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Mechanism of antinociceptive action of clonidine in nonmyelinated nerve fibres
Abstract
Despite a large body of clinical evidence in favour of a local anesthetic effect of clonidine, the underlying mechanism has not yet been elucidated. In this study we have used the sucrose-gap method to measure the effects of clonidine on the electrophysiological properties of nonmyelinated nerve fibers in the rabbit vagus nerve. The results showed that clonidine enhanced the hyperpolarizing and reduced the depolarizing afterpotential that follow compound action potentials during electrical activity. We showed that summation of these afterpotentials shifts the membrane potential toward more negative values, thus creating a region of low safety conduction, where the local circuit currents might fail to depolarize the axonal membrane to the threshold value needed to open voltage-dependent Na(+) channels. Yohimbine did not reverse the inhibitory effects of clonidine on impulse propagation, indicating that the observed effects of clonidine relies on mechanisms not mediated by alpha(2)-adrenoceptors.
... 10 Through in vivo and in vitro studies, the effects of clonidine, another ∝ 2 -adrenoceptor agonist, on the peripheral nerve were found to be likely mediated through blockade of the hyperpolarization-activated cation current (I h current), not due to agonism of the ∝ 2adrenoceptor. [11][12][13][14] An in vitro study of the effects of dexmedetomidine in the paraventricular nucleus neurons found that dexmedetomidine acts in part through inhibition of the I h current. 15 The present study was designed to test the hypothesis that the increased duration of analgesia from dexmedetomidine added to local anesthetic in an in vivo model of a peripheral nerve block in rat is due to blockade of the I h current and not due to ∝ 1 -or ∝ 2adrenoceptor agonism. ...
... The present study indicates that the mechanism of action for peripheral perineural dexmedetomidine is similar to clonidine. [12][13][14]21,22 Clonidine has been used as an additive to local anesthetics for peripheral nerve blocks for many years, dating back to the first human descriptions in the early 1990s. [23][24][25] Despite demonstrating clear efficacy with short-and intermediate-acting local anesthetics, the effects of clonidine added to long-acting local anesthetics for peripheral nerve blocks has been questioned by some experts and the data are conflicting. ...
... 12,13 There are limited human data to date using dexmedetomidine in peripheral nerve blocks, but both studies have clearly demonstrated efficacy when added to long-acting local anesthetics. 8,9 In a randomized, double-blind, controlled trial, Obayah et al. 9 found a statistically significant increase in the time to first analgesic request from the addition of 1 μg/kg of dexmedetomidine added to bupivacaine versus bupivacaine alone in greater palatine nerve blocks for cleft palate repair in children (mean 22 h [range 20.6-23.7] vs. 14.2 h [13][14][15], respectively). There were no noted differences in sedation, heart rate or blood pressure between the groups. ...
The current study was designed to test the hypothesis that the increased duration of analgesia caused by adding dexmedetomidine to local anesthetic results from blockade of the hyperpolarization-activated cation (I(h)) current.
In this randomized, blinded, controlled study, the analgesic effects of peripheral nerve blocks using 0.5% ropivacaine alone or 0.5% ropivacaine plus dexmedetomidine (34 μM or 6 μg/kg) were assessed with or without the pretreatment of α(1)- and α(2)-adrenoceptor antagonists (prazosin and idazoxan, respectively) and antagonists and agonists of the I(h) current (ZD 7288 and forskolin, respectively). Sciatic nerve blocks were performed, and analgesia was measured by paw withdrawal latency to a thermal stimulus every 30 min for 300 min postblock.
The analgesic effect of dexmedetomidine added to ropivacaine was not reversed by either prazosin or idazoxan. There were no additive or attenuated effects from the pretreatment with ZD 7288 (I(h) current blocker) compared with dexmedetomidine added to ropivacaine. When forskolin was administered as a pretreatment to ropivacaine plus dexmedetomidine, there were statistically significant reductions in duration of analgesia at time points 90-180 min (P < 0.0001 for each individual comparison). The duration of blockade for the forskolin (768 μM) followed by ropivacaine plus dexmedetomidine group mirrored the pattern of the ropivacaine alone group, thereby implying a reversal effect.
Dexmedetomidine added to ropivacaine caused approximately a 75% increase in the duration of analgesia, which was reversed by pretreatment with an I(h) current enhancer. The analgesic effect of dexmedetomidine was not reversed by an α(2)-adrenoceptor antagonist.
... Typically, the inter-diffusion between compartments is minimized by applying grease around the preparation at points which traverse between the compartments; however, the quality of this insulation remains low (discussed in Mert, 2007), and the grease insulation is not compact enough to suit short WM strips. Rubber membranes with holes closely matching the preparations proved highly efficient in earlier sucrose gap experiments (Berger, 1963;Boev and Golenhofen, 1974;Cleemann and Suenson, 1984;Hoyle, 1987), including studies on most challenging C-fibers in peripheral nerves, which require higher stimulation intensities and shorter conduction distances (Jirounek et al., 1991;Gaumann et al., 1992;Robert and Jirounek, 1994;Erne-Brand et al., 1999;Dalle et al., 2001). In this paper we designed and tested a DSG apparatus with rubber membrane separation of the compartments that enhances the conditions for recording and analysis of CAPs and by virtue of the compactness of the compartments is ideally designed to accommodate relatively short preparations such as those derived from rat and mouse spinal cords. ...
... Studying slowly conducting non-myelinated axons, like C-fibers of peripheral nerves, by CAP recording (Jirounek et al., 1991;Gaumann et al., 1992;Robert and Jirounek, 1994;Erne-Brand et al., 1999;Dalle et al., 2001), requires short conduction distances because of increased temporal dispersion of action potential arrival times in individual non-myelinated axons with increased distance. The use of 3.5 mm-wide ACSF module in our experiments on Shiverer mice presented here provided sufficient synchrony to detect the slow multi-component C-wave reflecting action potential propagation in dysmyelinated axons. ...
Compound action potential (CAP) recording is a powerful tool for studying the conduction properties and pharmacology of axons in multi-axonal preparations. The sucrose gap technique improves CAP recording by replacing the extracellular solution between the recording electrodes with a non-conductive sucrose solution to minimize extracellular shunting. The double sucrose gap (DSG), conferring similar advantages at the stimulation site, has been extensively used on guinea pig spinal cord white matter (WM) in vitro. Establishing the DSG methodology for WM preparations from smaller animals such as rats and mice is appealing due to their extensive use in basic and translationally oriented research. Here we describe a versatile modular DSG apparatus with rubber membrane separation of the compartments, suitable for WM strips from rat and mouse spinal cord. The small volumes of compartments (<0.1 ml) and the air-tight design allow perfusion rates of 0.5-1 ml/min with faster refreshment rates compared to commonly used 2-3 ml/min and larger compartments, providing economical usage of expensive pharmacological drugs. Our improved DSG design is particularly efficient for uncovering slower conducting, higher threshold CAP components, as demonstrated by recordings of C-wave (non-myelinated axons) in rat dorsal WM. In myelin-deficient Shiverer mice with genetically dysmyelinated axons, our DSG apparatus recordings revealed a multi-peak C-wave without preceding faster components. The improved stimulation and recording with our DSG apparatus, lowering the range of required stimulus intensities and reducing the artifact interference with recorded CAPs provide for critical technical advantages that allow for more detailed analysis of CAPs in relatively short preparations.
... 30 Dexmedetomidine can maintain the hyperpolarized state of cells by inhibiting the activation of the I h current, inhibit the next action potential by inhibiting the potassium channel, maintain the depolarization of cells, and increase the inhibition of the sodium channel, thereby enhancing the effect of LA. 28,[31][32][33][34][35] This inhibitory effect is more obvious in unmyelinated C fibers (pain fibers) and small myelinated A-δ fibers (temperature sensation and rapid pain sensation) than in large myelinated motor fibers; consequently, the effect of dexmedetomidine on the sensory block is more obvious than on the motor block. [36][37][38] Dexmedetomidine may exert its peripheral effect by activating α 2 adrenoceptors in peripheral blood vessels, constricting blood vessels around the injection site, delaying the absorption of local anesthetics, and prolonging their block time. 39 ...
Peripheral nerve block technology is important to balanced anesthesia technology. It can effectively reduce opioid usage. It is the key to enhance clinical rehabilitation as an important part of the multimodal analgesia scheme. The emergence of ultrasound technology has accelerated peripheral nerve block technology development. It can directly observe the nerve shape, surrounding tissue, and diffusion path of drugs. It can also reduce the dosage of local anesthetics by improving positioning accuracy while enhancing the block’s efficacy. Dexmedetomidine is a highly selective drug α2-adrenergic receptor agonist. Dexmedetomidine has the characteristics of sedation, analgesia, anti-anxiety, inhibition of sympathetic activity, mild respiratory inhibition, and stable hemodynamics. Numerous studies have revealed that dexmedetomidine in peripheral nerve blocks can shorten the onset time of anesthesia and prolong the time of sensory and motor nerve blocks. Although dexmedetomidine was approved by the European Drug Administration for sedation and analgesia in 2017, it has not yet been approved by the US Food and Drug Administration (FDA). It is used as a non-label drug as an adjuvant. Therefore, the risk-benefit ratio must be evaluated when using these drugs as adjuvants. This review explains the pharmacology and mechanism of dexmedetomidine, the effect of dexmedetomidine on various peripheral nerve block as an adjuvant, and compare it with other types of adjuvants. We summarized and reviewed the application progress of dexmedetomidine as an adjuvant in nerve block and look forward to its future research direction.
... This finding is also consistent with the previous studies [25] . The mechanism of Clonidine-induced potentiation of sensory block in spinal anesthesia is reported to be dependent on presynaptic (decrease in transmitter release) and postsynaptic (increase in hyperpolarization) action [26] . Bajwa et al. in their study concluded that addition of clonidine (50 g) to intrathecal bupivacaine provided prolonged postoperative analgesia in comparison to Fentanyl (25 g) [20] . ...
Background: There are many adjuvants used along with bupivacaine for subarachnoid block, but Fentanyl and Clonidine are commonly used as adjuvants to intrathecal bupivacaine for prolonging both sensory and motor blockade as well as postoperative analgesia in patients undergoing lower limb orthopedic surgery. Aim: The aim of the present study was to compare the effect of intrathecal Clonidine and Fentanyl as adjuvants to Bupivacaine in the subarachnoid block for lower limb orthopedic surgery. Materials and Methods: 200 patients belonging to American Society of Anaesthesiologists I or II, scheduled for lower limb orthopaedic surgery under spinal anaesthesia were randomly allocated to one of the two following groups to receive Bupivacaine 15mg combined with 50
... We have been unable to locate any publications illustrating recordings from unmyelinated C fibres from mouse sciatic nerve of equivalent duration to those illustrated in this paper. The primary model for electrophysiological examination of unmyelinated fibres has been the vagus nerve, which comprises 90% unmyelinated axons, where the preferred recording environment is either the sucrose (Gaumann et al. 1992(Gaumann et al. , 1994Erne-Brand et al. 1999;Dalle et al. 2001;Jirounek et al. 2002) or grease gap (Docherty et al. 2005) techniques. The sucrose gap technique requires a very short conducting distance in order to minimise the temporal dispersion of action potential arrivals, thereby maximising the amplitude of the CAP (Velumian et al. 5). ...
Key points:
We have developed an improved method that enables simultaneous recording of stimulus evoked compound action potentials from large myelinated A fibres and small unmyelinated C fibres in mouse sciatic nerves. Investigations into the ability of fructose to support conduction in sciatic nerve revealed a novel glia-to-axon metabolic pathway in which fructose is converted in Schwann cells to lactate for subsequent shuttling to A fibres. The C fibres most likely directly take up and metabolise fructose. These differences are indicative of fibre sub-type specific metabolic profiles. These results demonstrate that the physiological insights provided by the method can be applied to investigations of peripheral nerve, with a view to understanding the metabolic disruptions that underlie diabetic neuropathy.
Abstract:
The stimulus evoked compound action potential (CAP), recorded using suction electrodes, provides an index of the relative number of conducting axons within a nerve trunk. As such the CAP has been used to elucidate the diverse mechanisms of injury resulting from a variety of metabolic insults to central nervous white matter, whilst also providing a model with which to assess the benefits of clinically relevant neuroprotective strategies. In addition the technique lends itself to the study of metabolic cell-to-cell signalling that occurs between glial cells and neurones, and to exploring the ability of non-glucose substrates to support axon conduction. Although peripheral nerves are sensitive to metabolic insult and are susceptible to diabetic neuropathy, there is a lack of fundamental information regarding peripheral nerve metabolism. A confounding factor in such studies is the extended duration demanded by the experimental protocol, requiring stable recording for periods of many hours. We describe a method that allows us to record simultaneously the stimulus evoked CAPs from A and C fibres from mouse sciatic nerve, and demonstrate its utility as applied to investigations into fibre sub-type substrate use. Our results suggest that C fibres directly take up and metabolise fructose, whereas A fibre conduction is supported by fructose-derived lactate, implying there exist unique metabolic profiles in neighbouring fibre sub-types present within the same nerve trunk.
... 37 The mechanism is reported to be both the presynaptic (decrease in substance P release from primary afferent nerve terminals) and postsynaptic (increase in hyperpolarization of nerve terminations) effects of intrathecal clonidine. 38,39 A synergistic effect of alpha-2 agonists with opioids has also been demonstrated in animal models. 5,40 In pregnant rats, clonidine seems to have a synergistic antinociceptive effect with endogenous opioids that are present during late pregnancy. ...
Background
Clonidine is used as adjuvant to local anaesthetics for spinal anaesthesia. Its potential harm and benefits have not been systematically reviewed in obstetrics, and medical regulatory authorities do not recommend its intrathecal administration. The aim of this study was to assess the safety and efficacy of intrathecal clonidine for caesarean delivery.
Methods
We conducted a systematic literature search in Medline, Embase, the Cochrane Library databases and trial registries for randomised trials assessing intrathecal clonidine as an adjuvant to local anaesthetics in patients undergoing caesarean delivery. Studies were assessed for quality, and data were extracted on study characteristics, safety and efficacy. Pooled data analysis using random-effects models was performed. Relative risk (RR) or mean difference with 95% confidence intervals (CI) were used to analyse outcomes.
Results
Of 201 reports screened, 12 relevant clinical trials were included. Clonidine prolonged the duration of sensory block by 128.2 min (95% CI 81.7 to 174.8) and motor block by 44.7 min (95% CI 8.7 to 80.7). Clonidine increased sedation, RR 3.92 (95% CI 1.17 to 13.14), but did not increase the risk of hypotension, pruritus or postoperative nausea and vomiting. Apgar scores at 1 or 5 min were not influenced by the addition of intrathecal clonidine.
Conclusion
Clonidine is an effective and safe adjuvant to local anaesthetics for spinal anaesthesia for caesarean delivery. This opens the debate as to whether intrathecal clonidine as an “off label” prescription should be reconsidered by medicine regulatory authorities.
... Our findings are in the line with published literature which demonstrated that addition of intrathecal clonidine to bupivacaine, even in very small doses, significantly improves the onset and prolongs spinal anaesthesia. [1,10,11] These effects could be because of potentiation of sensory block by presynaptic (inhibition of transmitter release) [12] and postsynaptic (enhancing hyperpolarization) [13] effects of clonidine. The role of vasoconstriction in prolonging sensory block is minor. ...
... The intrathecal application of clonidine increases the duration of both sensory and motor block, 2-5 as well as postoperative analgesia. 6 The mechanism of clonidine in spinal anesthesia is reported to be mediated by presynaptic (inhibition of transmitter release) 7 and postsynaptic (enhancing hyperpolarization) 8,9 effects. ...
Introduction: The aim of this prospective, double-blinded studywas to investigate the effects of clonidine in co-administrationwith bupivacaine during spinal anesthesia, regarding the onset and regression of motor and sensory block, postoperative analgesia and possible side effects.Methods: We randomly selected 66 male patients (age 35 to 70), from the American Society of Anesthesiologists (ASA) class I-II; these patients were scheduled for transurethral surgical procedures. These patients were randomly allocated into two groups of 33 patients each: group B (bupivacaine) only received 0.5% isobaric bupivacaine 7.5 mg intrathecally and group BC (bupivacaine + clonidine) received bupivacaine 7.5 mg and clonidine 25 μg intrathecally. We performed the spinal anesthesia at a level of L3-L4 with a 25-gauge needle. We assessed the sensory block with a pinprick,the motor block using the Bromage scale, analgesia with thevisual analog scale and sedation with the modified Wilson scale.We also recorded the hemodynamic and respiratory parameters.Results: The groups were demographically similar. The mean time of achievement of moto block (Bromage 3) and sensory block at level T9 was significantly shorter in the BC group compared with B group (p = 0.002, p = 0.000, respeectively). The motor block regression time was not significantly different between the two groups (p = 0.237). The postoperative analgesia requirement was significantly longer in group BC compared with group B (p = 0.000). No neurological deficit, sedation or other significant adverse effects were recorded.Conclusion: The intrathecal application of clonidine in combination with bupivacaine improves the duration and quality of spinal anesthesia; it also provides longer duration of postoperative analgesia, without significant side effects.
... Sethi et al., [17] in a similar study in gynecological patients found that the mean time from injection to regression of the level of sensory analgesia by two segments was longer in the clonidine group than in control group (P < 0.001). The mechanism of clonidine-induced potentiation of sensory block in spinal anesthesia is reported to be mediated by presynaptic (inhibition of transmitter release) and postsynaptic (enhancing hyperpolarization) [18,19] effects. Although clonidine might have a vasoconstrictive effect in large concentrations, the role of vasoconstriction in prolonging sensory block seems to be minor, even in usual clinical doses (1-2 µg/kg). ...
Context
Various adjuvants are being used with local anesthetics for prolongation of intraoperative and postoperative analgesia. The α2-adrenergic agonist clonidine and potent opioid buprenorphine have the ability to potentiate the effects of local anesthetics.
Aims
The purpose of this prospective, double-blind study was to compare onset, duration of sensory and motor block, effect on hemodynamics, level of sedation, duration of postoperative analgesia, and any adverse effects of clonidine and buprenorphine.
Settings and Design
Seventy-five American Society of Anesthesiologists Class I and II patients undergoing lower limb surgery under spinal anesthesia were randomly allocated into three Groups A, B, and C.
Subjects and Methods
Control Group A received injection bupivacaine 0.5% (heavy) 2.5 ml + saline 0.5 ml whereas Group B received injection bupivacaine 0.5% (heavy) 2.5 ml + injection buprenorphine 50 μg and Group C received injection bupivacaine 0.5% (heavy) 2.5 ml + preservative free injection clonidine 50 μg intrathecally.
Statistical Analysis Used
Unpaired Student's t-test and Z-test were used for comparing data.
Results
Statistically highly significant differences in mean time of sensory regression to L1, mean time to attain the Bromage Score of 1, and mean time of first rescue analgesic request were observed between the three groups. The patients did not suffer any serious side effects.
Conclusion
Administration of buprenorphine and clonidine intrathecally does potentiate the duration of analgesia, sensory and motor block, with buprenorphine having a long-lasting effect.
... [18] The mechanism of clonidine-induced potentiation of sensory block in spinal anesthesia is reported to be dependent on presynaptic decrease in transmitter release and postsynaptic increase in hyperpolarization. [19] Parturients in both the group showed a significant fall in mean arterial pressure after 5-10min of spinal but MAP remained in the acceptable limit that is <20% of baseline. This stability may be attributed to low dose of bupivacaine used in our study. ...
BACKGROUND: Pain free postoperative period and early ambulation are the need of the
day for mothers and their neonates for early initiation of breast feeding. It is moral responsibility of
Anaesthesiologist to provide a safe and pain free postoperative period with use of various techniques
and drug combinations. Spinal anaesthesia has been widely used for caesarean section in normalas
well as preeclamptic parturients and has been found to be efficaciousand safe. The present study
aimed to compare the analgesic efficacy and side effect profile of intrathecal Bupivacaine with
Fentanyl and Bupivacaine with Clonidine in cesarean section of parturients with pregnancy induced
hypertension (PIH). METHODS: 50 full term parturients with pregnancy induced hypertension
scheduled for cesarean section were randomized into 2 groups of 25 each. GROUP BF (Bupivacaine
with Fentanyl) received 7.5mg of 0.5% hyperbaric Bupivacaine and 20µg Fentanyl intrathecally.
GROUP BC (Bupivacaine with Clonidine) received 7.5mg of 0.5% hyperbaric Bupivacaine and 60µg
clonidine intrathecally. RESULTS: Patients in group BC showed long lasting analgesia compared to
group BF (p value
... It actually targets the adrenergic hyperactivity hypothesised to be the basis of the NAS. At low doses, clonidine stimulates alpha 2 presynaptic adrenergic receptors, thereby reducing the quantity of nor epinephrine released into the synapse and lowering the firing rate of adrenergic neurons (Erne-Brand et al., 1999). ...
... This finding is also consistent with the previous studies [18,23,24]. The mechanism of clonidine-induced potentiation of sensory block in spinal anesthesia is reported to be dependent on presynaptic (decrease in transmitter release) and postsynaptic (increase in hyperpolarization) action [25,26]. ...
Objectives. To compare the analgesic efficacy of intrathecal clonidine and fentanyl added to bupivacaine after cesarean section. Methods. Ninety patients scheduled for cesarean section under spinal anesthesia were randomly allocated to one of the three following groups to receive bupivacaine 10 mg combined with 75 µg clonidine (group C), bupivacaine 10 mg combined with 0.5 mL fentanyl (group F), and bupivacaine 10 mg combined with 0.5 mL distilled water (group P), intrathecally. The time to first analgesic request, analgesic requirement in the first 24 hours after surgery, sensory and motor blockade onset time, duration of sensory and motor blockade, the incidence of hypotension, ephedrine requirements, bradycardia, and hypoxemia were recorded. Results. The duration of anesthesia in clonidine group (275.10 ± 96.09) was longer compared to the placebo (211.73 ± 74.80) and fentanyl (192.33 ± 30.36) groups. This difference between group C versus F (P = 0.006) and P groups (P < 0.001) was significant. Similarly, the mean time to first analgesic request was also longer in group C (519.44 ± 86.25) than in groups F (277.88 ± 94.25) and P (235.43 ± 22.35 min). This difference between group C versus F (P < 0.001) and P groups (P < 0.001) was significant. Conclusion. Intrathecal clonidine 75 µg with bupivacaine prolonged the time to first analgesic request compared to fentanyl; however, the total analgesic consumption within the first 24 h postoperative was similar in fentanyl and clonidine groups following cesarean section. This trial is registered with ACTRN12611000909921 and ClinicalTrials.gov NCT01425658.
... The locus coeruleus, the largest noradrenergic cell group in the brain and an important modulator of wakefulness, has been indicated to be the major site for the sedative-hypnotic action of alpha-2 adrenoceptor agonists via stimulation of the alpha-2a adrenoceptor (Scheinin 1992). A high density of alpha-2 adrenoceptors has also been demonstrated in the vagus nerve (Erne-Brand 1999). The intermediolateral cell column, the substantia gelatinosa, the dorsal horn of the spinal cord, as well as primary sensory neurones all contain alpha-2 adrenoceptors (Khan 1999). ...
... Intraaxonal, voltage-clamp, and patchclamp recordings produce high-quality data, but they are technically rather difficult and, as a rule, require expensive equipments. Furthermore, because some nerve fibers or electrically interconnected cells (smooth muscle cells) are extremely small objects, recording from them with intracellular or patchclamp electrodes for a sufficiently long time is either extremely complicated or even practically impossible [13][14][15][16]. Because of a severe difficulty of impaling axons/cells inevitably resulting in damage to these nerve structures, electrophysiological measurements on objects of such a type are largely restricted to recordings of the CAPs and constant (slowly changing) potentials (like, in particular, the membrane potential, MP) using modifications of the sucrose-gap technique [4,12,17]. ...
The sucrose-gap technique has been widely used as a convenient tool for recording of the membrane activities from myelinated
or unmyelinated nerves and muscle preparations (such as smooth and cardiac muscles). The quantitative measurements of membrane
and action potentials in preparations with electrical coupling between their compartments are made much easier by this technique;
the recorded potentials are rather similar to those recorded with a microelectrode. Recording of the membrane activities is
of great value to experimenters studying the nervous system due to the simplicity and ease of use of this technique and the
broad spectrum of sensitivity to agents influencing the electrical activity. This paper is focused on the set-up procedure
and operation of the sucrose-gap technique, which provides an inexpensive, practical, and effective method for the investigation
of the effects of drugs on the membrane activities of nerves and muscles in vitro.
... The intrathecal application of clonidine increases the duration of both sensory and motor block, 2-5 as well as postoperative analgesia. 6 The mechanism of clonidine in spinal anesthesia is reported to be mediated by presynaptic (inhibition of transmitter release) 7 and postsynaptic (enhancing hyperpolarization) 8,9 effects. ...
The aim of this prospective, double-blinded study was to investigate the effects of clonidine in co-administration with bupivacaine during spinal anesthesia, regarding the onset and regression of motor and sensory block, postoperative analgesia and possible side effects.
We randomly selected 66 male patients (age 35 to 70), from the American Society of Anesthesiologists (ASA) class I-II; these patients were scheduled for transurethral surgical procedures. These patients were randomly allocated into two groups of 33 patients each: group B (bupivacaine) only received 0.5% isobaric bupivacaine 7.5 mg intrathecally and group BC (bupivacaine + clonidine) received bupivacaine 7.5 mg and clonidine 25 μg intrathecally. We performed the spinal anesthesia at a level of L3-L4 with a 25-gauge needle. We assessed the sensory block with a pin-prick, the motor block using the Bromage scale, analgesia with the visual analog scale and sedation with the modified Wilson scale. We also recorded the hemodynamic and respiratory parameters.
The groups were demographically similar. The mean time of achievement of motor block (Bromage 3) and sensory block at level T9 was significantly shorter in the BC group compared with B group (p = 0.002, p = 0.000, respeectively). The motor block regression time was not significantly different between the two groups (p = 0.237). The postoperative analgesia requirement was significantly longer in group BC compared with group B (p = 0.000). No neurological deficit, sedation or other significant adverse effects were recorded.
The intrathecal application of clonidine in combination with bupivacaine improves the duration and quality of spinal anesthesia; it also provides longer duration of postoperative analgesia, without significant side effects.
... These interactions between a 2 -agonists and local anesthetics were considered to be due to (1) the inhibition of conduction in nerve fibers through interaction with Na ? channels [5] and/or (2) the local vasoconstriction mediated by a 2 -adrenoceptors [6]. In dorsal root ganglion (DRG) neurons, voltagedependent Na ? ...
Besides being administered systemically for sedation and analgesia, α(2)-agonists such as dexmedetomidine and clonidine have been administered with intrathecal, epidural, or perineural injections, leading to an antinociceptive effect at the spinal cord or peripheral nerve level. However, the mechanism for this remains unclear. In the present study, we examined whether dexmedetomidine and clonidine could inhibit the function of tetrodotoxin-sensitive Na(+) channels, which play important roles in the generation of pain.
Cultured bovine adrenal chromaffin cells expressing the tetrodotoxin-sensitive Na(v)1.7 Na(+) channel isoform were incubated in KRP buffer containing 2 μCi (22)NaCl for 5 min without or with dexmedetomidine or clonidine in the absence or presence of veratridine, α-scorpion venom, β-scorpion venom, Ptychodiscus brevis toxin-3 or ouabain. Cells were then washed and counted radioactively.
Dexmedetomidine and clonidine reduced veratridine-induced (22)Na(+) influx via Na(v)1.7 in a concentration-dependent manner (EC(50) = 50 μM and 530 μM), even in the presence of ouabain, an inhibitor of Na(+), K(+)-ATPase. Dexmedetomidine and clonidine shifted the concentration-response curve of veratridine for (22)Na(+) influx downward without altering the EC(50) of veratridine. Atipamezole and yohimbine, α(2)-antagonists, did not prevent the inhibition of veratridine-induced (22)Na(+) influx by dexmedetomidine. Dexmedetomidine and clonidine combined with lidocaine induced more inhibition of veratridine-induced (22)Na(+) influx than each drug did individually. Atipamezole and yohimbine did not prevent the lidocaine-enhancing effect of dexmedetomidine and clonidine.
Dexmedetomidine and clonidine inhibit the function of Na(v)1.7 independent of α(2)-adrenoceptor. These results may lead to a deeper understanding of the peripheral antinociceptive effects of α (2)-agonists.
... However, in a recent study performed in our laboratory, we observed that clonidine enhances progressively the hyperpolarizing afterpotential during repetitive stimulation at low frequency. 12 This result raises the possibility that clonidine could act on the activity-dependent changes in membrane potential occurring in nerve fibers. ...
Although the alpha2-adrenergic agonist clonidine has been shown to promote peripheral antinociception, its mechanism of action has not yet been clearly elucidated. By the use of the sucrose-gap method, we have shown that in C fibers of the rabbit vagus nerve, clonidine at micromolar concentrations enhances activity-dependent hyperpolarizations generated by the Na+-K+ pump during and after repetitive stimulation. Similar results were obtained with 10 microM of ZD 7288, a specific blocker of the hyperpolarization-activated cation current (I(h)) and with 2 mM of Ba2+ that blocks the inwardly rectifying potassium current (I(KIR)). Furthermore, clonidine had no added effect on the ZD 7288-induced response, whereas it produced a marked enhancement of Ba2+induced response. From these results, it can be concluded that clonidine enhances activity-dependent hyperpolarization by inhibiting the current I(h). We propose that clonidine, by increasing the threshold for initiating the action potential, induces a slowing or block of conduction and that this mechanism is the origin of the clonidine-induced antinociception. Finally, this study suggests a novel role for inwardly rectifying hyperpolarization-activated conductances in peripherally mediated antinociception.
... The mechanism of clonidine-induced potentiation of sensory block in spinal anesthesia is reported to be mediated by presynaptic (inhibition of transmitter release) (18) and postsynaptic (enhancing hyperpolarization) (19,20) effects. Although clonidine might have a vasoconstrictive effect in large concentrations, the role of vasoconstriction in prolonging sensory block seems to be minor, even in usual clinical doses (1-2 g/kg) (9,21). ...
... Additional evidence suggesting that ␣ 2 -receptors are not involved in the inhibition is that at high concentration, clonidine has non-␣ 2 -receptor-mediated effects. As described previously in rabbit (13,22), we demonstrated in every XII motoneuron examined that clonidine inhibited either action potential amplitude or repetitive firing. This inhibition, combined with the fact that the time course of the effect on repetitive firing was similar to the inhibitory actions of clonidine on XII inspiratory burst amplitude, suggests that a major mechanism underlying the inhibitory actions of clonidine on XII burst amplitude in neonatal rat is via nonspecific inhibition of Na ϩ channels. ...
Norepinephrine has powerful and diverse modulatory effects on hypoglossal (XII) motoneuron activity, which is important in maintaining airway patency. The objective was to test two hypotheses that alpha2-adrenoceptor-mediated, presynaptic inhibition of glutamatergic inspiratory drive (Selvaratnam SR, Parkis MA, and Funk GD. Brain Res 805: 104-115, 1998) and postsynaptic inhibition of the hyperpolarization-activated inward current (Ih) (Parkis MA and Berger AJ. Brain Res 769: 108-118, 1997) modulate XII inspiratory activity. Nerve and whole cell recordings were applied to rhythmic medullary slice preparations from neonatal rats (postnatal days 0-4) to monitor XII inspiratory burst amplitude and motoneuron properties. Application of an alpha2-receptor agonist (clonidine, 1 mM) to the XII nucleus reduced inspiratory burst amplitude to 71 +/- 3% of control but had no effect on inspiratory synaptic currents. It also reduced the Ih current by approximately 40%, but an Ih current blocker (ZD7288), at concentrations that blocked approximately 80% of Ih, had no effect on inspiratory burst amplitude. The clonidine inhibition was unaffected by the GABAA antagonist (+)bicuculline but attenuated by the alpha2-antagonist rauwolscine and the imidazoline 1 (I1) antagonist efaroxan. The I1 agonist rilmenidine, but not the alpha2-agonist UK14304, inhibited XII output. Clonidine also reduced action potential amplitude or impaired repetitive firing. Although a contribution from alpha2, and in particular I1, receptors remains possible, results demonstrate that 1) noradrenergic modulation of XII inspiratory activity is unlikely to involve alpha2-receptor-mediated presynaptic inhibition of glutamate release or modulation of Ih; 2) inhibition of repetitive firing is a major factor underlying the inhibition of XII output by clonidine; and 3) Ih is present in neonatal XII motoneurons but does not contribute to shaping their inspiratory activity.
... Although there is some limited evidence that a part of this mechanism may involve a pharmacokinetic interaction between the a 2 -agonist and the local anesthetic, it seems unlikely that local vasoconstriction causing reduced uptake and removal of local anesthetic could be the sole explanation for this effect (Eledjam et al. 1991; Gaumann et al. 1992; Kopacz & Bernards 2001). On the basis of in vitro and a limited number of in vivo studies, it appears likely that clonidine's effects on peripheral nerve function are related to hyperpolarization of C fibers through blockade of the so-called hyperpolarization-activated cationic current (I h ) (Gaumann et al. 1994; Erne-Brand et al. 1999; Dalle et al. 2001 ), and are not mediated by alpha 2 adrenoceptors at all. This proposed mechanism of 'peripheral analgesia' requires further study to clarify its role in intact animals and to investigate its clinical relevance. ...
To compare the sensory and motor effects of adding medetomidine to mepivicaine, administered either perineurally or systemically, for radial nerve block in dogs.
Prospective randomized cross-over study.
Six healthy Beagles, aged 18.7 +/- 6.3 months and weighing 10.4 +/- 1.3 kg.
Dogs were anesthetized briefly with sevoflurane on three separate occasions and received each treatment administered in random order: mepivacaine 5 mg kg(-1) perineurally around the radial nerve with saline 0.01 mL kg(-1) intramuscularly (CONTROL); mepivacaine 5 mg kg(-1) and medetomidine 0.01 mg kg(-1) combined, perineurally with saline 0.01 mL kg(-1) intramuscularly (MEDPN); mepivacaine 5 mg kg(-1) perineurally around the radial nerve with medetomidine 0.01 mg kg(-1) intramuscularly (MEDIM). All nerve blocks were performed with the aid of a nerve locator. Motor effects were evaluated based on the ability to bear weight. Sensory effects were evaluated by the response to a graded-electrical stimulus. These were evaluated at 5-minute intervals for the first hour, and at 10-minute intervals thereafter. Mean intervals were calculated as follows: time to motor block onset, duration of motor block, time to peak sensory block, duration of peak sensory block (i.e. period of no response to maximal stimulus intensity), and duration of residual sensory block (i.e. time to return to baseline sensory function). Treatment means were compared using a one-way analysis of variance for repeated measures and, where significant differences were noted, a Student-Newman-Keuls test was applied; p < 0.05 was considered significant.
Medetomidine, administered either systemically or perineurally, significantly prolonged duration of peak motor block, peak sensory block, and residual sensory block compared with CONTROL.
Medetomidine prolonged sensory and motor blockade after radial nerve block with mepivacaine in dogs.
Medetomidine may prove to be a useful adjunct to peripheral nerve blockade with local anesthetics.
Spinal α2-adrenoceptor induces analgesia by neuronal inhibition of primary afferent fibers. This family receptor coupled to G i/o proteins can be subdivided into three functional subtypes: α2A, α2B, and α2C-adrenoceptors, and current evidence on spinal analgesia supports the relevance of α2A and seems to exclude the role of α2B, but the functional contribution of α2C-adrenoceptors remains elusive. The present study was designed to pharmacologically dissect the contribution of spinal α2-adrenoceptor subtypes modulating tonic or acute peripheral nociception. Using male Wistar rats, we analyzed the effect of spinal clonidine (a non-selective α2A/α2B/α2C-adrenoceptor agonist) and/or selective subtype α2-adrenoceptor antagonists on: 1) tonic nociception induced by subcutaneous formalin (flinching behavior) or 2) acute nociception induced by peripheral electrical stimulus in in vivo extracellular recordings of spinal dorsal horn second-order wide dynamic range (WDR) neurons. Clonidine inhibited the nocifensive behavior induced by formalin, an effect blocked by BRL 44408 (α2A-adrenoceptor antagonist) but not by imiloxan (α2B-adrenoceptor antagonist) or JP 1302 (α2C-adrenoceptor antagonist). Similarly, spinal BRL 44408 reversed the clonidine-induced inhibition of nociceptive WDR activity. Interestingly, spinal JP 1302 per se produced behavioral antinociception (an effect blocked by bicuculline, a preferent GABAA channel blocker), but no correlation was found with the electrophysiological experiments. These data imply that, at the spinal level, 1) presynaptic α2A-adrenoceptor activation produces antinociception during acute or tonic nociceptive stimuli; and 2) under tonic nociceptive (inflammatory) input, spinal α2C-adrenoceptors are pronociceptive, probably by the inactivation of GABAergic transmission. This result supports a differential role of α2A and α2C-adrenoceptors modulating nociception.
Ropivacaine is a promising drug for subarachnoid block because of its lower cardiotoxic and neurotoxic potential, but onset and duration of anaesthesia is also low and motor block is often insufficient which may lead to use of its higher doses. The aim of this randomized double-blinded study was to see whether the addition of small dose clonidine to small dose ropivacaine for spinal anesthesia prolonged the duration of postoperative analgesia while minimizing the side effects associated with higher doses of ropivacaine. We randomized 60 patients to 2 groups receiving intrathecal isobaric ropivacaine 18 mg (2.4 ml) combined with normal saline (Group R) or clonidine 30 μg (Group RC); all solutions were diluted with saline to 2.6 ml. We compared block characterstics, hemodynamic changes, post-operative analgesia and adverse effects of both the groups. Results showed that clonidine not only significantly reduced the onset time both of sensory and motor block, but also prolonged the duration. Hypotension and bradycardia was more with clonidine group during first hour. The addition of clonidine prolonged time to first analgesic request and decreased postoperative pain with minimal risk of delayed hypotension. Level of sedation and other side effects were comparable in both the groups. We concluded that addition of clonidine 30 μg to ropivacaine 18 mg produced an early and prolonged spinal anaesthesia and decrease the dose of post-operative analgesic requirement.
Die Entdeckung der lokalanästhetischen Wirkung durch Blockade der Natriumionenkanäle war ein Meilenstein in der Anästhesie, die jedoch schon bald ihre Limitierung durch z. T. lebensbedrohliche toxische Wirkungen der Lokalanästhetika (LA) erfuhr. Durch Entwicklung neuartiger LA, aber auch durch Hinzunahme sog. Adjuvanzien wurde versucht, diese lebensbedrohlichen Wirkungen einzuschränken. Der vorliegende Beitrag hat zum Ziel, Hintergrund und aktuellen Stand der Anwendung dieser Adjuvanzien zur Regionalanästhesie zu betrachten. Durch Zusatz von Adrenalin, Clonidin oder Dexmedetomidin – jedoch nur als einmalige Gabe – kommt es zu einer schnelleren Anschlagzeit, einer längeren Wirkdauer und einer intensiveren neuronalen Blockade der Regionalanästhesie. Die Vorteile einer zusätzlichen Gabe von Natriumbikarbonat sind dagegen relativ gering und klinisch eher vernachlässigbar. Obwohl in der Literatur Belege für eine Verbesserung und Verlängerung der analgetischen Wirkung nach axonaler Gabe von Opioiden gefunden werden, sind zentrale Nebenwirkungen und eine systemische Wirkung nicht sicher ausgeschlossen. Die z. T. vorkommenden lokalanästhetischen Wirkungen der Opioide sind nicht immer klar abgrenzbar von den opioidrezeptorspezifischen Wirkungen. Mechanistische Untersuchungen postulieren eine funktionelle Kopplung von Opioidrezeptoren eher nach Störungen der axonalen Integrität des Nerven, nicht jedoch im intakten peripheren Nerv. Neuere Untersuchungen identifizieren Glukokortikoid- und Mineralokortikoidrezeptoren bevorzugt auf peripheren schmerzleitenden Nervenfasern. Dies geht einher mit zahlreichen klinischen Berichten einer deutlichen Verlängerung der lokalanästhetischen Wirkung. Neben bekannten genomischen Effekten, die sich über eine Änderung der Genexpression schmerzunterhaltender Proteinstrukturen ergeben, werden auch immer mehr schnell einsetzende, nichtgenomische Wirkungen der Steroide diskutiert, denen eine Veränderung intrazellulärer Signalwege zugrunde liegt. Zusammenfassend stehen dem Anästhesisten neue Erkenntnisse und Ergebnisse klinischer Studien zur Adjuvanzienapplikation im Rahmen der Regionalanästhesie zur Verfügung, die in der Bewertung ihres möglichen Einsatzes zur Schmerztherapie eines jeden individuellen Patienten Berücksichtigung finden sollten.
Pain is constant after cesarean delivery. It is often severe due to the combined stimulus of the surgical incision with the oxytocin-induced retraction of the uterus. It may cause maternal distress or even psychological sequelae if not properly treated. Pain also increases the risk of thromboembolism by impeding rapid rehabilitation and alters interactivity with the newborn and breastfeeding. The best approach is multimodal: it combines oral or intravenous non-opioid analgesics with a low dose of neuraxial morphine.
The goal of the present chapter is to revisit the conclusion of a review published 5 years ago in terms of the experimental and clinical data published from 1996 to 2000. It intends to provide the anaesthesiologist with an objective idea of what can be expected from this class of substance in the everyday practice of regional anaesthesia/analgesia. The chapter is divided in four parts, scrutinizing respectively the drugs available, the mechanisms of action, the clinical use and the side-effects. It is concluded, in accordance with the first review, that α2-adrenergic receptor agonists improve the reliability and efficacy of regional anaesthesia. The best way to take advantage of these drugs for regional anaesthesia/analgesia is to combine them, at low dose, with other classical drugs via the spinal or epidural route. In particular, clear evidence exists that α2-adrenergic agonists should be combined with the opioids any time the latter are required.
The aim of this study is to examine the duration and magnitude of vasodilative effect induced by sympathetic block with the addition of clonidine to mepivacaine.
We measured mean arterial pressure (MAP), heart rate (HR), and right and left brachial artery blood flow (BABF) before and after stellate ganglion block (SGB) in dogs. The experimental protocol was designed as follows: (1) left SGB using 1.0 mL 0.5% mepivacaine (n = 6) and (2) left SGB using the addition of clonidine 0.5 microg to 1.0 mL 0.5% mepivacaine (n = 6).
MAP and HR did not change significantly throughout the study in either group. Left SGB with mepivacaine increased left BABF significantly from 10 minutes through 50 minutes after SGB (baseline, 100%; peak at 10 minutes after SGB, 176% +/- 28%; P <.01). Left SGB with the addition of clonidine to mepivacaine induced a significant increase of left BABF from 10 minutes through 70 minutes after SGB (baseline, 100%; peak at 10 minutes after SGB, 223% +/- 42%; P <.01). The values of left BABF after SGB with the addition of clonidine to mepivacaine were significantly higher than those of SGB with mepivacaine alone from 10 minutes through 80 minutes after SGB (P <.05). Right BABF decreased significantly after SGB throughout the study in both groups.
The addition of clonidine increases both duration and magnitude of the vasodilative effect induced by sympathetic block over that caused by mepivacaine alone.
The purpose of the present study was to evaluate the postoperative analgesic and adverse effects of equal doses of oral or intrathecal clonidine in spinal anaesthesia with bupivacaine plain.
Forty-five ASA I-III orthopaedic patients scheduled for osteosynthesis of a traumatic femur fracture were randomised in a double-blind fashion to one of 3 groups. Patients received 15 mg of plain bupivacaine intrathecally (group B) or an intrathecal mixture of bupivacaine 15 mg and clonidine 150 mg (group CIT). In group CPO oral clonidine 150 mg was administered 60 min before intrathecal injection of bupivacaine 15 mg.
Oral and intrathecal clonidine prolonged the time until the first request for analgesics, 313 +/- 29 and 337 +/- 29 min, respectively, vs. 236 +/- 27 min in group B (P < 0.01). The total 24- h PCA morphine dose was significantly lower in group CIT(19.3 +/- 1.3 mg) compared to groups B and CPO(33.4 +/- 2.0 and 31.2 +/- 3.1 mg). MAP was decreased significantly during the first hour after intrathecal clonidine(14%) and during the first 5 h after oral clonidine(14-19%). HR decreased in CIT during the 5th and 6th postoperative hours(7-9%) and during the first 2 h(9%) in CPO (P < 0.01). The degree of sedation was more pronounced in group CPO during the first 3 h. Four patients had pruritus in group B.
Addition of intrathecal clonidine prolonged analgesia and decreased morphine consumption postoperatively more than oral clonidine. Hypotension was more pronounced after oral than after intrathecal clonidine. Intrathecal clonidine is therefore recommended.
Yohimbine, an indole alkaloid, is a natural alpha(2)-adrenoceptor antagonist and is frequently used to assess the mechanism of a drug's effect on alpha-adrenoceptors. Recently, several studies showed that yohimbine exhibited analgesic effects in in vivo animal models. However, the underlying mechanism is not known. We investigated the effects of yohimbine on Na(+) channels and vanilloid VR1 receptors in dorsal root ganglion cells. We found that yohimbine inhibited tetrodotoxin-sensitive Na(+) channels (Na(V)1.2), the tetrodotoxin-resistant Na(+) channels, including both slow inactivating (Na(V)1.8) and persistent (Na(V)1.9) Na(+) channels, and capsaicin-sensitive vanilloid VR1 receptors. Action potential firing activities of dorsal root ganglion neurons evoked by current injection or capsaicin were eliminated by yohimbine. The blocking effects of yohimbine on nociceptive-related ion channels and firing activities of dorsal root ganglion neurons may underlie the ionic mechanism of yohimbine's analgesic effects observed in in vivo studies.
Although clonidine is commonly combined with local anesthetics to extend duration of peripheral nerve block, the mechanism by which clonidine potentiates local anesthetic action in vivo is unclear.
Male Sprague-Dawley rats received percutaneous injections of 1% lidocaine with/without clonidine or epinephrine into the sciatic notch and duration of sensory blockade was quantified by inhibition of pinprick foot withdrawal. The antagonists prazosin or yohimbine were injected before lidocaine with clonidine or epinephrine to determine the role of alpha-adrenergic receptors. The role of the hyperpolarization-activated cation current (Ih) was evaluated by injecting the current blocker ZD 7288 as well as the current enhancers forskolin and 8-Br-cAMP before lidocaine alone or with 15 micrograms/ml clonidine.
Mean duration of sensory block for lidocaine alone was 69 +/- 2 min. Sensory block duration increased monotonically with increasing doses of added clonidine or epinephrine. Preinjection of prazosin but not yohimbine prevented the increase in block duration seen with epinephrine. Neither alpha-adrenergic antagonist attenuated the extended duration of block with clonidine. ZD 7288 extended sensory blockade equivalent to the prolongation observed with clonidine. There was no additive effect when ZD 7288 and clonidine were combined, and a decreased duration of nerve block when either forskolin or 8-Br-cAMP preceded injection of lidocaine with clonidine.
The findings indicate that prolongation of duration of in vivo lidocaine nerve blockade by clonidine is not mediated by an alpha-adrenergic mechanism but likely involves the Ih current.
Alpha-2 adrenoceptor agonists have been used in association with local anaesthetic to increase the duration of spinal anaesthesia. Intrathecal administration of clonidine prolonged motor blockade induced by local anaesthetic. Since the affinity of dexmedetomidine (DEX) to alpha-2 adrenoceptors is eight-times greater than clonidine, it is expected that DEX could be advantageous in clinical anaesthesia. We investigated the duration of motor nerve block induced by spinal injection of 0.5% levobupivacaine (LVB) associated with intrathecal or intraperitoneal administration of DEX. Seventy-two guinea-pigs were randomly divided in 12 groups, which were all treated with intrathecal injection of 50 microL of LVB. DEX was injected intrathecally with LVB in 6 groups or injected intraperitoneally after LVB in another 6 groups. Intrathecal DEX (0.1, 0.2 and 0.4 microg) increased the LVB-induced motor anaesthesia from 48 (41-66) min to 84.5 (52-91) min (P < 0.05), 101.5 (83-115) min (P < 0.05) and 105 (97-114) min (P < 0.05), respectively. Similarly, intraperitoneal DEX (20 and 40 microg kg(-1)) increased the motor blockade from 48.5 (33-59) min to 88 (71-114) min (P < 0.05) and 114.5 (103-156) min (P < 0.05), respectively. Pre-treatment with yohimbine reduced the duration of motor block from 101.5 (83-115) to 76.5 (68-86) min (P < 0.05) or from 114.5 (103-156) to 90 (83-93) min (P < 0.05) when DEX was administered by the intrathecal or intraperitoneal routes. Motor block induced by spinal injection of LVB was prolonged by intrathecal and systemic administration of DEX, which was partially dependent on activation of alpha-2 adrenoceptors.
Repeated lumbar sympathetic blockade (LSB) with local anesthetics is generally used in complex regional pain syndrome (CRPS) of the lower extremities if the initial block has been successful. However, the symptoms of CRPS may inevitably recur in spite of repeated LSB. Clonidine, an alpha2-adrenoceptor agonist, has both anesthetic and analgesic sparing effects, and when added to local anesthetics may enhance peripheral and central neural block due to its local or central analgesic effects. It is reasonable that clonidine has been used in chronic pain conditions such as neuropathic and sympathetically maintained pain. Here we report two cases of CRPS type 1 who got excellent analgesia and alleviation of clinical symptoms after receiving an LSB with lidocaine and clonidine.
In awake human subjects, neural responses in cutaneous nerves to electrical stimulation were recorded with intrafascicular tungsten micro-electrodes. Changes in the activity of individual fibre groups during blocking procedures were recorded and correlated with simultaneous alterations in the perception of standardized stimuli. Light touch sensibility in hairy skin was mediated by A-beta-gamma fibres, cold and pinprick by A-delta fibres and warmth and dull pain by C fibres.
Phenomena seen in axons exposed to subblocking doses serve as the basis for interpreting clinical and behavioral observations during onset and recovery of peripheral nerve block. To delineate the changes in excitability and in impulse conduction caused by subblocking concentrations of local anesthetics (LAs) in myelinated peripheral nerve fibers, LAs were applied to excised frog sciatic nerves while impulse conduction was monitored in single axons. For concentrations ranging from 0.01 to 1.2 times the LA concentration needed to block impulse conduction, three measures of susceptibility to LA were made to quantify the action of the drugs on "resting" fibers (firing rates < or = 0.5 Hz): the increase in the threshold for electrical activation of impulses, the increase in conduction latency reflecting the slowing of impulse conduction in the region exposed to LA, and the "critical blocking concentration" of LA just sufficient to prevent impulse conduction in the recorded fiber. Wide interfiber variation in these variables was observed (e.g., for lidocaine, latency increases at block ranged from 66% to 257% of control, blocking concentrations ranged from 0.29 to 1.40 mM), which was not correlated with fiber diameter (as indicated by resting conduction velocity). Mathematical modeling of impulse conduction in fibers exposed to LA demonstrated that the interfiber variation in susceptibility to LA block could result from interfiber differences in the density of sodium and potassium channels. The effects of LA were also studied in active fibers (firing rates > 0.5 Hz). Local anesthetics reversibly inhibited two normally occurring afteroscillations in membrane threshold related to afterpotentials following an impulse. These were "superexcitability," a transient lowering of threshold lasting as long as 1 s, and "depression," a phase of raised threshold peaking within 2-4 s after an impulse and recovering slowly over several minutes. Impulse activity also transiently increased the apparent potency of LAs. Such "use-dependent" increases in threshold and decreases in conduction velocity showed kinetics that were agent specific, lasting 1 s after a burst of impulses for lidocaine and lasting > 10 s for bupivacaine. At low concentrations, within the range of nontoxic plasma concentrations after systemic administration, the predominant actions of LAs on conducting fibers were transient decreases in excitability and conduction velocity in combination with a reduction of intrinsic oscillatory aftereffects of impulse discharge. These effects may degrade decoding of information in discharge patterns without actually blocking conduction of infrequent impulses, suggesting how functional blockade of coordinated movement and perception may occur even without complete blockade of impulse conduction.
We examined local anesthetic effects of clonidine and its interaction with lidocaine with regard to tonic inhibition of the C-fiber action potential (AP) on the isolated, desheathed rabbit vagus nerve by the sucrose gap method. Clonidine and lidocaine at 500 microM concentrations caused a comparable degree of C-fiber inhibition, corresponding to an AP area under the curve of 75.8% +/- 9.4% (mean +/- SE) and 82.2% +/- 5.9% of control, respectively. Concentrations of clonidine less than 500 microM did not inhibit C-fiber AP. Clonidine, added in concentrations of 500 nM, 500 microM, and 5 mM to a 500 microM lidocaine perfusion, caused a significant decrease in fiber blockade of 18%, 20%, and 54%, respectively, as compared with clonidine added to Locke perfusion (P less than 0.05). The sodium channel blocker tetrodotoxin (3 microM) decreased the AP area to 9.3% +/- 1.3% of control. The remaining tetrodotoxin-resistant AP was almost completely blocked by clonidine (500 microM) and lidocaine (500 microM), indicating a higher susceptibility of tetrodotoxin-resistant fibers to the two drugs than the C-fiber population as a whole. The enhancing effect of a low dose of clonidine (500 nM) on lidocaine-induced (500 microM) inhibition of C-fiber AP might explain the clinical observation that clonidine, at approximately 1000-fold lower concentrations than lidocaine, prolongs the action of lidocaine in peripheral nerve block.
This study evaluates the effects of clonidine added to mepivacaine on the duration of anesthesia and analgesia after axillary brachial plexus block.
Thirty patients scheduled for elective hand surgery were divided into three equal groups in a randomized, double-blinded fashion. An axillary perivascular brachial plexus block was performed with 40 ml 1% mepivacaine plus 1:200,000 epinephrine in the three groups. Group B also received 150 micrograms clonidine subcutaneously and Group C had the same dose of clonidine mixed with the local anesthetic and injected into the plexus sheath. The following variables were recorded: onset time, duration of anesthesia, duration of analgesia, postoperative pain score, intake of analgesics, and adverse effects.
The three groups were comparable in terms of age, sex, weight, height, onset time of anesthesia, postoperative pain score, and analgesic requirement. The duration of anesthesia and analgesia was comparable in Groups A and B, but both variables were significantly increased in Group C: the duration of anesthesia and analgesia were prolonged, respectively, by 37 +/- 6% and 103 +/- 16% when compared to Group A and by 32 +/- 7% and 89 +/- 15% when compared to Group B. No side effects were reported.
One hundred fifty micrograms clonidine added to mepivacaine for brachial plexus block prolongs the duration of anesthesia and analgesia. Our results suggest that this effect of clonidine is local rather than systemic.
The sucrose-gap technique was employed to examine the different types of afterpotentials that follow, in desheathed rabbit vagus nerves, a single action potential (AP) elicited by a short (0.4 ms) supramaximal depolarizing pulse. A fast and a slow hyperpolarizing afterpotential (fHAP and sHAP) as well as a depolarizing afterpotential (DAP) followed a single spike. Both the fHAP and the sHAP showed a dependence on the K+ electrochemical gradient, indicating that they are due to an outwardly oriented current of K+ ions. The fHAP was sensitive to low concentrations of tetraethylammonium (TEA; 1 mM) and 4-aminopyridine (4-AP; 10 μM) and to millimolar concentrations of Ba2+. We conclude that the fHAP reflects the tail of the delayed rectifier K+ current. The sHAP contained a Ca2+-sensitive component that showed a requirement for voltage-dependent Ca2+ entry during the AP. This component was completely blocked by low concentration of TEA (1 mM) and by Cd2+ (1 mM), but unaffected by 4-AP. These observations suggest that it reflects a current flowing through Ca2+-activated K+ channels. The remaining, apparently Ca2+-insensitive, component was insensitive to 4-AP and could be blocked by TEA only at concentrations >50 mM. The DAP usually appeared when the external concentration of K+ was increased to above ~8 mM, but sometimes it was clearly visible even at lower [K+](o). The DAP was TEA insensitive and entirely Ca2+ dependent. This latter property is inconsistent with the widely accepted hypothesis according to which the DAP reflect the accumulation of K+ in the extracellular space during the AP. The origins of both the Ca2+-insensitive component of the sHAP and the DAP are not clear. However, in view of the fact that the sucrose-gap technique records not only the membrane potential of the nerve fibers but also of the surrounding glia, there is the possibility that these afterpotentials reflect changes in the electrical properties of the satellite Schwann cells.
Impulse block by LA occurs through the inhibition of voltage-gated Na+ channels. Both protonated and neutral LAs can inhibit Na+ channels though interference with the conformational changes that underly the activation process (the sequence of events that occurs as channels progress from the closed resting state to the open conducting state). The occlusion of open channels contributes little to the overall inhibition. Local anesthetic inhibition of Na+ currents increases with repetitive depolarizations in a process called phasic block. Phasic block represents increased LA binding, either because more channels become accessible during depolarization or because the channel conformations favored by depolarization bind LA with higher affinity. The details of phasic block are dependent on LA chemistry: certain LAs bind and dissociate quite rapidly, others act more slowly; some LAs interact effectively with closed states that occur intermediately between resting and open states, others favor the open channel, and still others have a higher affinity for inactivated states. Channel activation accelerates LA binding, and LAs may bind more tightly to activated and inactivated than to resting channels. In this regard, both the modulated receptor and the guarded receptor hypotheses are valid. In binding to activated and inactivated channels, LAs prevent the conformational changes of activation and antagonize the binding of activator agents that poise channels in activated, open states. These reciprocal actions are one aspect of the concerted conformational rearrangements that occur throughout Na+ channels during gating. The LA binding site may exist in the channel's pore, at the membrane-protein interface, or within the protein subunits of the channel. Judging from its susceptibility to intracellular proteases and its accessibility to LAs with limited membrane permeability (i.e., quaternary LAs in the cytoplasm), the site lies nearer to the cytoplasmic than the external surface of the membrane. Nevertheless, protons in the external medium influence the dissociation of LA from the closed channel. Binding of LAs at the inhibitory site is weak and loose. If one accounts for the membrane-concentrating effects of LA hydrophobicity that are expressed as membrane: buffer partition coefficients equal to 10(2)-10(4), then the apparent LA affinities are low. The equilibrium dissociation constants calculated on the basis of free drug in the membrane are 1-10 mM, with a correspondingly weak binding to the inhibitory LA site. The stereospecificity of LA action is also relatively nonselective, suggesting a loose fit between ligand and binding site.(ABSTRACT TRUNCATED AT 400 WORDS)
The sucrose gap technique, though widely employed in many tissues, could not be used for quantitative measurements of the membrane potential, because the value of the short-circuiting factor and the influence of junction potential on the recorded potential difference were unknown. The formula that relates the recorded potential to the true resting membrane potential was found by application of the cable equations to a core conductor placed in a system with three different media, e.g. Ringer, sucrose, and KCl. The formula shows that the potential difference recorded over the sucrose insulator depends on the extracellular and the intracellular longitudinal resistances, the membrane resistance and the membrane potentials in each region, and on the junction potentials between the different media. The true membrane potential in the Ringer region can be calculated from the potential difference recorded after complete depolarization by KCl on one side of the preparation, if the longitudinal resistances, the membrane resistances, the extracellular potential in the sucrose, and the junction potential between Ringer and sucrose are determined by separate measurements.
The local anaesthetic action of a series of nerve blocking agents was examined at temperatures between 4°C and 20°C in isolated sciatic nerves from cold‐adapted frogs. Cooling alone had little effect on the amplitude of the action potential but the conduction velocity was decreased and the duration increased. Cooling had little effect on the local anaesthetic action of the short chain alkanols but that of the long chain alkanols, benzyl alcohol, benzocaine and pentobarbitone was markedly enhanced.
The partition of both short and long chain alkanols and of pentobarbitone into a liposome suspension of similar composition to axonal membrane lipids was reduced by cooling from 40°C to 4°C.
The results are not compatible with the lipid hypotheses of anaesthetic action. The implications for the nature of the site of action are discussed.
The distribution of extracellular and intracellular potential in the sucrose gap apparatus, previously established for a single fiber using the cable equations for a core conductor model (Jirounek and Straub, Biophys. J., 11:1, 1971), is obtained for a multifiber preparation. The exact equation is derived relating the true membrane potential change to the measured potential differences across the sucrose gap, the junction potentials between sucrose and physiological solution, the membrane potential in the sucrose region, and the electrical parameters of the preparation in each region of the sucrose gap. The extracellular potential distribution has been measured using a modified sucrose gap apparatus for the frog sciatic nerve and the rabbit vagus nerve. The results indicate a hyperpolarization of the preparations in the sucrose region, of 60--75 mV. The hyperpolarization is independent of the presence of junction potentials. The calculation of the correction terms in the equation relating the actual to the measured potential change is illustrated for the case of complete depolarization by KC1 on one side of the sucrose gap. The correction terms in the equation are given for various experimental conditions, and a number of nomographic charts are presented, by means of which the correction factors can be rapidly evaluated.
The morphological and physiological features of the rabbit vagus nerve were studied at different ages after birth. The total fibre count is about 37,500 of which at birth 1-2% and in the adult animal approximately 10% are myelinated. In the postnatal period the cross-sectional area of the vagus grows to 5 times its perinatal size due to an increase of endoneural collagen, fibre growth and myelinization. The myelinization is most pronounced in the first 2 weeks after birth, axonal growth is predominant thereafter. The available data suggest that the begin of myelinization as well as the subsequent development of the myelin sheath are not dependent on axonal size. There seems to be no fundamental difference between the morphological development of the vagus and other peripheral nerves, e.g. the sciatic nerve of the rat. At birth the vagus nerve contains 2 fibre groups as can be measured from the compound action potential with conduction velocities of 11.4 and 0.9 m.s-1 respectively. Upon subsequent development the conduction velocity of these fibres increases to 31.9 and 1.2 m.s-1 in full-grown animals. THe compound action potential of the adult nerve implies 2 additional fibre groups with conduction velocities of 12.3 and 4.6 m.s-1 respectively. These two fibre populations develop gradually from 1 to 2 weeks after birth and arise probably from the slowest conducting, non-myelinated or C-fibres. It is concluded that the functional innervation of the sinoauricular node may be operational at birth as far as the cervical vagus nerve is concerned.
1. The electrophysiological properties of the rabbit vagus nerve (membrane potential, compound action potentials, and afterpotentials) and potassium accumulation were measured simultaneously during low-frequency stimulation (LFS) (0.5 and 1 Hz) by using a modified sucrose-gap apparatus and potassium-sensitive microelectrodes (KSM). 2. During LFS at 0.5 and 1 Hz, the concentration of K+ in the extracellular space ([K+]c) increased in approximately 30 s to a maximal level that was 0.6 and 1.5 mM, respectively, above the resting concentration. Concomitantly the preparation developed an ouabain-sensitive hyperpolarization. 3. The compound action potential (CAP) was followed by a fast hyperpolarizing afterpotential (fHAP), a depolarizing afterpotential (DAP), and a slow hyperpolarizing afterpotential (sHAP). During LFS the characteristics of all these afterpotentials were profoundly modified. In parallel to the increase in [K+]e, the fHAP was decreased and the amplitude of the DAP was dramatically enhanced. Furthermore, the sHAP which had a duration of < 1 s when it followed a single CAP, turned into a ouabain-sensitive hyperpolarization (indicating that it was generated by the electrogenic Na(+)-K+ pump) that lasted several minutes. 4. The application of external Ba2+ produced a hyperpolarizing sag on the sHAP following a single isolated CAP. During LFS, Ba2+ enhanced the build-up of the DAP, raised the maximal level of [K+]e, and increased the activity-induced ouabain-sensitive hyperpolarization. 5. The increase by Ba2+ of the activity-induced hyperpolarization shifted the spikes from both myelinated and nonmyelinated fibers toward a more negative potential but did not increase their amplitude, indicating that this Ba(2+)-induced hyperpolarization originated from an extra-axonal source, presumably the Schwann cells. 6. It is proposed that the electrogenic activity of the Na(+)-K+ pump was enhanced in Schwann cells situated near active axons. This hyperpolarization was, however, not recorded in normal conditions because it was fully short-circuited by a K+ influx through Ba(2+)-sensitive channels. 7. Our results lead to the hypothesis that the Na(+)-K+ pump of the nonmyelinating Schwann cells is important in the mechanisms maintaining the homeostasis of K+ in the axonal microenvironment. They show that the Na(+)-K+ pump contributes to the K+ buffering not only by actively pumping K+ but also by generating a hyperpolarization that drives a passive K+ influx through Ba(2+)-sensitive K+ channels.
To determine whether alpha 2-adrenergic agonists inhibit impulse conduction, clonidine and guanfacine were applied to rat sciatic nerve fibers studied in vitro. Clonidine and guanfacine produced concentration-dependent, tonic inhibition of compound action potentials in large, myelinated A alpha fibers. The 50% effective concentration (EC50) of clonidine measured 2.0 +/- 0.8 mM (mean +/- standard deviation); the EC50 of guanfacine measured 1.2 +/- 0.2 mM. Clonidine was also less potent than guanfacine at phasic block of A alpha compound action potentials examined at 10 Hz. Both drugs inhibited tonic impulse conduction in C fibers in a concentration-dependent, reversible fashion, and produced greater inhibition of C fiber than A alpha compound action potentials at all drug concentrations. Again, clonidine appeared to inhibit C fiber compound action potentials (EC50 = 0.45 +/- 0.01 mM) with less potency than guanfacine (EC50 = 0.17 +/- 0.06 mM). We conclude that clonidine and guanfacine, unlike traditional local anesthetics, demonstrate a tendency toward steady-state differential nerve block wherein C fibers are blocked to a greater extent than A alpha fibers.
Effects of clonidine and lidocaine on the hyperpolarizing after-potential (HAP) and frequency-dependent block in C fibers were examined on desheathed rabbit vagus nerves, using the sucrose gap technique. A single action potential (AP) was followed by a fast and a slow HAP. Clonidine, at concentrations from 0.05 to 50 mumol/l, decreased the fast HAP, while the AP amplitude was unchanged. At a 500 mumol/l concentration of clonidine, the fast HAP amplitude was similar to control, the slow HAP was increased, and the AP amplitude decreased. Lidocaine at 500 mumol/l delayed and broadened the HAP, making a distinction between fast and slow HAP impossible, and decreased and delayed the AP amplitude. In the presence of lidocaine (500 mumol/l), clonidine at concentrations from 0.05 to 500 mumol/l decreased the HAP amplitude, without modifying the lidocaine-induced shape of the HAP. The modifications of the HAP, however, do not contribute to the local anesthetic effects of clonidine, as the addition of clonidine (0.5 and 500 mumol/l) to Locke or lidocaine (500 mumol/l) solution does not enhance the frequency-dependent block (3 and 10 Hz) observed with either Locke or lidocaine solution alone.
Zusammenfassung Beschreibung einer neuen Methode, die es gestattet, mit Aussenelektroden die wahre Grösse der Membranpotentialschwankungen, die durch den Einfluss von hyper- oder hypopolarisierenden Substanzen oder durch die Erregung in markhaltigen Nervenfasern erzeugt werden, zu registrieren.
A new method for measuring membrane potentials with external electrodes Adrenergic neuron block-¨ ade by clonidine: comparison with guanethidine and local anesthetics
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