Peter Gerner

ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model

&NA; Activation of extracellular signal‐regulated kinase (ERK), a mitogen activated‐protein kinase (MAPK), in dorsal horn neurons contributes to inflammatory pain by transcription‐dependent and ‐independent means. We have now investigated if ERK is activated in the spinal cord after a spinal nerve ligation (SNL) and if this contributes to the neuropathic pain‐like behavior generated in this model. An L5 SNL induces an immediate (<10 min) but transient (<6 h) induction of phosphoERK (pERK) restricted to neurons in the superficial dorsal horn. This is followed by a widespread induction of pERK in spinal microglia that peaks between 1 and 3 days post‐surgery. On Day 10, pERK is expressed both in astrocytes and microglia, but by Day 21 predominantly in astrocytes in the dorsal horn. In the L5 DRG SNL transiently induces pERK in neurons at 10 min, and in satellite cells on Day 10 and 21. Intrathecal injection of the MEK (ERK kinase) inhibitor PD98059 on Day 2, 10 or 21 reduces SNL‐induced mechanical allodynia. Our results suggest that ERK activation in the dorsal horn, as well as in the DRG, mediates pain through different mechanisms operating in different cells at different times. The sequential activation of ERK in dorsal horn microglia and then in astrocytes might reflect distinct roles for these two subtypes of glia in the temporal evolution of neuropathic pain.

Tricyclic antidepressants as long-acting local anesthetics

&NA; Amitriptyline, nortriptyline, imipramine, doxepin, desipramine, protriptyline, trimipramine, and maprotiline are tricyclic antidepressants (TCAs) used orally in treating major depressive disorders. Recent studies showed that amitriptyline is more potent in blocking the sciatic nerve functions in vivo by local injection than bupivacaine, a long‐acting local anesthetic. We therefore tested whether various TCAs could likewise act as local anesthetics in vivo after single injection via the rat sciatic notch. The duration of complete sciatic nerve blockade by TCAs and the time to reach full recovery were measured with neurobehavioral assays and compared with results from bupivacaine. Amitriptyline, doxepin, and imipramine at 5 mM elicited a longer complete sciatic nerve blockade than did bupivacaine at 15.4 mM (0.5%), whereas trimipramine and desipramine at 5 mM produced a shorter blockade. In contrast, nortriptyline, protriptyline, and maprotiline failed to elicit complete sciatic nerve blockade. Thus, TCAs have very different efficacy as local anesthetics in vivo. The duration of rat sciatic nerve blockade in vivo by TCAs is not well correlated with the 50% inhibitory concentration (IC50) of TCAs in blocking human cardiac Nav1.5 Na+ channels expressed in human embryonic kidney cells. With this in vitro expression system, TCAs appear more potent than bupivacaine as Na+ channel blockers in Nav1.5 Na+ channels. We suggest that the ability of TCAs to pass through various membrane barriers within peripheral nerve trunks is crucial to their local anesthetic efficacy in vivo. TCAs with a tertiary amine appear more effective in penetrating these membrane barriers than TCAs with a secondary amine.

Trends in in-hospital major morbidity and mortality after total joint arthroplasty: United States 1998-2008.

BACKGROUND:The use of total joint arthroplasties is increasing worldwide. In this work we aim to elucidate recent trends in demographics and perioperative outcomes of patients undergoing total hip (THA) or total knee arthroplasty (TKA). METHODS:Data from the US Nationwide Impatient Sample between 1998 and 2008 were gathered for primary THAs and TKAs. Trends in patient age, comorbidity burden, length of hospitalization, frequency of major perioperative complications, and in-hospital mortality were analyzed. In-hospital outcomes were reported as events per 1000 inpatient days to account for changes in length of hospitalization over time. Deyo index, discharge status, and the interaction effect of time and discharge status were included in the adjusted trend analysis for morbidity. RESULTS:Between 1998 and 2008, the average age of patients undergoing TKA and THA decreased by 2 to 3 years (P < 0.001). The average length of stay decreased by approximately 1 day over the time interval studied (P < 0.001). The percentage of patients being discharged home declined from 29.7% to 25.4% after TKA and from 29.3% to 24.2% after THA, in favor of dispositions to long- and short-term care facilities (P < 0.0001). Comorbidity burden as measured by the Deyo comorbidity index increased by 35% and 30% for TKA and THA patients, respectively (P < 0.0001). After TKA, there was an increase in the incidence of the following major complications: pulmonary embolism (coefficient estimate [CE] 0.069; 95% confidence interval [CI], 0.059–0.079; P < 0.0001), sepsis (CE 0.034; 95% CI, 0.014–0.054; P = 0.001), nonmyocardial infarction cardiac complications (CE 0.038; 95% CI, 0.035–0.041; P < 0.0001), and pneumonia (CE 0.039; 95% CI, 0.031–0.047; P < 0.0001). After THA, there was an increase in the incidence of the following major complications: pulmonary embolism (CE 0.031; 95% CI, 0.012–0.049; P = 0.001), sepsis (CE 0.060; 95% CI, 0.039–0.081; P < 0.0001), nonmyocardial infarction cardiac complications (CE 0.040; 95% CI, 0.036–0.043; P < 0.0001), and pneumonia (CE 0.039; 95% CI, 0.029–0.048). In-hospital mortality declined after both TKA (CE −0.059; 95% CI, −0.077 to −0.040; P < 0.0001) and THA (CE −0.068; 95% CI, −0.086 to −0.051; P < 0.0001). CONCLUSION:Between 1998 and 2008, trends show increases in several major in-hospital complications after THA and TKA, including pulmonary embolism, sepsis, nonmyocardial infarction cardiac complications, and pneumonia. Despite the increase in complications, declining in-hospital mortality was noted over this period.

Amitriptyline versus bupivacaine in rat sciatic nerve blockade.

BackgroundAmitriptyline, a tricyclic antidepressant, is frequently used orally for the management of chronic pain. To date there is no report of amitriptyline producing peripheral nerve blockade. The authors therefore investigated the local anesthetic properties of amitriptyline in rats and in vitro. MethodsSciatic nerve blockade was performed with 0.2 ml amitriptyline or bupivacaine at selected concentrations, and the motor, proprioceptive, and nociceptive blockade was evaluated. Cultured rat GH3 cells were externally perfused with amitriptyline or bupivacaine, and the drug affinity toward inactivated and resting Na+ channels was assessed under whole-cell voltage clamp conditions. In addition, use-dependent blockade of these drugs at 5 Hz was evaluated. ResultsComplete sciatic nerve blockade for nociception was obtained with amitriptyline for 217 ± 19 min (5 mm, n = 8, mean ± SEM) and for 454 ± 38 min (10 mm, n = 7) versus bupivacaine for 90 ± 13 min (15.4 mm, n = 6). The time to full recovery of nociception for amitriptyline was 353 ± 12 min (5 mm) and 656 ± 27 min (10 mm) versus 155 ± 9 min for bupivacaine (15.4 mm). Amitriptyline was approximately 4.7–10.6 times more potent than bupivacaine in binding to the resting channels (50% inhibitory concentration [IC50] of 39.8 ± 2.7 vs. 189.6 ± 22.3 &mgr;m) at −150 mV, and to the inactivated Na+ channels (IC50 of 0.9 ± 0.1 vs. 9.6 ± 0.9 &mgr;m) at −60 mV. High-frequency stimulation at 3 &mgr;m caused an additional approximately 14% blockade for bupivacaine, but approximately 50% for amitriptyline. ConclusionAmitriptyline is a more potent blocker of neuronal Na+ channels than bupivacaine in vivo and in vitro. These findings suggest that amitriptyline could extend its clinical usefulness for peripheral nerve blockade.

Amitriptyline for prolonged cutaneous analgesia in the rat

Background Amitriptyline has been reported to be a more potent local anesthetic than bupivacaine. In keeping with the objective of identifying drugs for prolonged cutaneous analgesia, the authors compared the cutaneous analgesic effectiveness of amitriptyline and bupivacaine in rats. Methods Rats were subcutaneously injected on shaved dorsal skin. The skin wheal raised after injection of 0.6 ml of various concentrations of either amitriptyline or bupivacaine with and without epinephrine (1:200,000) was marked. Inhibition of the cutaneous trunci muscle reflex was evaluated quantitatively by the fraction of times a total of six pinpricks applied to the marked area failed to elicit a nocifensive motor response compared with control responses. No responses out of six pinpricks was defined as 100% maximum possible effect. Results Complete recovery from the cutaneous analgesia elicited by 0.05% and 0.5 amitriptyline versus 0.05 and 0.5% bupivacaine occurred in 9.9 ± 0.2 and 19.3 ± 0.4 h versus 2.2 ± 0.1 and 16.1 ± 0.2 h, respectively (mean ± SE). Addition of epinephrine increased this duration to 14.1 ± 0.1 and 21.4 ± 0.2 h versus 3.2 ± 0.1 and 17.0 ± 0.3 h, respectively. Complete nociceptive blockade after coinjection of 0.25% amitriptyline, 0.25% bupivacaine, and epinephrine lasted 24 ± 0.5 h, and com-plete recovery from this block took 33 ± 0.5 h. Areas under the percent maximum possible effect versus time curve were 1,770 ± 24 and 1,471 ± 50% h for 0.5% amitriptyline and bupivacaine with epinephrine, respectively, whereas this value was 2,836 ± 62% h for the coinjected 0.25% amitriptyline, 0.25% bupivacaine, and epinephrine admixture. Conclusion Amitriptyline is a longer-acting local anesthetic compared with bupivacaine for cutaneous infiltration. Its analgesic effectiveness is significantly enhanced by epinephrine. Coinjection of amitriptyline and bupivacaine with epinephrine enhances the analgesic duration of both drugs.

Postthoracotomy Pain Management Problems

Pain after thoracotomy is very severe, probably the most severe pain experienced after surgery. Thoracic epidural analgesia has greatly improved the pain experience and its consequences and has been considered the standard for pain management after thoracotomy. This view has been challenged recently by the use of paravertebral nerve blocks. Nevertheless, severe ipsilateral shoulder pain and the prevention of the postthoracotomy pain syndrome remain the most important challenges for management of postthoracotomy pain.

Coapplication of Lidocaine and the Permanently Charged Sodium Channel Blocker QX-314 Produces a Long-lasting Nociceptive Blockade in Rodents

Background:Nociceptive-selective local anesthesia is produced by entry of the permanently charged lidocaine-derivative QX-314 into nociceptors when coadministered with capsaicin, a transient receptor potential vanilloid 1 (TRPV1) channel agonist. However, the pain evoked by capsaicin before establishment of the QX-314–mediated block would limit clinical utility. Because TRPV1 channels are also activated by lidocaine, the authors tested whether lidocaine can substitute for capsaicin to introduce QX-314 into nociceptors through TRPV1 channels and produce selective analgesia. Methods:Lidocaine (0.5% [17.5 mm], 1% [35 mm], and 2% [70 mm]) alone, QX-314 (0.2% [5.8 mm]) alone, and a combination of the two were injected subcutaneously and adjacent to the sciatic nerve in rats and mice. Mechanical and thermal responsiveness were measured, as was motor block. Results:Coapplication of 0.2% QX-314 with lidocaine prolonged the nociceptive block relative to lidocaine alone, an effect attenuated in TRPV1 knockout mice. The 0.2% QX-314 alone had no effect when injected intraplantary or perineurally, and it produced only weak short-lasting inhibition of the cutaneous trunci muscle reflex. Perisciatic nerve injection of lidocaine with QX-314 produced a differential nociceptive block much longer than the transient motor block, lasting 2 h (for 1% lidocaine) to 9 h (2% lidocaine). Triple application of lidocaine, QX-314, and capsaicin further increased the duration of the differential block. Conclusions:Coapplication of lidocaine and its quaternary derivative QX-314 produces a long-lasting, predominantly nociceptor-selective block, likely by facilitating QX-314 entry through TRPV1 channels. Delivery of QX-314 into nociceptors by using lidocaine instead of capsaicin produces sustained regional analgesia without nocifensive behavior.

Topical amitriptyline in healthy volunteers

Background and Objectives The antidepressant amitriptyline is used as an adjuvant in the treatment of a variety of chronic pain conditions. This drug interacts with many receptors and ion channels, such as Na+ channels. In a randomized, double-blinded, and placebo-controlled trial, we investigated whether amitriptyline also is capable of providing cutaneous analgesia when applied topically in 14 healthy volunteers. Methods Amitriptyline hydrochloride was prepared as a 45% water/45% isopropanol/10% glycerin solution and titrated to pH 8.5 with sodium hydroxide. Four areas, 2 on each arm, of approximately 1 cm2 each were marked on the ventral aspect of the upper arm. A piece of gauze, placed on each of the marked areas and affixed to the arm with an occlusive plastic dressing, was saturated via syringe with placebo and amitriptyline solutions (10 mmol/L, 50 mmol/L, and 100 mmol/L). After 1 hour, the dressings and gauze were removed. A 16-G blunt needle was used to grade the pain at the marked area once per hour (1 = complete analgesia, 10 = normal pain sensation). Results The analgesic effects of 50 mmol/L and 100 mmol/L solutions of amitriptyline were significantly higher than those of the placebo or the 10 mmol/L solution. However, no significant difference was found between the analgesia provided by the placebo solution versus the 10 mmol/L solution or between the 50 mmol/L versus the 100 mmol/L solution. The only side effect observed was a concentration-dependent redness of the skin. Conclusions Topically applied amitriptyline is effective as an analgesic in humans. Different vehicles may improve its efficacy and decrease the skin redness observed.

Comparative perioperative outcomes associated with neuraxial versus general anesthesia for simultaneous bilateral total knee arthroplasty.

Background and Objectives The influence of the type of anesthesia on perioperative outcomes after bilateral total knee arthroplasty (BTKA) remains unknown. Therefore, we examined a large sample of BTKA recipients, hypothesizing that neuraxial anesthesia would favorably impact on outcomes. Methods We identified patient entries indicating elective BTKA between 2006 and 2010 in a national database; subgrouped them by type of anesthesia: general (G), neuraxial (N), or combined neuraxial-general (NG); and analyzed differences in demographics and perioperative outcomes. Results Of 15,687 identified procedures, 6.8% (n = 1066) were performed under N, 80.1% (n = 12,567) under G, and 13.1% (n = 2054) under NG. Comparing N to G and NG, patients in group N were, on average, younger (63.9, 64.6, and 64.8 years; P = 0.030) but did not differ in overall comorbidity burden. Patients in group N required blood product transfusions significantly less frequently (28.5%, 44.7%, 38.0%; P < 0.0001). In-hospital mortality, 30-day mortality, and complication rates tended to be lower in group N, without reaching statistical significance. After adjusting for covariates, N and NG were associated with 16.0% and 6.0% reduction in major complications compared with G, but only the reduced odds for the requirement of blood transfusions associated with N reached statistical significance (N vs G: odds ratio, 0.52 [95% CI, 0.45–0.61], P < 0.0001; NG vs G: odds ratio, 0.77 [95% CI, 0.69–0.86], P < 0.0001). Conclusions Neuraxial anesthesia for BTKA is associated with significantly lower rates of blood transfusions and, by trend, decreased morbidity. Although by itself the effect may be limited, N might be used within a multimodal approach to reduce complications after BTKA.

In vitro, inhibition of mitogen-activated protein kinase pathways protects against bupivacaine- and ropivacaine-induced neurotoxicity.

BACKGROUND:Animal models show us that specific activation of the p38 mitogen-activated protein kinase (MAPK) may be a pivotal step in lidocaine neurotoxicity, but this has not been investigated in the case of two very widely used local anesthetics, bupivacaine and ropivacaine. We investigated the hypotheses that these drugs (A) are less neurotoxic than the prototype local anesthetic, lidocaine (B) are selectively toxic for subcategories of dorsal root ganglion neurons and (C) induce activation of either p38 MAPK or related enzymes, such as the c-jun terminal N-kinase (JNK) and extracellular signal-regulated kinase (ERK). METHODS:We incubated primary sensory neuron cultures with doses of lidocaine, bupivacaine, and ropivacaine equipotent at blocking sodium currents. Next, we sought to determine potential selectivity of bupivacaine and ropivacaine toxicity on neuron categories defined by immunohistochemical staining, or size. Subsequently, the involvement of p38 MAPK, JNK, and ERK was tested using enzyme-linked immunosorbent assays. Finally, the relevance of MAPK pathways in bupivacaine- and ropivacaine-induced neurotoxicity was determined by selectively inhibiting activity of p38 MAPK, JNK, and ERK. RESULTS:We found that the neurotoxic potency of bupivacaine and ropivacaine is dose-dependent and similar in vitro, but is not selective for any of the investigated subgroups of neurons. Neurotoxicity of bupivacaine and ropivacaine was mediated, at least in part, by MAPKs. Specifically, we demonstrated the relevance of both p38 MAPK and JNK pathways for the neurotoxicity of bupivacaine and characterized the involvement of the p38 MAPK pathway in the neurotoxicity of ropivacaine. CONCLUSIONS:Given equipotent doses, the neurotoxic potential of lidocaine does not appear to be significantly different from that of bupivacaine and ropivacaine in vitro. Moreover, bupivacaine and ropivacaine do not exert their neurotoxicity differently on specific subsets of dorsal root ganglion neurons. Their neurotoxic effects are brought about through the activation of specific MAPKs; the specific pharmacologic inhibition of these kinases attenuates toxicity in vitro.