The combined effects of N-type calcium channel blockers and morphine on A delta versus C fiber mediated nociception.

UNLABELLED: Intrathecal mu opiates produce analgesia presynaptically by inhibiting calcium ion influx and postsynaptically by increasing potassium flux. Mu receptors are expressed on presynaptic terminals of unmyelinated (C), but not myelinated (A delta) nociceptors. Thus, mu-opioids such as morphine may act presynaptically to inhibit C, but not A delta, neurotransmission, and postsynaptically on dorsal horn cells that receive input from A delta and/or C fiber nociceptors. N-type calcium ion channel blockers, such as omega-conotoxin GVIA (omega-CTX), produce analgesia by impeding flux of calcium ions into A delta and C fiber nociceptor terminals. Thus, morphine and omega-CTX attenuated C fiber nociception additively, possibly indicating the same presynaptic site of action. Conversely, morphine and omega- CTX were supraadditively analgesic on an A delta test, indicating that these agents probably have different sites of action. We conclude that although intrathecal application of either morphine or omega-CTX attenuates both A delta and C fiber mediated nociception in rats, the combined effects are quite different for the two fiber types. Specifically, although coadministration of morphine with omega-CTX produces an additive, apparently presynaptic antinociception for C fiber-mediated responses, the combination produces a clearly supraadditive, and likely synergistic effect on A delta mediated nociception, probably by acting at pre and postsynaptic sites, respectively. IMPLICATIONS: This study demonstrates that combined spinal administration of mu opioids and N-type calcium channel blockers may be useful in providing analgesia for A delta mediated (first, sharp) pain while minimizing the side effects of both drugs.

Can we do better with postoperative pain management?

BACKGROUND: In the last decade, there has been heightened awareness that pain management needs to be a priority for all health care settings and clinicians. The article will overview practice guidelines and new technology, and assess their impact on pain relief in inpatient and outpatient surgeries from a patient's perspective. METHODS: Literature was retrieved by searches from 1996 to 2000 Medline and CINAHL (nursing database), using keywords "postoperative pain," "postsurgical pain," "patient outcomes," "pain outcomes," "survey," "questionnaire," and "practice guidelines." RESULTS: Overall, current practice standards have had minimal impact on decreasing patients' reports of pain. The incidence of moderate to severe pain with cardiac, abdominal, and orthopedic inpatient procedures has been reported as high as 25% to 50%, and incidence of moderate pain after ambulatory procedures is 25% or higher. CONCLUSIONS: Despite the advances, the incidence of pain remains high. Yet the future is promising, with new standards from the Joint Commission on Accreditation of Health care Organizations paving the way for reduction of institutional barriers and improved implementation of guidelines.

Purification of adrenal chromaffin cells increases antinociceptive efficacy of xenotransplants without immunosuppression.

We have found that immunosuppression is necessary for the survival of xenogeneic adrenal medullary transplants. Because chromaffin cells are essentially nonimmunogenic, it is likely that the highly immunogenic "passenger" cells in the transplant preparation bring about rejection. This article describes a procedure that produces an essentially pure preparation of chromaffin cells for transplantation. Bovine adrenal medullary cells were isolated and differentially plated, resulting in a semipurified preparation of chromaffin cells. Ferromagnetic beads were added to the cell suspension, some of which were phagocytized by endothelial cells, which allowed their removal by exposure to a magnet. The remaining cells were then exposed to ferromagnetic beads coated with isolectin B4 from Griffonia simplicifolia and once again to a magnetic field. The "semipurified" preparation contained approximately 90% chromaffin cells, whereas the "highly purified" preparation was > 99.5% chromaffin cells as determined immunohistochemically. The immunogenicity of the two cell preparations was assessed in vitro by determining their capacity to evoke lymphocyte proliferation. Rat spleen lymphocytes were mixed with either a highly purified or semipurified population of bovine chromaffin cells. The results of this assay demonstrated that the highly purified preparation was a much weaker stimulant of lymphocyte proliferation than was the semipurified preparation and may demonstrate better graft survival in vivo. Transplantation via intrathecal catheter of either 80,000 or 250,000 cells from the highly or partially purified preparations onto the lumbar spinal cord of nonimmunosuppressed and non-nicotine-stimulated rats produced a cell number-dependent antinociception for both A(delta) and C fiber-mediated thermonociception at 6 days after transplantation. After 6 days and up to 28 days, only the "highly purified" preparation showed antinociception. These results suggest that nearly complete purification of bovine chromaffin cells minimizes immunorejection of xenogeneic transplants of these cells.

Malignant ventricular dysrhythmias in a patient with isovaleric acidemia receiving general and local anesthesia for suction lipectomy.

We report the occurrence of severe ventricular arrhythmias in a patient with isovaleric acidemia during general anesthesia for suction lipectomy. The timing of events and character of the ECG changes are most consistent with bupivacaine toxicity after subcutaneous injection of tumescence solution containing this local anesthetic. The patient had previously documented carnitine deficiency, a condition which, we speculate, may lower the threshold for bupivacaine induced cardiotoxicity. We review clinical considerations in isovaleric acidemia and conclude that the use of bupivacaine in these patients probably should be avoided.

Nitric oxide synthase inhibition modulates the ventilatory depressant and antinociceptive actions of fourth ventricular infusions of morphine in the awake dog.

BACKGROUND: The role of nitric oxide (NO) production, at the brain-stem level, in ventilatory control and pain perception is poorly understood. Furthermore, it is not clear whether NO synthase (NOS) inhibition can affect morphine-induced ventilatory depression or analgesia. The central hypothesis of this investigation was that NO, at supraspinal sites, can influence ventilation and nociception and can modulate the ventilatory depressant and antinociceptive actions of morphine. Using drug delivery via the fourth cerebral ventricle, the authors examined the ventilatory and nociceptive effects of an NOS inhibitor and an NO donor in the presence or absence of morphine sulfate (MS). METHODS: The studies were performed in awake dogs that were restrained in a stanchion using a fourth ventricle to cisterna magna perfusion system. The dogs were chronically prepared with fourth ventricle and cisterna magna guide cannulae, femoral arterial/venous catheters, and a tracheostomy. Agents were prepared in a temperature- and pH-controlled artificial cerebrospinal fluid, perfused at 1 ml/min through the fourth ventricle cannula, and permitted to flow out through the cisterna magna cannula. The authors measured PaCO2, ventilatory drive (inspiratory occlusion pressures during carbon dioxide rebreathing), and nociception (hindpaw withdrawal threshold to increasing electrical current). Study groups were organized according to the following perfusion sequences (40 min each step): (1) MS (1 microgram/ml)-->MS + the NOS inhibitor, nitro-L-arginine (L-NA; 10(-6), then 10(-5) M)-->MS + L-NA (10(-5) M) + the NO donor, S-nitroso-acetylpenicillamine (SNAP; 10(-4) M); (2) SNAP (10(-5) M)-->SNAP (10(-4) M); (3) L-NA (10(-6), then 10(-5) M)-->L-NA (10(-5) M) + MS (1 microgram/ml)-->L-NA (10(-5) M) + MS + SNAP (10(-4) M); (4) MS (1 microgram/ml)-->MS + SNAP (10(-4) M); and (5) continuous MS (1 microgram/ml) perfusion (time control). Each perfusion sequence was preceded by a 45- to 60-min perfusion with drug-free artificial cerebrospinal fluid, during which time baseline values for each measured variable were obtained. RESULTS: Nitro-L-arginine alone dose dependently and significantly reduced PaCO2 and increased the nociceptive threshold. S-nitroso-acetylpenicillamine alone did not change the ventilation or nociceptive threshold. Morphine sulfate elicited a marked increase in PaCO2, a decrease in ventilatory drive, and an increase in nociceptive threshold (P < 0.05 compared with baseline). With L-NA pretreatment (sequence 3), but not posttreatment (sequence 1), MS-induced ventilatory depression, relative to baseline, was significantly attenuated. For both the L-NA pre- and posttreatment protocols, combined MS/L-NA perfusions produced a significantly greater antinociceptive effect than seen when MS was given alone. The L-NA effects on MS-induced ventilatory depression and antinociception were reversed with SNAP coadministration. CONCLUSIONS: Endogenous NO, produced at supraspinal sites, acts as a ventilatory depressant and as a nociceptive mediator. When NOS is inhibited, the ventilatory depressant actions of morphine can be reduced and the antinociceptive actions of morphine can be potentiated. However, NOS inhibitor treatment is more effective in suppressing morphine-induced ventilatory depression when given before, rather than after, morphine administration. The specific mechanisms involved in these actions remain to be identified.

Pharmacologic management of postdural puncture headache.

OBJECTIVE: To discuss the pathogenesis, incidence, and clinical presentation of postdural puncture headaches (PDPHs) and to provide a comprehensive evaluation on the pharmacologic management of PDPH. DATA SOURCE: A MEDLINE search was used to identify pertinent literature published in English including review articles, case reports, letters, and abstracts. Information was also extracted from textbooks for background purposes. STUDY SELECTION: All clinical studies, case reports, abstracts, and letters were included because of the limited amount of literature available on the pharmacologic therapy for PDPH. Related research articles and review articles were also used to provide background information on PDPH. DATA EXTRACTION: Methodology and results from clinical trials and abstracts were described and evaluated. Case reports and letters were summarized and critically reviewed for the feasibility of the different treatment modalities. Information on the pathophysiology, incidence and severity, and clinical presentation of PDPH was extracted from related research articles, review articles, and textbooks. DATA SYNTHESIS: The epidural blood patch (EBP) is one of the most effective treatments for PDPH. Pharmacologic management of PDPH offers a less invasive treatment modality than the EBP. Numerous drug therapies have been presented in the literature, though few merit clinical application. Caffeine therapy, both oral and parenteral, is the most commonly used pharmacologic treatment modality. Theophylline and sumatriptan are potentially promising agents for the treatment of PDPH. Epidural administration of fluids and drugs is also effective in the treatment of PDPH. Epidural adrenocorticotropic hormone and epidural morphine also demonstrate some potential in the treatment of PDPH. Individual patient characteristics (i.e., HIV, sepsis) need to be considered when deciding on a treatment. More reports, especially clinical studies, are necessary before a definitive statement can be made regarding any one treatment. In the meantime, therapy will be guided by clinical judgement based on the literature reviewed in this article. CONCLUSIONS: Intravenous and oral caffeine are effective and noninvasive treatments for PDPH. Epidural NaCl 0.9% or dextran are alternatives when the EBP is unsuccessful or contraindicated. Several methods of pharmacologic management have been cited in the literature, but all require further evaluation.

Use of continuous-infusion alfentanil for analgesia during spark-gap lithotripsy.

The painful stimuli produced by a new generation of electrohydraulic/electromagnetic lithotripters are such that continuous infusion analgesia rather than general or regional anesthesia is appropriate. We describe our experience with continuous alfentanil infusion supplemented with intravenous bolus midazolam in caring for patients treated with an unmodified Medstone STS 1050 lithotripter. Ninety consecutive treatments using this technique averaged 63 minutes, compared with 69 minutes for 14 treatments done with general anesthesia and 88 minutes for 58 treatments done with epidural anesthesia. The stone burden, kilovoltage, and number of shocks were similar for the three groups, as was the immediate stone fragmentation rate. Only 2 of 90 patients received inadequate analgesia with the intravenous technique and required the induction of general anesthesia. Continuous-infusion analgesia appears sufficient to blunt the stimulus provided by the unmodified spark-gap lithotripters still in common use.

Effects of subcutaneous verapamil on the duration of local anesthetic blockade.

STUDY OBJECTIVES: To determine whether a subcutaneous injection of verapamil will provide local anesthesia and whether a mixture of lidocaine and verapamil will prolong the anesthetic effect of lidocaine alone. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Preanesthetic area of a large metropolitan teaching hospital. PATIENTS: 20 volunteers. INTERVENTIONS: All volunteers received 4 injections of normal saline, verapamil, lidocaine, and lidocaine-verapamil at the volar aspect of the forearm. The sites were tested with a 26-gauge needle to be sure the sensation of sharp could be appreciated. The injections were performed in a randomized, double-blind fashion using a sterile technique. The 4 areas were tested at 1-minute intervals using a 26-gauge needle until the sensation of sharp was again perceived. MEASUREMENTS AND MAIN RESULTS: Injection sites were examined for the presence and degree of erythema. Volunteers were asked to rate the degree of pain felt during and immediately after injection. The time elapsed until the person was again able to perceive sharp from a 26-gauge needle prick was measured at all 4 sites. When compared with the effects of normal saline, subcutaneous verapamil provided local anesthesia to pinprick. The mixture of verapamil and lidocaine also provided anesthesia to pinprick, but the duration of effect was less than that provided by lidocaine alone. The use of verapamil alone and in combination with lidocaine was associated with a marked degree of erythema and edema. CONCLUSIONS: Verapamil injected subcutaneously provides a degree of local anesthesia. However, this effect is hampered by a local reaction at the injection site and a short duration of action. The mixture of lidocaine and verapamil provides a shorter duration of action than does lidocaine alone.

Comparative pharmacokinetics of oral versus sublingual clonidine.

STUDY OBJECTIVE: To compare the pharmacokinetic and pharmacodynamic profile of orally versus sublingually administered clonidine. DESIGN: Randomized, crossover, nonblinded, open-label study. SETTING: University tertiary-care center. PATIENTS: 10 healthy male and female volunteers aged 20 to 42 years. INTERVENTIONS: A heparinized catheter was placed intravenously for blood-sampling purposes. An automatic sphygmomanometer was placed on the volunteers' left upper arm to obtain systolic and diastolic blood pressure, and a pulse oximeter was placed on the right index finger to measure heart rate (HR). MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected throughout the 24-hour study period to determine clonidine concentrations. The effect of clonidine on blood pressure (BP) and HR also was measured. The half-life, area under the curve, maximum concentration, and time to reach maximum concentration were similar for both the sublingual and oral routes. BP and HR changes were similar for both sublingual and oral clonidine. CONCLUSION: Both routes of administration resulted in similar pharmacokinetic and pharmacodynamic profiles. Attempts to shorten clonidine's latency with sublingual administration were unsuccessful. Our study shows that a single dose of clonidine 0.3 mg has the same pharmacokinetic and dynamic profile when administered orally or sublingually. Therefore, the sublingual route can be predictably used in fasting patients, those having difficulty swallowing, or those who are unable to absorb drugs through the gastrointestinal tract; the sublingual dose is the same as the oral dose.

Oral clonidine blunts the hemodynamic responses to brief but not prolonged laryngoscopy.

STUDY OBJECTIVE: To determine whether a 300 micrograms dose of oral clonidine given 90 minutes prior to laryngoscopy and intubation provides hemodynamic protection from the stress of a brief (15-second) and/or a prolonged (45-second) laryngoscopy. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Inpatients and outpatients scheduled for general anesthesia with intubation at a university-affiliated medical center. PATIENTS: Forty patients who gave informed, written consent to receive either an oral placebo or clonidine 5 micrograms/kg (up to a maximum dose of 300 micrograms) 90 minutes prior to induction of anesthesia and to undergo either brief or prolonged laryngoscopy prior to intubation. INTERVENTIONS: The patients underwent a standardized induction sequence that included d-tubocurarine 3 mg, thiopental sodium 5 mg/kg, and succinylcholine 1.5 mg/kg. The four treatment groups (each n = 10) included (1) placebo with 15-second laryngoscopy, (2) placebo with 45-second laryngoscopy, (3) clonidine with 15-second laryngoscopy, and (4) clonidine with 45-second laryngoscopy. Heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were mechanically obtained and recorded at 1-minute intervals for 12 minutes. MEASUREMENTS AND MAIN RESULTS: There were no differences between groups in the premedication hemodynamic measurements. Within each group, maximal hemodynamic variables increased significantly over the corresponding baseline values for that group. In the 15-second, but not the 45-second, laryngoscopy, clonidine successfully blunted the maximum SBP and DBP obtained when compared with the corresponding control group. In both the 15- and 45-second clonidine groups, maximum HR was significantly lower than in the corresponding placebo groups. CONCLUSIONS: Oral clonidine, when used as a preoperative medication, affords hemodynamic protection to patients undergoing a 15-second laryngoscopy. However, the stress of a 45-second laryngoscopy may be too great or the 300 micrograms dose of clonidine too low to provide hemodynamic protection for patients in this group.

Lidocaine blood levels following aerosolization and intravenous administration.

STUDY OBJECTIVE: To determine whether, following aerosolization of lidocaine for topical airway anesthesia, intravenous (IV) lidocaine produces toxic lidocaine blood concentrations. DESIGN: Randomized, double-blind study. SETTING: University-affiliated hospital. PATIENTS: Forty healthy patients scheduled for outpatient surgery. INTERVENTIONS: The patients received in a randomized, double-blind manner aerosolized lidocaine or placebo followed 10 minutes later by IV lidocaine or placebo. MEASUREMENTS AND MAIN RESULTS: After completion of lidocaine or placebo aerosolization and 2 minutes following IV administration of either lidocaine or the placebo, venous blood samples were obtained. Lidocaine concentration was measured using a homogenous enzyme assay. The group receiving both aerosolized and IV placebo and the group receiving aerosolized lidocaine and an IV placebo had undetectable (less than 0.05 micrograms/ml) serum lidocaine levels. The groups that received either an aerosolized placebo or aerosolized lidocaine and IV lidocaine had similar serum lidocaine concentrations [3.34 +/- 0.46 vs. 3.24 +/- 0.55 micrograms/ml (mean +/- SEM); p greater than 0.05 by Mann-Whitney U test]. CONCLUSION: IV lidocaine can be safely administered following aerosolization of lidocaine in spontaneously breathing patients without producing toxic blood lidocaine concentrations.

Examination of the hypopharynx predicts ease of laryngoscopic visualization and subsequent intubation: a prospective study of 665 patients.

STUDY OBJECTIVE: To determine (a) whether the ability to visualize a patient's airway preoperatively correlates with the ability to visualize his or her larynx during laryngoscopy and (b) whether the presence of certain anatomic characteristics allows anesthetists to predict difficult laryngoscopic visualization and intubation. DESIGN: Observational. Patients were categorized into two groups: those who had one or more physical characteristics to alert an anesthetist to the possibility of difficult intubation (obesity, overbite, short neck, or decreased neck/jaw mobility) and those with none of these characteristics. SETTING: University-affiliated hospital. PATIENTS: Six hundred sixty-five patients scheduled for general anesthesia and requiring endotracheal intubation. Patients were between the ages of 18 and 88 years, with body weight ranging from 21 kg to 141 kg. INTERVENTIONS: Preoperatively, the anesthetist obtained the best view of the hypopharynx by having the patient extend the tongue and phonate. The airway was then categorized into one of three classes by the ability to see the tonsillar pillars and uvula (Class A, best view--all four tonsillar pillars and uvula seen; Class B, part of the pillars and uvula seen; Class C, worst view--pillars not seen and uvula partially or not seen). After induction, the same anesthetist graded laryngeal visibility into one of four groups depending on his ability to see the patient's epiglottis and vocal cords. MEASUREMENTS AND MAIN RESULTS: Patients with one or more clinical clues were more likely to have poor visualization of the hypopharynx and, in turn, poor laryngoscopic visualization of the glottis. Patients who had a Class A airway tended to have easy laryngoscopic visualization and were relatively easy to intubate. Conversely, patients with no clinical clues and a Class C airway had poor glottic exposure. CONCLUSIONS: Our study confirms work showing that the ability to visualize structures of the hypopharynx is a good predictor of subsequent glottic visualization during laryngoscopy and of ease of intubation.

Grand mal seizure in a postpartum patient following intravenous infusion of caffeine sodium benzoate to treat persistent headache.

A 27-year-old parturient developed a severe headache after placement of a labor epidural catheter. A presumptive diagnosis of an occult postdural puncture headache (PDPH) was made, and the patient was treated with an intravenous (IV) infusion of 500 mg of caffeine sodium benzoate (CSB) to vasoconstrict dilated cerebral vessels. Shortly after the infusion was completed, the patient experienced a self-limited grand mal seizure, which recurred later during her hospitalization. Despite a neurologic consultation and extensive testing, no definitive cause for the seizure was found. In light of the temporal relationship between caffeine use and the development of seizure activity, reports implicating caffeine's contribution to seizure activity, and evidence of a prolongation of the substance's half-life during and after pregnancy, we urge caution in the use of this drug in parturients.

The effectiveness of oral clonidine as a sedative/anxiolytic and as a drug to blunt the hemodynamic responses to laryngoscopy.

STUDY OBJECTIVE: To determine the effects of oral clonidine premedication on sedative, anxiolytic, and hemodynamic responses during the immediate preoperative period, laryngoscopy/intubation, and postanesthetic recovery. DESIGN: Randomized double-blind assignment to one of four treatment groups (clonidine 0.1 mg, clonidine 0.2 mg, triazolam 0.25 mg, or placebo); n = 10 per group. SETTING: Inpatient surgery in a university-staffed tertiary center. PATIENTS: Forty ASA physical status I and II adults of both sexes scheduled for a variety of procedures requiring general anesthesia. INTERVENTIONS: Anxiety and sedation scored on ordinal scale at time of treatment and 90 minutes later, just prior to anesthetic induction. Standardized induction protocol with automated hemodynamic monitoring at 1-minute intervals and a 45-second laryngoscopy to ensure a vigorous stress response. MEASUREMENTS AND MAIN RESULTS: Triazolam and both doses of clonidine increased sedation at 90 minutes both absolutely and compared with a placebo. Clonidine 0.2 mg decreased anxiety absolutely at 90 minutes but no more than a placebo. Clonidine 0.2 mg decreased systolic, mean, and diastolic blood pressures (BPs) but not heart rate (HR) at 90 minutes. Clonidine 0.2 mg also blunted the increase in systolic blood pressure (SP) [but not in diastolic blood pressure (DP) or HR] that accompanied laryngoscopy. There were no treatment differences in postanesthetic hemodynamics or duration of recovery. CONCLUSIONS: Oral clonidine 0.2 mg was effective in reducing the level of behavioral and hemodynamic responses preoperatively and in blunting systolic hypertension produced by prolonged laryngoscopy.

Atracurium use in a patient with familial periodic paralysis.

We describe a patient with the hypokalemic type of familial periodic paralysis (FPP) who received atracurium for muscle relaxation as required for diagnostic laparoscopy. Electrocardiographic (EKG) T-wave changes suggestive of hypokalemia were not supported by blood determinations. Arterial blood measurements of potassium (K+), pH, and arterial carbon dioxide tension (PaCO2) and the patient's esophageal temperature were maintained within normal limits. The degree of muscle relaxation was closely monitored by a peripheral nerve stimulator and train-of-four (TOF) measurement of muscle twitch height. At the conclusion of the surgical procedure, no reversal to the muscle relaxant was needed or given. The patient regained preoperative muscle strength, and her postoperative course was uneventful.