Darrell L. Tanelian

Analgesic concentrations of lidocaine suppress tonic A-delta and C fiber discharges produced by acute injury

Intravenous lidocaine has been shown to relieve acute postoperative pain and chronic neuropathic pain. It is not known whether analgesia produced by 2-10 micrograms/ml plasma concentrations of lidocaine is due to an effect on peripheral-pain-transducing nerves or to central nervous system effects. The current study examined effects of analgesic concentrations of lidocaine on injury-induced discharge of A-delta and C fibers, using the in vitro rabbit corneal nerve preparation. Lidocaine at concentrations from 1-20 micrograms/ml reversibly suppressed tonic action potential discharge of acutely injured nerves. The median effective concentration (ED50) (5.7 micrograms/ml) corresponds to clinically effective plasma concentrations for analgesia. Electrically evoked nerve conduction was not blocked until lidocaine concentrations were greater than 250 micrograms/ml. Thus, analgesia produced by lidocaine appears to result from suppression of tonic neural discharge in injured peripheral A-delta and C fiber nociceptors.

Halothane enhances tonic neuronal inhibition of elevating intracellular calcium

Whether the major action of anesthetics is to depress the central nervous system (CNS) by reducing excitation or enhancing inhibition remains unknown. Using whole cell patch-clamp recording in hippocampal slices, halothane and pentobarbital were found to prolong the decay time constant (TAU(D)) of GABAA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs). Intracellular administration of the Ca2+ chelator BAPTA or the Ca2+ release inhibitor dantrolene significantly (ANOVA, P less than 0.005) reduced halothanes effect; in contrast, the pentobarbital effect was unchanged. Halothane induced depression of population spike amplitude was blocked by the GABAA antagonist bicuculline. Together, these findings suggest that a major depressant effect of halothane involves enhancement of GABAA-mediated inhibition through release of intraneuronally stored Ca2+.

Corneal pain evoked by thermal stimulation

&NA; The thermal sensitivity of the eyelid and cornea was compared using an automated apparatus to produce stimulus pulses of known magnitude and duration over the range 33–45°C. Subjects reported only temperature sensation when the skin of the upper eyelid was tested; however, corneal stimulation in the same subjects was always perceived as nociceptive. The possibility that other ocular tissues may be involved in the pain responses was shown to be unlikely by direct experimentation or by calculation of heat flow in those tissues. Cornea and eyelid thresholds were compared in relationship to the structural and physical properties of these tissues. It was found that the nerve endings of the corneal epithelium are less sensitive to temperature change when compared to the thermal receptors of the eyelid. It is concluded that the cornea is useful for the experimental study of pain.

CSF and blood pharmacokinetics of hydromorphone and morphine following lumbar epidural administration

&NA; Sixteen consenting patients scheduled for elective thoracotomy were enrolled into a randomized trial of epidural morphine and hydromorphone. Each patient had a lumbar epidural catheter placed preoperatively for the purpose of post‐thoracotomy analgesia. Shortly before the end of the operative procedure each patient received 5 mg of morphine and 0.75 mg of hydromorphone via the epidural catheter. Blood was sampled at regular intervals following the opiate administration and patients were randomized to 1 of 7 cervical CSF sampling times. Blood and CSF samples were assayed for morphine and hydromorphone concentration to determine blood and CSF pharmaco‐kinetic profiles. A maximum blood morphine concentration of 60 ± 25 ng/ml (mean ± S.D.) was obtained at 11 ± 6 min (mean ± S.D.). The blood hydromorphone peak of 14 ± 13 ng/ml (mean ± S.D.) occurred 8 ± 6 min The mean peak CSF opioid concentrations of 1581 ng/ml for morphine and 309 ng/ml for hydromorphone occurred 60 min after epidural administration. The blood and CSF pharmacokinetic profiles for morphine and hydromorphone are presented. These profiles are similar for the two drugs after lumbar epidural administration.

Activation of C fibers by metabolic perturbations associated with tourniquet ischemia.

Peripheral A-delta and C fibers are activated during the production of ischemic or tourniquet pain; however, individual metabolic or molecular factors responsible for neural activation are not known. To elucidate these mechanisms the in vitro corneal nerve preparation was used. Electrophysiologic effects of individual metabolic perturbations associated with ischemia (hypoxia, hypoglycemia, lactic acid, and decreased pH) were investigated on A-delta and C fiber nociceptors. Increased tonic action potential activity occurred in C fibers but not in A-delta fibers after ischemia. The conduction velocity of C fibers was 0.85 +/- 0.2 m/s (mean +/- SD). Under control conditions (n = 43) there was very little fluctuation in the baseline action potential frequency (+/- 3.2%). Hypoxia (n = 12) resulted in a 213 +/- 3.4% (mean +/- SD) increase in C fiber action potential frequency relative to control (P less than 0.001, ANOVA). L-glucose substitution for D-glucose (n = 8) increased C fiber discharge frequency by 653 +/- 28% relative to control (P less than 0.001) as did the combination of hypoxia and L-glucose substitution (n = 6) by 671 +/- 14%. Comparison of hypoxia versus hypoxia and hypoglycemia conditions did not show them to be statistically different (P greater than 0.5). Lactate (10-1000 micrograms/ml) at a pH of 6.9 or 7.4 did not alter the action potential discharge frequency in corneal C fibers (n = 5, P greater than 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiologic recording and thermodynamic modeling demonstrate that helium-neon laser irradiation does not affect peripheral Aδ- or C-fiber nociceptors

&NA; The effect of helium‐neon laser irradiation (632.5 nm) on A&dgr;‐ and C‐fiber sensory afferents was investigated in the rabbit cornea, to determine the physiologic basis for reports that low power (0.1–5 mW) helium‐neon (He‐Ne) lasers produce acute analgesia and alleviate chronic pain. Multiple and single unit extracellular recordings from nociceptive corneal afferent nerves (C‐fiber cold, C‐fiber chemical, A&dgr; mechanical and A&dgr; bimodal) were used to study the effects of He‐Ne laser radiation upon the electrophysiologic responses to mechanical, thermal, chemical and electrical stimulation of the cornea. Action potentials were analyzed for latency, amplitude, rise time, duration and frequency. Exposure of the neural receptive field and/or nerve bundle to a 4‐mm diameter He‐Ne laser (0–5 mW; 0–1800 sec) did not alter spontaneous or evoked neural activity. In addition, single unit action potential parameters were not altered by laser irradiation. Modeling of thermal changes produced by He‐Ne radiation on corneal nerves indicated that effects predicted for receptor and axonal depths in both skin and cornea were minimal (< 0.15°C) and unlikely to alter sensory transduction or transmission.

Combined neurogenic and nociceptive pain in a patient with Pancoast tumor managed by epidural hydromorphone and oral carbamazepine

A 43-year-old male with a Pancoast syndrome suffered severe unrelieved pain for approximately 10 months after diagnosis. The results of administration and cessation of lidocaine and carbamazepine strongly suggest that a neurogenic component contributed to the severity of this patients pain. This was also supported by a long period of previous sensory and motor loss in the upper limb and upper chest wall. Initially pain relief was attainable with a combination of oral carbamazepine and oral hydromorphone. However, as the patients condition worsened, this combination produced only partial pain relief. Complete relief of the patients pain was then attained only with a combination of epidural hydromorphone and oral carbamazepine. Hydromorphone was administered via an implanted, externalized silastic epidural catheter and infused by a miniaturized battery-operated pump which permitted a background infusion and the administration of patient and family-delivered boli. With this combination of oral carbamazepine and epidural hydromorphone, the patient was able to obtain complete pain relief for a period of 3 months until the time of death.

Simultaneous visualization and electrophysiology of corneal A-delta and C fiber afferents

Fluorescent staining of neuronal elements has become an important tool in neuroscience research; however, investigations have been limited by the toxic effects produced by most dyes, especially following excitation by strong epifluorescent illumination. The present study investigated effects produced by the methylpyridinium fluorescent dyes, 4-di-1-ASP and 4-di-2-ASP, on electrophysiologic responses from corneal A-delta and C fiber afferents. Rabbit corneal tissue was isolated and maintained in vitro to facilitate staining, visualization, and electrophysiologic recording of corneal nerves. Nerve fibers were selectively stained by the dyes and could be followed from their point of entry in small nerve bundles at the cornea-sclera border to individual free nerve ending terminals in the corneal epithelium. Neither the dyes nor epifluorescence, alone or in combination, produced any statistically significant changes (P greater than 0.1; t test) in spontaneous discharge activity, spike amplitude, spike dV/dt or stimulus evoked activity in A-delta and C fibers. Epifluorescent visualization of corneal afferents and simultaneous electrophysiologic recording will permit detailed investigations of sensory transduction processes and structure-function relationships in mammalian sensory nerves.

Failure of epidural opioid to control cancer pain in a patient previously treated with massive doses of intravenous opioid

A patient with disseminated cancer pain failed to obtain pain relief despite the intravenous infusion of hydromorphone at a rate equivalent to over 7 g of morphine/day. Temporary pain relief occurred with an epidural injection of the local anesthetic lidocaine. Subsequently, the patient failed to obtain pain relief with a dose of epidural hydromorphone equivalent to approximately 3 g of morphine epidurally/day. At this time a syndrome of agitation, sweating, tachycardia and severe muscle cramps developed in the lower half of the body. After eliminating the possibility of spinal cord compression by diagnostic CT scanning, the patient was treated by reducing the dose of hydromorphone and adding local anesthetic, which provided pain relief but did not eliminate the severe muscle spasms and other symptoms. The addition of oral clonidine followed by clonidine dermal patch rapidly and completely eliminated the other symptoms, suggesting that the response was due to too rapid withdrawal of opioid. Maintenance of pain relief required the simultaneous administration of epidural bupivacaine and hydromorphone. A low-dose infusion of epidural bupivacaine was continued for more than 3 weeks and during this entire period the patient showed no evidence of motor or sympathetic block.

Celiac plexus block following high-dose opiates for chronic noncancer pain in a four-year-old child

This is the first case report documenting the use of a neurolytic celiac plexus block for relieving chronic noncancer pain in a pediatric patient. The child was a 4-yr-old male with an unknown form of inflammatory bowel disease since 1 yr of age. Chronic abdominal pain became a problem at 3 yr of age, following multiple bowel resections; continuous intravenous narcotic administration was implemented for pain control. The patients pain became refractory to high-dose morphine administration (maximum dose, 267 mg/kg/day, iv), and, for that reason, a CT-guided neurolytic celiac plexus block was performed. This procedure resulted in improved pain control along with a major reduction in narcotic use to 7 mg/kg/day of morphine.