No hyperalgesia following opioid withdrawal after the oripavine derivative etorphine compared to remifentanil and sufentanil.

BACKGROUND AND OBJECTIVE: The concept of opioid-induced hyperalgesia has recently gained prominence as a contributing factor for long-term treatment failure. METHODS: To evaluate possible differences of opioids used in anaesthesia, cumulative doses of sufentanil and remifentanil were compared with escalating doses of the oripavine derivative etorphine, in awake and trained canines. This was followed by naloxone unmasking a possible hyperalgesic state, which had developed during opioid administration. Heart rate, blood pressure and propagation of nociceptive volleys in somatosensory-evoked potentials as well as the skin-twitch reflex were evaluated. RESULTS: Opioid-related hypotension and bradycardia were reversed by naloxone with a late (30 min) overshoot of R43 and R17% after remifentanil and sufentanil, respectively. Following etorphine, overshoot in mean blood pressure was R9%, whereas heart rate still remained below S9% when compared with control. Peak hyperalgesia, as detected in the somatosensory-evoked potential and skin-twitch, increased by R70% after remifentanil and by R43% after sufentanil. This reflected a significant (P<0.005) increase in propagation of nociceptive afferents as late as 30 min after naloxone reversal. Such potentiation was not observed in the etorphine group, as peak somatosensory-evoked potential deflection and skin-twitch remained below S80% when compared with control. CONCLUSION: The pure mu-agonists sufentanil or remifentanil seem to induce a 'bimodal' inhibitory followed by an excitatory effect. The latter is unmasked by naloxone in the postadministration period. In contrast, this is not seen with etorphine, a close congener of buprenorphine. The proposed mode of action of such hyperexcitatory effects may involve second-messenger-mediated G-protein activation, originally proposed by others. Ligands of the oripavine series may present an alternative for prevention of opioid-induced hyperalgesia in patients.

A new transmucosal drug delivery system for patients with breakthrough cancer pain: the fentanyl effervescent buccal tablet.

Breakthrough pain, a transitory severe pain with the background of otherwise controlled persistent pain has a prevalence between 52% and 67% in outpatients with cancer. Medications for such sudden-onset pain require non-invasive delivery of a potent and short-acting opioid for rapid pain relief. Although oral transmucosal delivery of fentanyl citrate (OTFC) has been shown to provide better pain relief than a typical oral opioid administration such as morphine sulfate immediate release (MSIR) in the management of breakthrough pain in patients with cancer-related pain, newer delivery systems offer a potential for further enhancement of pain relief. The fentanyl effervescent buccal tablet (FBT) formulation employs a novel drug delivery system that relies on an effervescence reaction to improve buccal fentanyl absorption. Using the effervescence reaction results in the production and dissipation of carbon dioxide with a dynamic shift in pH as the tablet dissolves. The induced low pH favors dissolution of fentanyl citrate in saliva (higher water solubility). The subsequent increase in pH thereafter favors the buccal absorption of non-ionized fentanyl across the buccal mucosa. Such a pH "pumping" mechanism increases the permeation of fentanyl into and through the buccal to the vascular system from where the agent is transported to the specific opioid receptor sites in the CNS. Compared with OTFC, data in healthy volunteers show that the effervescence reaction employed in FBT increases the total amount and the speed of absorption of fentanyl being absorbed. Compared with OTFC there is an increase in peak fentanyl blood concentrations, and an enhancement of the amount of buccal delivery of fentanyl. Such favorable data are underlined by the results of clinical studies where the FBT technology was studied in patients with breakthrough pain in chronic malignant pathologies.

Effervescent morphine results in faster relief of breakthrough pain in patients compared to immediate release morphine sulfate tablet.

Morphine tablets have been formulated to produce an easily ingested effervescent solution when placed in water. It was hypothesized that an aqueous solution would result in fast gastrointestinal transit with a more rapid onset of action compared to immediate release morphine sulfate (IRMS), which would be especially beneficial in treating breakthrough pain (BTP). In an open-label safety and efficacy study, effervescent morphine was given to 76 chronic cancer pain patients for treatment of BTP evaluating time until pain relief, global satisfaction and side effects. Results were compared to those obtained using an IRMS formulation in a preceding run-in period. For BTP, a mean dose of 28 mg of effervescent morphine (range 10-80 mg) resulted in a highly significant reduction of pain score (mean 7.8 to mean 3.2; P < 0.001). Efficacy was not different from that observed with IRMS. However, mean time until sufficient pain relief was significantly shorter than with IRMS (13 +/- 5.6 vs. 27 +/- 4.4 minutes; P < 0.01). The incidence of side effects was similar with the new morphine formulation and with IRMS. There was no relationship between the previous dose of the daily opioid and the effective dose of effervescent morphine. The dose for treatment of BTP was determined by individual titration and not predicted by the dose taken with the basic pain medication. Compared to IRMS, overall satisfaction for effervescent morphine was rated "superior" by 16.7%, and "better" by 63.2% of patients. Effervescent morphine offers an alternative for management of breakthrough cancer pain compared with the commonly used IRMS.

Opioid rotation from high-dose morphine to transdermal buprenorphine (Transtec) in chronic pain patients.

Opioid rotation is increasingly becoming an option to improve pain management especially in long-term treatment. Because of insufficient analgesia and intolerable side effects, a total of 42 patients (23 male, 19 female; mean age 64.1 years) suffering from severe musculoskeletal (64%), cancer (21%) or neuropathic (19%) pain were converted from high-dose morphine (120 to >240 mg/day) to transdermal buprenorphine. The dose of buprenorphine necessary for conversion (at least 52.5 microg/h) was titrated individually by the treating physician. No conversion recommendations were given and the treating physician used his or her own judgment for dose adjustment. Pain relief, overall satisfaction and quality of sleep (very good, good, satisfactory, poor, or very poor), and the incidence and severity of adverse drug reactions over a period of at least 10 weeks and up to 1 year was assessed. Following rotation, patients experiencing good/very good pain relief increased from 5% to 76% (P < 0.001). Only 5% reported insufficient relief. Relief was achieved with buprenorphine alone in 77.4%, while 17% needed an additional opioid for breakthrough pain. Sleep quality (good/very good) increased from 14% to 74% (P < 0.005). Adverse effects were reported in 11.9%, mostly because of local irritation, did not result in termination of therapy. Neither tolerance nor refractory effect following rotation from morphine to buprenorphine was noted. Conversion tables with a fixed conversion ratio are of limited value in patients treated with high-dose morphine.

S(+)-ketamine attenuates increase in electroencephalograph activity and amplitude height of sensory-evoked potentials during rapid opioid detoxification.

Anesthesia-assisted opioid detoxification offers an opportunity for patients who have undergone unsuccessful conventional detoxifications. Little is known of excitatory effects taking place in the central nervous system during this procedure. Because acute withdrawal is accompanied by N-methyl-d-aspartic acid (NMDA)-receptor activation we tested whether the administration of the nonspecific N-methyl-d-aspartic acid antagonist S(+)-ketamine results in a reduction of hyperactivity in the central nervous system. Thirty-one patients with a long history of opioid abuse were acutely withdrawn with naltrexone during propofol/clonidine anesthesia and mechanical ventilation. Electroencephalogram (EEG) power spectra as well as median nerve-evoked somatosensory potentials (SSEP) were determined at the following times: evening before detoxification (control), steady-state propofol/clonidine-anesthesia, 30 min after naltrexone administration, and 5 min and 60 min after additional S(+)-ketamine (1.5 mg/kg). Compared to steady-state anesthesia, naltrexone induced a decrease by 270% in the low delta (0.5-3 Hz) and an increase by 110% in the fast beta (13-30 Hz) domain of the EEG with only minor changes in the theta-(3-7 Hz) and alpha-(7-13 Hz) band. Simultaneously, mean amplitude of the late N(100) peak of the SSEP increased from 3.3 muV to 10.5 muV. The changes could be attenuated by the additional administration of S(+)-ketamine, 5 min and 60 min after injection. Cardiovascular changes were not a reliable index for monitoring acute withdrawal symptoms and determining termination of rapid opioid detoxification. In this regard, EEG power spectra and SSEP were more consistent and clinically useful variables. S(+)-ketamine is a valuable adjunct in the anesthetic regimen, since it attenuates hyperactivity of the central nervous system during rapid opioid detoxification.

Cerebral monitoring in the operating room and the intensive care unit: an introductory for the clinician and a guide for the novice wanting to open a window to the brain. Part I: The electroencephalogram.

While there is an increasing body of knowledge in regard to central nervous system function and/or the mode of action of centrally active agents on neuronal function, little is done to develop new techniques on how to measure such changes. Also, monitoring of the cardiovascular system in the past has made extensive progress especially when it comes to evaluate the failing heart. In contrast monitoring of the central nervous system is only done in rare cases where operative procedures likely impede nervous function integrity. Since in the past decade the aging population undergoing operation has rise considerably, the risk of cerebral malperfusion or minute signs of degradation of the aging central nervous system (CNS) to anesthetics and agents being used in the operation room (OR) or the intensive care unit (ICU), needs continuous monitoring of an organ which presents the highest vulnerability and is likely to deteriorate faster than the cardiovascular system. In spite the rapid improvement in technology regarding the electroencephalogram (EEG) and evoked potential monitoring, physicians still are reluctant to use a technology on a routine base, which will give them insight information into brain function and activity. Such "windows to the brain" now not just are reserved to specialists working in the area of neurology and/or psychiatry. More so, cerebral monitoring is getting an integrated part in the overall therapy in patients undergoing operation or who need ventilatory support in the ICU as it effects the well-being and the outcome. The present book therefore, is intended for the practitioners who work with the patient, guide the clinician in his decision making and outlining those situations where cerebral monitoring presents an integrated part in the diagnosis and therapy of patient care. Without going too much into the technical details, representative cases underline the potential use of cerebral monitoring in the underlying clinical situation where either the patient presents borderline perfusion of the CNS, undergoes vascular surgery, or where monitoring of cerebral function in the intensive care in a head trauma patients is an integrated part in therapy. The book therefore is meant for all those clinicians who have to deal with the CNS in a day-to-day situation. This may be the anesthesiologist, the surgeon, the intensive care therapist, the nurse anesthetist as well as all other medical personal involved in intensive care therapy. The aim of the book therefore is to outline the possibilities, the limitations, and the options for therapy when the windows to the brain are opened, how to interpret the data in the light of other physiological parameters and aid the user in the technical details of how to avoid artifacts in recording which may have an impact on final decision making. Therefore, emphasis is placed on the electrode placement, artifact and electrical noise reduction, as well as data interpretation so that cerebral function diagnosis can be made on reliable grounds. The following serves as an introduction to and as a reference guide for Cerebral Monitoring in the OR and the ICU: Gives complete coverage of EEG power spectra analysis. Describes in detail the EEG machines available to be used in the OR and ICU setting. Describes in detail the major features of EEG power spectra and evoked potential measurements, including amplifiers, filter setting and microprocessor algorithm for data reduction. Gives suggestions for assessing and improving signal quality, including noise and artifact rejection, which usually are encountered in the operation room and the intensive care unit, both of which can be considered as electrically contaminated. Gives examples of EEG power spectra and evoked potential monitoring related to different types of anesthesia, in coma, after head trauma, and for the detection of ischemic events. In addition, gives complete coverage of those machines being available for the OR and the ICU, including a list of parameters regarding latency and amplitude in evoked potential As an introductory, recommendations are given for the novice to start cerebral monitoring and guide the beginner in setting up cerebral monitoring in the clinical environment.

Cerebral monitoring in the operating room and the intensive care unit - an introductory for the clinician and a guide for the novice wanting to open a window to the brain. Part II: Sensory-evoked potentials (SSEP, AEP, VEP).

An evoked potential differs from the EEG mainly in two ways: 1. The EEG is a random, continuous signal, which arises from the ongoing activity of the outer layers of the cortex. An evoked potential is the brain's response to a repetitive stimulus along a specific nerve pathway. 2.EEG signals range from 10-200 milliVolt (mV). Evoked potentials are smaller in amplitude (1-5-20 microVolt requiring precise electrode positioning and special techniques (signal averaging) to extract the specific response from the underlying EEG "noise". The technique of signal averaging, as originally described by Dawson in 1954 [69J, has been further developed in computer processing. The technique is now used by applying a stimulus repeatedly--preferably at randomized intervals--and to record the evoked response over the corresponding area of the brain, averaging out mathematically the change over the number of stimuli. Rationale for the use of EPs in the OR and the ICU. Evoked potentials (EPs) serve the following major purposes: 1. Monitoring of the functional integrity of neural structures that may be at risk during, for instance, ECC (extracorporeal circulation) or endarterectomy indicating cerebral hypoxia. 2. Monitoring of the effects of anesthetic agents and other centrally active drugs, which, besides the cortex, affect deeper neuronal structures. 3. Orthopedic cases where the spinal cord is at risk such as Harrington rod insertion and removal. 4. Clamping of the abdominal aortic artery during aneurysmectomy resulting in a potential damage of the lower parts of the spinal cord. 5. Clipping of an intracerebral aneurysm, which may be impeding blood flow to vital cerebral textures. 6. An indicator of cerebral hypoxia when the blood pressure is deliberately lowered. 7. Operation on peripheral nerves and nerve roots to identify early trauma. 8. Monitoring the cerebral function during controlled hypothermia when the EEG becomes flat. 9. Monitoring of the pathophysiological conditions after severe head trauma and the effects of therapy. 10. An intraoperative warning device of unsuspected awareness during light anesthesia when movement is abolished by muscle relaxants and cardiovascular responses are modified by vasoactive drugs. In case of the latter the stimulus is a small electrical potential applied to the skin of the hand. Thereafter, the stimulus travels along the specific nervous pathways inducing (= generating) potential activation at various sites. The generation of potential changes at various sites along the pathway is an index for the integrity of the nerve. Thus, the evoked potential can be considered a neurophysiological response (usually of the cortex) to impulses originating from some externally stimulated sensory nerve. They provide a physiological measure of the functional integrity of the sensory nerve pathway, which can be used as a clinical diagnostic tool as well as for intraoperative monitoring. The evoked potential usually is recorded from the specific cortical area corresponding to the stimulus input. The classification of evoked potentials. Stimulating a sensory nervous pathway induces evoked potentials. If the auditory nerve is stimulated by "clicks" from headphones, it is called the auditory evoked potential (AEP). The early part of the AEP waveform (less than 10 msec) is called the Brainstem Auditory Evoked Potential (BAEP) since it reflects the passing of the impulse through the brainstem. If a nerve on the arm or the leg is stimulated by a small electrical current applied to the overlying skin, it is called the Somatosensory Evoked Potential (SSEP). If, however, the retina is stimulated by means of flicker light or a sudden change in a checkerboard pattern, the evoked potential thus recorded over the corresponding cortical area is called the Visual Evoked Potential (VEP). Evoked potentials are used both as a diagnostic tool and as a monitoring technique. As diagnostic tests, evoked potentials are useful to evaluate neurologic disorders such as: a) multiple sclerosis, b) acoustic nerve tumors, and c) optic neuritis. As a monitoring modality, evoked potentials are used during all surgical procedures, which might compromise part of the brain or the spinal cord.

Withdrawal following sufentanil/propofol and sufentanil/midazolam. Sedation in surgical ICU patients: correlation with central nervous parameters and endogenous opioids.

PURPOSE: Patients in the ICU after long-term administration of an opioid/hypnotic often develop delirium. To assess the nature of this phenomenon, patients in a surgical ICU following ventilatory support and sedation with an opioid/hypnotic/sedative were studied. METHODOLOGY: Following sufentanil/midazolam (group 1; n =14) or sufentanil/propofol (group 2; n =15) sedation, patients were evaluated for changes in mean arterial blood pressure and heart rate, the activity of the central nervous system (sensory evoked potentials, spectral edge frequency of EEG), and the endogenous opioids plasma concentrations (beta-endorphin, met-enkephalin). Data obtained were correlated with the individual intensities of withdrawal symptoms 6-, 12-, and 24 h following sedation. RESULTS: Following a mean duration of ventilation of 7.7 days (+/-3.6 SD) in groups 1 and 3.5 (+/-1.7 SD) in group 2, withdrawal intensities peaked within the 6th hour after cessation. Plasma beta-endorphin and met-enkephalin levels were low during sedation, and only the sufentanil/midazolam group demonstrated a postinhibitory overshoot. Withdrawal symptom intensities demonstrated an inverse correlation with beta-endorphin and met-enkephalin levels, a direct linear correlation with amplitude height of the evoked potential, and blood pressure and heart rate changes. Withdrawal intensities did not correlate with EEG power spectral edge frequency. CONCLUSION: The endorphinergic system is suppressed when a potent exogenous opioid like sufentanil is given over a long period of time. Following sedation, abstinence symptoms seem to be related to postinhibitory increased endorphin synthesis. This is mostly seen in the combination of sufentanil/midazolam. In addition, an increase in the amplitude of the sensory-evoked potential suggests a postinhibitory excitatory state within the nociceptive system.

No potentiation of fentanyl by use of transdermal buprenorphine in patients undergoing fast-track anesthesia for open-heart surgery.

Simultaneous use of opioids with a different pharmacological profile during anesthesia may lead to unexpected prolongation of effects. In addition, long-term use of transdermal buprenorphine may result in a reduced sensitivity to opioid anesthesia. In a prospective study, possible overlap of opioid effects and vigilance was determined in a group of patients (n = 22) using a buprenorphine patch for at least two months for treatment of chronic pain, and undergoing fentanyl-based fast-track enflurane anesthesia for open-heart surgery. The patients using buprenorphine were compared with a control group (n = 21) undergoing similar open-heart procedures with no opioid other than fentanyl on board. Aside from time to extubation, total dose of fentanyl, postoperative blood gases, and vigilance assessment score were used to determine possible overlap of opioid effects and/or development of opioid tolerance in the buprenorphine group compared to the control group. Both groups had similar operation and anesthesia times and comparable doses of fentanyl (0.69 mg +/- 0.23 vs. 0.67 mg +/- 0.16 SD). There was no significant difference in postoperative arterial blood gases (PaO2 136 +/- 48 torr vs. 128 +/- 35 torr SD; PCO2 43.3 +/- 3.3 torr vs. 41.9 +/- 1.2 torr SD), time until extubation (27 +/- 22 min vs. 33 +/- 24 min), and postanesthetic vigilance and recovery score (6.8 +/- 1.0 vs. 7.5 +/- 0.8, arbitrary units) between the two groups. Because of adaptive mechanisms and the development of tolerance in patients using buprenorphine, respiratory depression or sedation does not project into the postoperative period. The significant (p < 0.05) lower incidence of nausea and emesis in patients with transdermal buprenorphine owes to the development of tolerance to these opioid-related side effects.

Sufentanil-related respiratory depression and antinociception in the dog. Mediation by different receptor types.

The mu-receptor purportedly is considered the site responsible for the mediation of opioid-related respiratory depression. However, there is no equivocal understanding whether the same site is also responsible for antinociception. For blockade of effects, the selective mu-antagonist beta-funaltrexamine (CAS 72782-05-9, beta-FNA) was given intracerebroventricularly (i.c.v.) prior to increasing doses of sufentanil (CAS 60561-17-3) (3, 6 and 12 micrograms/kg) in the conscious dog. This was followed by the selective delta-antagonist naltrindole (CAS 111555-53-4) (160 micrograms/kg). After one week, using the same dosages and the same animals, saline instead of beta-FNA was given i.c.v., again followed by sufentanil and naltrindole. Arterial blood gases (paO2, paCO2) were used to demonstrate respiratory impairment while somatosenory-evoked potentials reflected sensory blockade. Maximal depression of paO2 was 73.9 with and 55.0 mmHg without beta-FNA, while paCO2 rose to 44.7 without and to 35.0 mmHg with beta-FNA (p < 0.005). In the evoked potential, maximal depression was 39.1% with and 92.7% without beta-FNA (p < 0.005). Naltrindole reversed residual hypoxia, however, not hypercarbia or amplitude reduction of the evoked potential. For regulation of paO2, a mu-delta-receptor interaction is postulated while paCO2 and sensory blockade are affected solely by the opioid mu-site.