Development of opioid tolerance -- molecular mechanisms and clinical consequences]. / Toleranzentwicklung unter Opioidgabe -- Molekulare Mechanismen und klinische Bedeutung.

INTRODUCTION: One often identified effect of opioid administration is that of the development of tolerance to the analgesic effect. While it is generally agreed that tolerance to opioid analgesia does occur, it does not appear to be a limiting factor. Dose escalation in chronic pain therapy is considered to be predominantly a consequence of increasing pain, which is a result of increasing nociceptive input as the disease progresses. The underlying cause of tolerance to opioids, however, as commonly identified in the ICU can be identified as an adaptation process. When the opioid is given continuously several causes of adaptation can be identified, all of which can be traced back to the cellular and molecular level. RECEPTOR RELATED CHANGES INVOLVED IN TOLERANCE: Initial effects of opioid administration in most individuals are analgesia, sedation, nausea/vomiting, respiratory depression, pupillary constriction, constipation and euphoria or dysphoria. However, numerous studies and clinical experience suggest that tolerance to different opioid effects develop at different rates, which has been termed selective tolerance. While tolerance to nausea, vomiting, sedation, euphoria and respiratory depression occur rapidly, there is minimal development of tolerance to constipation and miosis. Such diversity suggest receptor-related differences in the speed of development of tolerance. In the ICU other compounds such as benzodiazepines, when given together with opioids, seem to speed up the rate of development of tolerance of the latter. Such an effect very likely is due to a reduction in activity of the descending inhibitory nervous system. In addition, there is surmountable data suggesting that the higher the intrinsic activity of the opioid at only one receptor site, lesser receptors are needed in order to induce a potent analgesic effect. As a net result the incidence of tolerance is less likely to become clinically apparent when potent ligands such as fentanyl or sufentanil are administered. N-METHYL-D-ASPARTATE (NMDA) ACTIVATION, OPIOID RECEPTOR INTERNALIZATION AND DESENSITIZATION: An altered metabolism has little effect on the rate of development of tolerance. In chronic pain treatment with morphine, however, an increased ratio of the metabolite morphine-3-glucuronide, with antiopioid effects, to morphine-6-glucuronide is associated with staggering doses of the analgesic. Opioids which interact with micro - and/or kappa-binding sites, demonstrate an adaptation process called desensitization which is due to a reduced interaction with the internal second messenger system called G-protein. This is only a short-lived phenomenon following binding of the ligand. Another underlying mechanism of tolerance development is that of internalization of the opioid receptors. This short-lived phenomenon, termed endocytosis, results in lesser binding sites available for the mediation of analgesia. Another and more relevant mechanism of long-term opioid binding is that of subsequent protein kinase C (PKC), phospholipase C (PLC) translocation and activation of nitric oxide synthetase (NOS). All of this contributes to a N-methyl-D-aspartate (NMDA) receptor activation with ensuing antiopioid effect and tolerance. CLINICAL CONSEQUENCES FOLLOWING THE DEVELOPMENT OF TOLERANCE: Most likely genetic difference in opioid receptor synthesis and difference in their affinities for various ligands is the cause for the wide margin of dose variability in patients (genetic polymorphism). Once tolerance to the analgesic effect of the opioid is observed and in order to avoid unnecessary further development of tolerance, simultaneous administration of other receptor mediated analgesics is advocated. In the perioperative period strategies like the multimodal analgesic concept is fostered. It consists of the simultaneous administration of low-dose ketamine, co-administration of an alpha 2-agonist, and the administration of a selective COX-2 inhibitor (refecoxib, parecoxib) respectively. In chronic pain therapy combined administration with either dextromethorpharphane, or opioid rotation of a more potent ligand such as methadone, fentanyl TTS or oxycodone is suggested. Since conversion factors are not reliable in opioid rotation, it is best to start off with 50 % of the equivalent dose and rapidly titrate to the desired effect. With regard to tolerance development in the ICU, co-administration of an alpha 2-agonist (clonidine, dexmedetomidine), and daily intermittent cessation of benzodiazepine administration are advocated. Since continuous dosing of an opioid, commonly handled in the ICU setting is more likely to induce tolerance, intermittent administration is advocated. Taken together, there is an abundance of experimental data which suggests, that with every dose of an opioid several adaptive processes are being initiated. Due to genetic polymorphism such adaptation is seen clinically with striking individual different dosages, the degree and the time of onset of tolerance. Although tolerance development may result in staggering doses of an opioid, there is no reason to evade the use of such agents. On the contrary, the concept of multimodal analgesia consisting of the simultaneous use of analgesics with a different mode of action can counteract tolerance development.

[Pain and opioids in preterm and newborns]. / Schmerz und Opioide bei Neugeborenen und Säuglingen.

Despite the fact that neonates and infants are not capable of expressing their subjective pain sensations, it has become clear that they do perceive nociception, as pain correlates to hormonal, metabolic, immune, and cardiovascular changes. New findings support the notion that repetitive painful stimuli result in long term psycho-physiological effects with ensuing decreased attentiveness and orientation, poor regulation of behavioral state and motor processes, increase in irritability as well as an altered pattern of feeding and sleeping. These sequelae of repetitive painful experiences with an increase in sensitization of sensory afferent input supports the view of a sufficient analgesia during all kinds of painful procedures in the preterm and neonate. In order to sufficiently diminish nociceptive afferent input during surgery opioids are the drugs of choice aside from local anesthetics. However, the use of opioids in neonates and especially preterm infants must be considered in the light of certain pharmacokinetic and pharmacodynamic differences when compared to adults: 1. There is a longer elimination rate, which may result in post-operative overhang of respiratory depression, especially when opioids are given repetitively, resulting in an accumulation and an increased duration of action. 2. There is a reduced hepatic enzyme activity, which ultimately affects clearance rate. 3. The blood-brain-barrier is not fully developed in the preterm, which results in more access of opioids to binding sites in the CNS. 4. Differentiation of opioid-binding sites into mu, delta, and kappa has not reached its peak; thus, higher doses relative to body weight are needed to establish a sufficient deep plane of analgesia. 5. Caudal parts of the CNS, especially the pons-medullar region exhibit an earlier expression of receptors than the rostral parts. Sequelae of such differences are a more pronounced respiratory depression, often due to muscular rigidity, and bradycardia after which a full analgesic effect takes place. Despite such potential drawbacks, opioids are still the best choice as they sufficiently block nociceptive afferent input and when compared to other anesthetics, they show the least cardiovascular changes. One, however, has to bear in mind that dosing is done according to effect and not to body weight while potential side effects are most prominent in the preterm infant.

Dose-related effects of controlled release dihydrocodeine on oro-cecal transit and pupillary light reflex. A study in human volunteers.

It is well accepted that long-term administration of opioids results in a dose-related constipation. No data so far have demonstrated conclusively whether such constipation is also seen after intake of a controlled release formulation. It was therefore of interest to evaluate whether increasing doses of a controlled release formulation of dihydrocodeine (DHC, CAS 125-28-0) after oral administration also induces a dose-related increase in constipation. Additionally, it was of interest to study whether such a peripheral opioid-related side effect is also seen in another, central receptor-mediated effect, the constriction of the pupil, at clinically relevant doses. Twelve volunteers were given controlled release DHC (60 and 120 mg, respectively) or placebo orally within a randomized, double-blind cross-over study. In order to determine the degree of constipation, oro-cecal transit time was measured using the H2-exhalation test. Additionally, in order to evaluate a centrally mediated effect, the response of the pupil to light was quantified using the pupillary light reflex technique. Both, peripherally and centrally mediated effects were compared to placebo. DHC at both dosages induced a significant (p < 0.01) prolongation of oro-cecal transit time when compared to placebo. However, prolongation of oro-cecal transit was not significantly longer when comparing the lower (60 mg) with the higher dose (120 mg). DHC also induced a significant (p < 0.005) depression of the pupillary light reflex from 53.9 mm (control) to 8.3 and 7.4 mm, respectively. Similar to intestinal transit, the pupillary light reflex was not significantly different among the two doses of DHC. Also, both dosages induced a similar amount of side effects. Tiredness and dry mouth were reported in 80% after both doses while vertigo was reported in 5% and 1% complained of headache. None of the volunteers reported nausea or emesis. It is concluded that opioid receptor sites, which are located in the plexus myentericus of the intestinal wall, are responsible for the delay in propulsion. Because of the controlled release of a fixed amount of DHC over time there is constant binding of the ligand followed by a constant conformational change of peripheral and central receptor sites. Thus constant release induces no dose-related increase in oro-cecal transit and inhibition of the pupillary light reflex.

Acute abstinence syndrome following abrupt cessation of long-term use of tramadol (Ultram): a case study.

We report on a patient who had taken the centrally acting analgesic tramadol for over 1 year. The compound had proven to be sufficient to treat her painful episodes related to fibromyalgia. Due to lack of supply while being on a trip, intake of the drug was stopped abruptly, resulting in the development of classical abstinence-like symptoms within 1 week. Abstinence-like symptoms consisted of restlessness and insomnia for which the benzodiazepine lorazepam was given. Diarrhoea and abdominal cramps were treated with the peripherally active opioid loperamide, while bouts of cephalgia were treated with sumatriptan. Diffuse musculoskeletal-related pain and restless leg syndrome (RLS) were treated with dextromethorphan. All these different medications proved to be efficacious as they resulted in the cessation of symptoms. Within 1 week symptoms ceased and the patient regained her normal activities without any sequelae. Although tramadol is considered a non-habit- and non-dependence-forming analgesic, abstinence symptoms are likely to develop following abrupt cessation of intake, especially when the compound had been taken over 1 year. Therefore patients should be advised of such an effect whenever they decide to stop intake or their physician is planning to switch to another medication. To avoid abstinence-like symptoms doses should be slowly tapered down.

14-methoxymetopon, a potent opioid, induces no respiratory depression, less sedation, and less bradycardia than sufentanil in the dog.

UNLABELLED: Opioids of the mu-receptor type depress respiration and induce addiction. At 10-min intervals 14-methoxymetopon (HS-198), which is 20,000 times more potent than morphine in the acethylcholine-writhing test, was given in graded IV doses (3, 6, and 12 microg/kg) to awake, trained canines (n = 7). The following variables were derived: PaO(2), PaCO(2), heart rate (lead II of the electrocardiogram), mean arterial blood pressure, relative changes in the delta domain and the beta domain of the electroencephalogram, the somatosensory evoked potential, and the skin-twitch reflex to electrical stimuli. Thereafter, 20 microg/kg naltrexone was given for reversal. After a washout period, the same animals were exposed to similar doses of sufentanil (SUF) followed by naltrexone. Both opioids induced a dose-related bradycardia and hypotension. The maximal bradycardic effect was 19% after HS-198 and 42% after SUF (P < 0.005). The maximal hypotension was 6% after HS-198 and 20% after SUF (P < 0.01). In the electroencephalogram, power in the delta band increased by 288% after HS-198 and by 439% after SUF (P < 0.01); simultaneously, power in the beta band decreased by 71% and by 95.7%, respectively (P < 0.01). PaO(2) decreased by 41% after SUF and by 4% after HS-198, and PaCO(2) increased by 56.8% and 6.6% in SUF and HS-198, respectively (P < 0.001). Both opioids induced a dose-related depression in the somatosensory evoked potential and increased tolerance to skin-twitch. The maximal effect was 92.7% after SUF and 81.3% after HS-198 was not significant. Naltrexone reversed all changes back to control. Compared with SUF, HS-198 does not induce hypoxia and hypercarbia, induces less hypotension and bradycardia, and induces less sedative effects. IMPLICATIONS: Compared with sufentanil, 14-methoxymetopone does not induce hypoxia and hypercarbia, induces less hypotension and bradycardia, and induces less sedative effects (electroencephalogram). Antinociception is similar to sufentanil (skin-twitch method, amplitude depression in the evoked potential). All effects are reversed by naltrexone. Interaction of kappa-receptor is suggested.

Effects of tramadol and tilidine/naloxone on oral-caecal transit and pupillary light reflex.

As has been demonstrated in binding studies the two opioids tilidine (CAS 27107-79-7)/naloxone (CAS 357-08-4) and tramadol (CAS 36282-47-0) differ in regard to their affinities to the opioid receptor site. Therefore it is of interest to evaluate whether such a difference in opioid affinity is also seen in the pharmacological effects of clinically relevant doses in man. Following institutional approval by the local ethical committee and informed consent, 12 volunteers received oral doses of tramadol (100 mg), tilidine/naloxone (100 mg) and placebo, respectively, in a randomized, double-blind cross-over design. In order to determine the degree of constipation, oral-caecal transit time was measured using the H2-exhalation test. Additionally, in order to evaluate a centrally mediated effect, the response of the pupil to light was quantified using the pupillary light reflex technique. Both, peripheral and central mediated effects were compared to placebo. Tramadol as well as tilidine/naloxone induced a significant (p < 0.05) prolongation of oral-caecal transit when compared to placebo. However, prolongation of oral-caecal transit was significantly longer in the tilidine/naloxone (p < 0.05) than in the tramadol group. Compared to tramadol, the pronounced constipating effect of tilidine/naloxone is likely to be due to the 10 fold higher affinity of that drug to the peripheral opioid receptor sites in the intestinal tract, which are responsible for normal propulsion. Such difference in binding is underlined by a central effect, the pupillary light reflex response. The amount of constriction of the iris to light was reduced after both opioids. Again, tilidine/naloxone significantly reduced (p < 0.001) the pupillary light reflex when compared to tramadol. Other side effects such as tiredness, nausea, emesis and dry mouth were more often reported after tilidine/naloxone than after tramadol (40% versus 15%; p < 0.05). Vertigo and perspiration were more often reported after tramadol than after after tilidine/naloxone (58% and 78% versus 8%; p < 0.01). All these data support the findings that while tramadol is considered an opioid, it does not mediate its main clinical relevant properties via binding at the opioid receptor. More likely, due to its monoaminergic reuptake mechanism, to a lesser extent opioid-like effects are induced.

No reduction in the sufentanil requirement of elderly patients undergoing ventilatory support in the medical intensive care unit.

The aim of the study was to test the hypothesis that the requirement of sufentanil is reduced in elderly patients when the opiate is primarily used to facilitate mechanical ventilation in a medical intensive care unit. A further aim was to study whether elderly patients developed withdrawal symptoms after discontinuing prolonged sufentanil administration. We have studied prospectively two groups of patients requiring mechanical ventilation for more than 96 h; group 1 age < 60 years (n = 316 or 68%) and group 2 age > 70 years (n = 150 or 32%). In all patients sufentanil and midazolam were administered continuously in order to facilitate ventilatory support. After an initial intravenous bolus injection of sufentanil 3.0-8.0 micrograms kg-1, the dosage was adjusted to the patients needs (0.75-1.0 microgram-1 kg-1 h) using a modified Ramsey score by accepting between 3b and 4a as the end point. The amount of sufentanil administered and side effects were recorded at 24-h intervals. Seventy-two hours following the start of sedation with sufentanil/midazolam the dose of sufentanil required for sedation increased significantly (P < 0.05) in both groups when compared with the first 24 h. There was no statistical difference between the two groups in sufentanil requirement at any time during the study. This suggests that tachyphylaxis develops to a similar degree in patients in both age groups. In addition, weaning in the elderly was characterized by a similar degree of withdrawal-like symptoms suggesting that independent of age, there are similar receptor related reactions once the opiate is withdrawn.

Slow EEG-power spectra correlate with haemodynamic changes during laryngoscopy and intubation following induction with fentanyl or sufentanil.

We studied nociception-associated arousal following laryngoscopy and intubation in patients scheduled for elective open heart surgery, using EEG power spectra and hemodynamics. Either fentanyl (7 micrograms/kg; n = 30) or sufentanil (1 microgram/kg; n = 30) were given in a randomized fashion to induce anesthesia in heavily premedicated patients, followed by pancuronium bromide (100 micrograms/kg). EEG-power spectra (delta, theta, alpha, beta) as well as mean arterial blood pressure (MAP) and heart rate (HF) were measured at the following end-points: before the induction of anesthesia (control), 1 and 10 minutes after laryngoscopy and intubation (L & I). Linear regression analysis was computed to determine which of the EEG power spectra was most sensitive to detect insufficient blockade of nociceptive-related arousal when correlated with haemodynamics. In the fentanyl group the change in HF closely correlated with the decrease of power in the slow delta- and theta-domain (r2 = 0.98 and r2 = 0.89 respectively) of the EEG. The change in MAP also closely correlated with a decrease in the slow delta- and theta-domain (r2 = 0.97 and r2 = 0.99 respectively). There was little correlation in regard to spectral edge frequency (SEF) and HF and MAP changes (r2 = 0.36 and r2 = 0.12 respectively). In the sufentanil group the change in HF correlated closely with an increase of power in the fast alpha and a decrease in the slow theta-domain (r2 = 0.91 and r2 = 0.98 respectively) of the EEG. The changes in MAP closely correlated with an increase in the fast alpha-band a decrease in the slow theta-domain (r2 = 0.98 and r2 = 0.73 respectively). Also there was little correlation of SEF with HF and MAP changes (r2 = 0.09 and r2 = 0.02 respectively). Among the EEG-spectra, reduction of power in the slow delta- and theta-bands are the most sensitive parameters to determine insufficient antinociception of opioids commonly used for the induction in cardiac anesthesia. Increase of power in the alpha-band seems to be closely correlated with cortical reactivation and reduction of hypnosis, while a reduction of power especially in the deltabut more so in the theta-band of the EEG reflects nociception related arousal.