Constantine Sarantopoulos

Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer

We evaluated the effect of multimodal analgesia on acute and chronic pain after breast surgery for cancer. Fifty patients scheduled for breast cancer surgery were blindly randomized to receive gabapentin, eutectic mixture of local anesthetics cream, and ropivacaine in the wound or three placebos. Pain (visual analog scale) and analgesics were recorded in the postanesthesia care unit (PACU) 3, 6, and 9 h and 8 days after surgery. Three and 6 mo later, patients were assessed for chronic pain. The treatment group consumed less paracetamol in the PACU (469 versus 991 mg; P < 0.002) and less Lonalgal® (1.0 versus 4.4 tablets; P = 0.003) than the controls, exhibited lower visual analog scale scores at rest in the PACU (P = 0.001) and on postoperative Days 1, 3, and 5 (P = 0.040, P = 0.015, and P = 0.045, respectively), and after movement in the PACU (P = 0.001) and on postoperative Days 2, 4, and 8 (P = 0.028, P = 0.007, and P = 0.032, respectively). Three and 6 mo after surgery, 18 of 22 (82%) and 12 of 21 (57%) of the controls reported chronic pain versus 10 of 22 (45%) and 6 of 20 (30%) in the treatment group (P = 0.028 and P = 0.424, respectively); 5 of 22 and 4 of 21 of the controls required analgesics versus 0 of 22 and 0 of 20 of those treated (P = 0.048 and P = 0.107, respectively). Multimodal analgesia reduced acute and chronic pain after breast surgery for cancer.

EMLA reduces acute and chronic pain after breast surgery for cancer.

Background and Objectives A significant percentage of women undergoing breast surgery for cancer may develop neuropathic pain in the chest, and/or ipsilateral axilla and/or upper medial arm, with impairment in performing daily occupational activities. We designed this study to determine if the perioperative application of EMLA (eutectic mixture of local anesthetics; AstraZeneca) cream in the breast and axilla area reduces analgesic requirements, as well as the acute and chronic pain after breast surgery. Methods Forty-six female patients scheduled for breast surgery received randomly 5 g of EMLA or placebo on the sternal area 5 minutes before surgery, and 15 g on the supraclavicular area and axilla at the end of the operation. Treatment with EMLA cream (20 g) or placebo was also applied daily on the 4 days after surgery. In the postanesthesia care unit (PACU), 3, 6, 9, and 24 hours after surgery, and on the second to sixth day postoperatively, pain was assessed by visual analogue scale (VAS) at rest and after movement, and postoperative analgesic requirements were recorded. Three months later, patients were asked if they had pain in the chest wall, axilla and/or medial upper arm, decreased sensation, if they required analgesics at home, and for the intensity of pain. Results Acute pain at rest and with movement did not differ between the EMLA and control groups, and the analgesics consumed during the first 24 hours were the same for the EMLA and control groups. However, time to the first analgesia requirement was longer (P = .04), and codeine and paracetamol consumption during the second to fifth days was less (P = .001, and P = .004, respectively) in the EMLA versus the control group. Three months postoperatively, pain in the chest wall, axilla, and the total incidence and the intensity of chronic pain were significantly less in the EMLA versus the control group (P = .004, P = .025, P = .002 and P = .003, respectively). The use of analgesics at home and abnormal sensations did not differ between the 2 groups. Conclusions The application of EMLA to patients undergoing breast surgery for cancer reduced the postoperative analgesic requirements and the incidence and intensity of chronic pain.

Painful neuropathy decreases membrane calcium current in mammalian primary afferent neurons

&NA; Hyperexcitability of the primary afferent neuron leads to neuropathic pain following injury to peripheral axons. Changes in calcium channel function of sensory neurons following injury have not been directly examined at the channel level, even though calcium is a primary second messenger‐regulating neuronal function. We compared calcium currents (ICa) in 101 acutely isolated dorsal root ganglion neurons from 31 rats with neuropathic pain following chronic constriction injury (CCI) of the sciatic nerve, to cells from 25 rats with normal sensory function following sham surgery. Cells projecting to the sciatic nerve were identified with a fluorescent label applied at the CCI site. Membrane function was determined using patch‐clamp techniques in current clamp mode, and in voltage‐clamp mode using solutions and conditions designed to isolate ICa. Somata of peripheral sensory neurons from hyperalgesic rats demonstrated decreased ICa. Peak calcium channel current density was diminished by injury from 3.06±0.30 pS/pF to 2.22±0.26 pS/pF in medium neurons, and from 3.93±0.38 pS/pF to 2.99±0.40 pS/pF in large neurons. Under these voltage and pharmacologic conditions, medium‐sized neuropathic cells lacked obvious T‐type calcium currents which were present in 25% of medium‐sized cells from control animals. Altered Ca2+ signalling in injured sensory neurons may contribute to hyperexcitability leading to neuropathic pain.

Gabapentin decreases membrane calcium currents in injured as well as in control mammalian primary afferent neurons.

Background and Objectives Neuropathic pain following injury to peripheral sensory neurons is a common clinical problem and frequently difficult to treat. Gabapentin (GBP), a novel anticonvulsant, has significant analgesic effects in clinical neuropathic states and in relevant preclinical models, but its mechanism of action remains unclear. Because calcium currents play a significant role in neuronal function, this study was designed to assess the effect of GBP on the membrane voltage-activated inward calcium currents (ICa) in dorsal root ganglia (DRG) primary afferent neurons of neuropathic versus control rats. Methods Male rats were prepared according to the chronic constriction injury (CCI) model. The L4 and L5 dorsal root ganglia of those selected as CCI or control after appropriate behavioral testing were removed, and neurons were enzymatically dissociated. Fluorescent dye (DiI) placed at the injury site allowed identification of neurons projecting to that site. These were acutely studied using whole-cell, perforated (with β-escin) patch-clamp recordings. Additionally, neurons from sham or nonoperated rats were also studied. Results Although there was marked variability among cells, concentrations of GBP ranging from 0.1 to 300 μmol/L decreased neuronal peak ICa in midsized neurons (30 to 40 μm) of both sham and neuropathic rats, in a fast, reversible, and concentration-dependent manner. Intergroup differences were not significant, however the concentration-response EC50s were 2.7 μmol/L for the sham and 16.5 μmol/L for the CCI neurons. The drug suppressed ICa in nonoperated rats to a lesser degree, but changes did not differ significantly from the operated groups. Calcium currents in either small or large diameter neurons were also variably decreased by 10 μmol/L of GBP in sham and CCI neurons. Current inhibition by GBP was partly voltage dependent. Conclusions GBP, at clinically relevant concentrations, results in significant reduction of ICa in both sham and neuropathic neurons, while in nonoperated rats reduced ICa to a smaller degree. Sensitivity to drug was not affected by neuropathy. This current inhibition is partly voltage dependent. Depression of ICa may be partly related to the binding of the drug to the α2δ modulatory subunit of the voltage activated calcium channels (VACC). Analgesia may be due to diminished release of neurotransmitter by sensory neurons, a Ca2+-dependent process.

Nitric oxide activates ATP-sensitive potassium channels in mammalian sensory neurons: action by direct S-nitrosylation

BackgroundATP-sensitive potassium (KATP) channels in neurons regulate excitability, neurotransmitter release and mediate protection from cell-death. Furthermore, activation of KATP channels is suppressed in DRG neurons after painful-like nerve injury. NO-dependent mechanisms modulate both KATP channels and participate in the pathophysiology and pharmacology of neuropathic pain. Therefore, we investigated NO modulation of KATP channels in control and axotomized DRG neurons.ResultsCell-attached and cell-free recordings of KATP currents in large DRG neurons from control rats (sham surgery, SS) revealed activation of KATP channels by NO exogenously released by the NO donor SNAP, through decreased sensitivity to [ATP]i.This NO-induced KATP channel activation was not altered in ganglia from animals that demonstrated sustained hyperalgesia-type response to nociceptive stimulation following spinal nerve ligation. However, baseline opening of KATP channels and their activation induced by metabolic inhibition was suppressed by axotomy. Failure to block the NO-mediated amplification of KATP currents with specific inhibitors of sGC and PKG indicated that the classical sGC/cGMP/PKG signaling pathway was not involved in the activation by SNAP. NO-induced activation of KATP channels remained intact in cell-free patches, was reversed by DTT, a thiol-reducing agent, and prevented by NEM, a thiol-alkylating agent. Other findings indicated that the mechanisms by which NO activates KATP channels involve direct S-nitrosylation of cysteine residues in the SUR1 subunit. Specifically, current through recombinant wild-type SUR1/Kir6.2 channels expressed in COS7 cells was activated by NO, but channels formed only from truncated isoform Kir6.2 subunits without SUR1 subunits were insensitive to NO. Further, mutagenesis of SUR1 indicated that NO-induced KATP channel activation involves interaction of NO with residues in the NBD1 of the SUR1 subunit.ConclusionNO activates KATP channels in large DRG neurons via direct S-nitrosylation of cysteine residues in the SUR1 subunit. The capacity of NO to activate KATP channels via this mechanism remains intact even after spinal nerve ligation, thus providing opportunities for selective pharmacological enhancement of KATP current even after decrease of this current by painful-like nerve injury.

Postoperative Pain and Analgesic Requirements After Anesthesia with Sevoflurane, Desflurane or Propofol

BACKGROUND: General anesthetics may have nociceptive actions that affect postoperative pain. In studies evaluating postoperative pain, the effect of general anesthetics on analgesic requirements has not been considered except for one recent study suggesting that propofol anesthesia provides better analgesia after surgery than isoflurane. METHODS: In this prospective, blind, randomized trial we recorded postoperative analgesic requirements (mg of morphine) and pain scores (visual analog scale in mm) 2, 4, 8, and 24 h postoperatively in patients undergoing abdominal hysterectomy or myomectomy under sevoflurane, desflurane or propofol anesthesia, titrated to maintain Bispectral Index values between 35 and 45. Pain scores were also recorded immediately after transfer to the postanesthesia care unit. RESULTS: Cumulative morphine consumption did not differ among the three groups 2, 4, 8, or 24 h postoperatively (P = 0.50). The morphine consumed within 24 h postoperatively was 28 ± 13.8 mg in the sevoflurane group, 25 ± 11.7 mg in the desflurane group and 27 ± 16.1 mg in the propofol group. The visual analog scale values at rest or after cough immediately after patient transport to the postanesthesia care unit and 2, 4, 8, and 24 h after surgery did not differ among the three groups (P = 0.40, 0.39, 0.50, 0.47, 0.06 at rest and P = 0.67, 0.45, 0.22, 0.26, 0.29 after cough respectively). CONCLUSION: Morphine consumption and pain 24 h postoperatively did not differ among the sevoflurane, desflurane, and propofol groups.

Suppressed Ca2+/CaM/CaMKII-dependent KATP channel activity in primary afferent neurons mediates hyperalgesia after axotomy

Painful axotomy decreases KATP channel current (IKATP) in primary afferent neurons. Because cytosolic Ca2+ signaling is depressed in injured dorsal root ganglia (DRG) neurons, we investigated whether Ca2+–calmodulin (CaM)–Ca2+/CaM-dependent kinase II (CaMKII) regulates IKATP in large DRG neurons. Immunohistochemistry identified the presence of KATP channel subunits SUR1, SUR2, and Kir6.2 but not Kir6.1, and pCaMKII in neurofilament 200–positive DRG somata. Single-channel recordings from cell-attached patches revealed that basal and evoked IKATP by ionomycin, a Ca2+ ionophore, is activated by CaMKII. In axotomized neurons from rats made hyperalgesic by spinal nerve ligation (SNL), basal KATP channel activity was decreased, and sensitivity to ionomycin was abolished. Basal and Ca2+-evoked KATP channel activity correlated inversely with the degree of hyperalgesia induced by SNL in the rats from which the neurons were isolated. Inhibition of IKATP by glybenclamide, a selective KATP channel inhibitor, depolarized resting membrane potential (RMP) recorded in perforated whole-cell patches and enhanced neurotransmitter release measured by amperometry. The selective KATP channel opener diazoxide hyperpolarized the RMP and attenuated neurotransmitter release. Axotomized neurons from rats made hyperalgesic by SNL lost sensitivity to the myristoylated form of autocamtide-2-related inhibitory peptide (AIPm), a pseudosubstrate blocker of CaMKII, whereas axotomized neurons from SNL animals that failed to develop hyperalgesia showed normal IKATP inhibition by AIPm. AIPm also depolarized RMP in control neurons via KATP channel inhibition. Unitary current conductance and sensitivity of KATP channels to cytosolic ATP and ligands were preserved even after painful nerve injury, thus providing opportunities for selective therapeutic targeting against neuropathic pain.

ATP-sensitive potassium channels in rat primary afferent neurons: the effect of neuropathic injury and gabapentin

ATP-sensitive potassium (K(ATP)) currents were examined in dorsal root ganglion neurons from neuropathic and control rats using whole-cell voltage clamp recordings. K(ATP) channel openers (diazoxide and pinacidil) enhanced, and the blocker glibenclamide inhibited an outward current in control neurons in a manner dependent on the pipette ATP concentration. Analysis of reversal potentials showed that this current is carried by K(+) ions. Outward current in cells from rats with peripheral nerve injury was not sensitive to modulators of K(ATP) channels. Gabapentin, a putative K(ATP) channel opener, had minimal effect on currents in either group of neurons. We conclude that normal primary afferent neurons express K(ATP) channels that conduct current which is eliminated by peripheral nerve injury. Gabapentin does not affect this current significantly.

Regional block and mexiletine: The effect on pain after cancer breast surgery

Background and Objectives Breast surgery for cancer is associated with chronic pain and sensory abnormalities. The present study investigates the effect of regional block, oral mexiletine, and the combination of both, on acute and chronic pain associated with cancer breast surgery. Methods One hundred patients scheduled for cancer breast surgery received either regional block with 18 mL of 1% ropivacaine intraoperatively and oral mexiletine for the first 6 postoperative days (R + M group), or regional block and placebo (R + PL), or normal saline instead of ropivacaine and mexiletine (PL + M), or normal saline and placebo (PL + PL). Postoperative analgesic requirements were recorded daily. Pain was assessed 0, 3, 6, 9, and 24 hours in the postanesthesia care unit (PACU) and on the second to sixth day postoperatively, at rest, and after movement using the visual analog scale (VAS). Three months after surgery, patients were interviewed for the presence and intensity of pain, abnormal sensations, and analgesic requirements. Results Regional block reduced the number of intramuscular (IM) injections required the first 24 hours (P = .05), the R + PL group requiring less injections versus the PL + M group (P = .037). Lonarid tablet (paracetamol and codeine) consumption from the second to the fifth postoperative day differed among the 4 groups (P = .0304), the R + M group requiring fewer tablets than the PL + PL group (P = .009). Three hours postoperatively, the R + PL group had less pain at rest when compared with all other groups (P < .05 for all comparisons). On the second postoperative day, VAS at rest and after movement was less in the R + M versus the R + PL group (P < .01 and P < .05, respectively). Three months after surgery, the 4 groups were similar with regard to incidence or intensity of pain or analgesic requirements. The R + PL group had a lower incidence (77%) of reduced or absent sensation (P = .016). Conclusions Regional block reduced the analgesic requirements in the early postoperative period, while mexiletine combined with regional block reduced the total analgesic requirements during the next 5 postoperative days. Although chronic pain was not affected by these treatments late-abnormal sensation may be diminished by combination of these treatments.

Transcutaneous electrical nerve stimulation reduces the incidence of vomiting after hysterectomy

The possible postoperative antiemetic effect of transcutaneous electrical nerve stimulation (TENS) on the P6 point (on the Pericardium Channel of Hand-Jueyin) was evaluated in 103 women undergoing hysterectomy. TENS on the P6 point was applied 30-45 min before induction of anesthesia in 51 patients and continued for 6 h postoperatively. The control group, 52 patients, was treated exactly in the same way but with the electrical stimulator turned off. Incidence of vomiting was assessed blindly 2 h, 4 h, 6 h, and 8 h postoperatively. The incidence of vomiting postoperatively was significantly less in the TENS-treated group when compared with the control group (between 0 h and 2 h: 23% vs 43%, P < 0.05; between 2 h and 4 h: 27% vs 50%, P < 0.025; and between 4 h and 6 h: 31% vs 67%, P < 0.001, respectively). Six hours postoperatively TENS was discontinued, and 8 h postoperatively the two groups did not differ significantly for incidence of vomiting (between 6 h and 8 h: 51% vs 65%). The authors conclude that TENS reduces the incidence of vomiting after hysterectomy.