Anesthetic care for electroconvulsive therapy

Counselling and medication are often thought of as the only interventions for psychiatric disorders, but electroconvulsive therapy (ECT) has also been applied in clinical practice for over 80 years. ECT refers to the application of an electric stimulus through the patient’s scalp to treat psychiatric disorders such as treatment-resistant depression, catatonia, and schizophrenia. It is a safe, effective, and evidence-based therapy performed under general anesthesia with muscle relaxation. An appropriate level of anesthesia is essential for safe and successful ECT; however, little is known about this because of the limited interest from anesthesiologists. As the incidence of ECT increases, more anesthesiologists will be required to better understand the physiological changes, complications, and pharmacological actions of anesthetics and adjuvant drugs. Therefore, this review focuses on the fundamental physiological changes, management, and pharmacological actions associated with various drugs, such as anesthetics and neuromuscular blocking agents, as well as the comorbidities, indications, contraindications, and complications of using these agents as part of an ECT procedure through a literature review and our own experiences.

Nasotracheal intubation for airway management during anesthesia

Nasotracheal intubation is used as a basic method for airway management, along with orotracheal intubation under anesthesia and intensive care. It has become an effective alternative method to orotracheal intubation with increased benefits of offering better mobility and surgical field in oral and maxillofacial surgery and possibly in trauma and critically ill patients. Nasotracheal intubation is performed through a relatively narrow nasal cavity; therefore, additional precautions are needed. Accordingly, nasotracheal intubation methods have evolved over the years with accumulated clinical experience and improved instruments to facilitate safe intubation with reduced complications. Therefore, in this review article, we summarize the basic anatomy of the nasal airways to clarify the precautions, delineate the history and development of various methods and instruments, and describe the indications, contraindications, complications, and preventive methods of nasotracheal intubation.

Effects of preanesthetic single administration of dexmedetomidine on the remifentanil and propofol requirement during laparoscopic cholecystectomy

BACKGROUND: Dexmedetomidine, an α2-adrenergic agonist, can be used for sedation and as an adjuvant to anesthetics. This study aimed to evaluate the effects of preanesthetic administration of dexmedetomidine on the propofol and remifentanil requirement during general anesthesia and postoperative pain in patients undergoing laparoscopic cholecystectomy. METHODS: Sixty patients were randomly assigned to group D or S (n = 30 each). Dexmedetomidine (0.5 µg/kg) and a comparable volume of saline were administered in groups D and S, respectively, over a 10 minutes period before induction. General anesthesia was induced and maintained with propofol and remifentanil; the bispectral index was maintained at 40–60. The intraoperative remifentanil and propofol dosages were recorded, and postoperative pain was assessed using a visual analog scale (VAS). RESULTS: In groups S and D, propofol dosage was 8.52 ± 1.64 and 6.83 ± 1.55 mg/kg/h, respectively (P < 0.001), while remifentanil dosage was 7.18 ± 2.42 and 4.84 ± 1.44 µg/ kg/h, respectively (P < 0.001). VAS scores for postoperative pain were 6.50 (6–7) and 6.0 (6–7), respectively, at 30 minutes (P = 0.569), 5 (4–5) and 4 (3–5), respectively, at 12 hours (P = 0.039), and 2 (2–3) and 2 (1.25–2), respectively, at 24 hours (P = 0.044). The Friedman test revealed that VAS scores changed over time in both groups (P < 0.001). CONCLUSIONS: Preanesthetic single administration of a low dose of dexmedetomidine (0.5 µg/kg) can significantly decrease the remifentanil and propofol requirement during short surgeries and alleviate postoperative pain.

Combined use of a double-lumen tube and Fogarty catheter to prevent the endobronchial spread of infection: a case report / 대한마취과학회지

Huntington's disease is a neurodegenerative disorder with an autosomal dominant inheritance pattern. Patients with Huntington's disease show an increased risk of aspiration pneumonia when the pharyngeal muscle is invaded. We report a case of advanced-stage Huntington's disease in which the patient received right middle lobectomy for a lung abscess caused by repeated aspiration. The best lung isolation technique has not yet been established in these patients. We successfully performed selective lobar isolation of the right lower and middle lobes using a double lumen tube and a Fogarty embolectomy catheter.

Correction of malposition of central venous catheter with 9-Fr introducer sheath assisted by mobile type diagnostic X-ray apparatus: a case report / 대한마취과학회지

Central venous catheters provide long-term available vascular access. They are useful for central venous pressure monitoring, rapid fluid management, massive transfusion and direct cardiovascular medication, especially in operation. Central venous catheterization is usually performed by the landmark bedside technique without imaging guidance. The complications of central venous catheterization are frequent, which include malposition, pneumothorax, hemothorax, chylothorax, arterial puncture, hematoma, air embolism and infection. Malposition of a central venous catheter is not rare and may cause several complications such as malfunction of the catheter, default measurement of central venous pressure, catheter erosion, thrombophlebitis and cardiac tamponade. In this case, we report a malposition of central venous catheter with 9-Fr introducer sheath which is located in the right subclavian vein via ipsilateral internal jugular vein and the correction of this misplacement assisted by mobile type diagnostic X-ray apparatus (C-arm fluoroscope).

Anesthetic experience of a patient with Prune-belly syndrome / 대한마취과학회지

No abstract available.

Postoperative nausea and vomiting after total thyroidectomy: sevoflurane combined with prophylactic ramosetron vs. propofol-based total intravenous anesthesia / 대한마취과학회지

BACKGROUND: The frequent and distressing adverse events (AEs) of postoperative nausea and vomiting (PONV) are of major concern in 63-84% of adult patients undergoing thyroidectomy. We conducted this prospective study to compare two prophylactic strategies; sevoflurane combined with ramosetron and propofol-based total intravenous anesthesia in a homogenous group of non-smoking women undergoing total thyroidectomy. METHODS: In the current prospective study, we enrolled a consecutive series of 64 female patients aged between 20 and 65 years with an American Society of Anesthesiologists physical status of I or II who were scheduled to undergo elective total thyroidectomy under general anesthesia. Patients were randomized to either the SR (sevoflurane and remifentanil) group or the TIVA group. We evaluated the incidence and severity of PONV, the use of rescue anti-emetics and the severity of pain during the first 24 h after surgery. RESULTS: There were no significant differences in the proportion of the patients with a complete response and the Rhodes index, including the occurrence score, distress score and experience score, between the two groups. In addition, there were no significant differences in the proportion of the patients who were in need of rescue anti-emetics or analgesics and the VAS scores between the two groups. CONCLUSIONS: In conclusion, TIVA and ramosetron prophylaxis reduced the expected incidence of PONV in women undergoing total thyroidectomy. In addition, there was no significant difference in the efficacy during the first 24 h postoperatively between the two prophylactic regimens.

Postoperative nausea and vomiting after mastoidectomy with tympanoplasty: a comparison between TIVA with propofol-remifentanil and balanced anesthesia with sevoflurane-remifentanil / 대한마취과학회지

BACKGROUND: There is growing interest in the anesthetic approach using total intravenous anesthesia (TIVA) with propofol and remifentanil for the prevention of postoperative nausea and vomiting (PONV). The aim of this study was to compare between the two anesthetic techniques for preventing PONV in the patients undergoing mastoidectomy with tympanoplasty. METHODS: After obtaining informed consent, 62 patients aged between 20 to 60 years undergoing elective mastoidectomy and tympanoplasty were randomized into two equal study groups: group P/R (n = 31) included patients undergoing TIVA with propofol and remifentanil, and group S/R (n = 31) included patients undergoing balanced anesthesia with sevoflurane and remifentanil. The incidences of PONV and complete response (no PONV, no rescue) were assessed at 1 and 24 h after surgery, using the Rhodes Index. Also, the usage of rescue antiemetics and pain intensity were recorded. RESULTS: The Rhodes Index including the occurrence score, distress score and experience score was significantly lower in the P/R group compared to that in the S/R group during the study period (P < 0.05), and the incidence of complete response was significantly higher in the P/R group compared to that in the S/R group, during the first 24 h after surgery. 4 patients in the S/R group requested antiemetics during the first 1 h after surgery. There were no significant differences in pain intensity among groups. CONCLUSIONS: Compared to balanced anesthesia with sevoflurane and remifentanil, TIVA with propofol and remifentanil was followed by significantly lower incidence and severity of PONV.

Efficacy of the combination of cold propofol and pretreatment with remifentail on propofol injection pain / 대한마취과학회지

BACKGROUND: Pain upon the injection of propofol is a common adverse effect. This study was conducted to evaluate the analgesic effect of remifentanil and cold propofol during propofol injection for the induction of anesthesia and to determine if a combination of cold propofol and remifentanil produced additional analgesic efficacy. METHODS: A total of 160 patients aged 20-65 years old were randomly allocated into one of four groups (n = 40, in each). Control and remifentanil group patients received 2 mg/kg propofol that had been stored at room temperature (20-23degrees C), while the cold and combination group received cold (4degrees C) propofol. The patients received remifentanil 0.5 microg/kg IV in the remifentanil and combination groups or saline in the control and cold groups. Ninety seconds after administration the patients were administered propofol over a 30 second period. The pain intensity and incidence were then evaluated using a 4-point verbal rating scale. RESULTS: The incidence of pain was significantly reduced in groups that received remifentanil in the cold and combination groups when compared with the control group (27.5%, 30%, and 2.5% vs. 70%, respectively). Moreover, the severity of pain was significantly lower in groups that received remifentanil in the cold and combination groups when compared with the control group. The incidence and severity of pain from the propofol injection in the combination group was significantly lower than that in the remifentanil and cold groups. CONCLUSIONS: The combination of cold propofol and pretreatment with remifentanil more effectively reduced the incidence of pain upon the injection of propofol than either treatment alone.

The effect of remifentanil and lidocaine on time interval acquired for successful tracheal intubation in inhalational induction using sevoflurane / 대한마취과학회지

BACKGROUND: This study was conducted to investigate the optimal time interval for tracheal intubation and the effect of adjuvant drugs such as remifentanil and lidocaine during induction and tracheal intubation using sevoflurane inhalation without muscle relaxant. METHODS: This study enrolled patients with the age of 20-60 years old and ASA 1 or 2. Patients were randomly assigned into one of 4 groups (S, SR, SRL, SL), in which they were given remifentanil (R) i.v. at a rate of 0.25microgram/kg/min, or lidocaine (L) i.v. bolus of 1.5 mg/kg during sevoflurane inhalation (S). Anesthesia was performed as inhalation induction 2 minutes after pre-filling with sevoflurane 8 vol%. The time interval between induction and tracheal intubation was determined using up-and-down method. When satisfied all of the categories of response to tracheal intubation, the case was assigned to 'success', otherwise 'fail'. In each groups, effective time for successful intubation in 50% (ET50) and 95% (ET95) were calculated by probit analysis. RESULTS: ET50 was 3.90 minutes (95% confidence interval 3.32-4.38) in group S, 3.18 minutes (2.92-3.48) in group SL, 2.83 minutes (2.47-3.07) in group SR, and 2.68 minutes (2.37-2.95) in group SRL. In group S, SL, SR, and SRL, ET95 was 4.52 minutes (4.17-7.95), 3.63 minutes (3.37-4.97), 3.30 minutes (3.06-4.64), and 3.12 minutes (2.89-4.42), respectively. CONCLUSIONS: The optimal time to intubate successfully using sevoflurane without muscle relaxant in 95% patients was 4.5 minutes. The optimal time is reduced to 3.1 minutes by coadministration of remifentanil and lidocaine.

The effect of remifentanil and lidocaine on time interval acquired for successful tracheal intubation in inhalational induction using sevoflurane / 대한마취과학회지

BACKGROUND: This study was conducted to investigate the optimal time interval for tracheal intubation and the effect of adjuvant drugs such as remifentanil and lidocaine during induction and tracheal intubation using sevoflurane inhalation without muscle relaxant. METHODS: This study enrolled patients with the age of 20-60 years old and ASA 1 or 2. Patients were randomly assigned into one of 4 groups (S, SR, SRL, SL), in which they were given remifentanil (R) i.v. at a rate of 0.25microgram/kg/min, or lidocaine (L) i.v. bolus of 1.5 mg/kg during sevoflurane inhalation (S). Anesthesia was performed as inhalation induction 2 minutes after pre-filling with sevoflurane 8 vol%. The time interval between induction and tracheal intubation was determined using up-and-down method. When satisfied all of the categories of response to tracheal intubation, the case was assigned to 'success', otherwise 'fail'. In each groups, effective time for successful intubation in 50% (ET50) and 95% (ET95) were calculated by probit analysis. RESULTS: ET50 was 3.90 minutes (95% confidence interval 3.32-4.38) in group S, 3.18 minutes (2.92-3.48) in group SL, 2.83 minutes (2.47-3.07) in group SR, and 2.68 minutes (2.37-2.95) in group SRL. In group S, SL, SR, and SRL, ET95 was 4.52 minutes (4.17-7.95), 3.63 minutes (3.37-4.97), 3.30 minutes (3.06-4.64), and 3.12 minutes (2.89-4.42), respectively. CONCLUSIONS: The optimal time to intubate successfully using sevoflurane without muscle relaxant in 95% patients was 4.5 minutes. The optimal time is reduced to 3.1 minutes by coadministration of remifentanil and lidocaine.

Hemodynamic Changes according to the Remifentanil Effect Site Concentration for Patients under Total Intravenous Anesthesia during Laryngeal Microscopic Surgery / 대한마취과학회지

BACKGROUND: Laryngeal microscopic surgery directly stimulates an airway via endotracheal intubation and insertion of a suspension laryngoscope, and this can result in acute elevation of the blood pressure and heart rate. Therefore, an anesthesia that can maintain a sufficient depth of anesthesia and simultaneously makes awakening and recovery possible in a short period is required. We wanted to present the effect site concentration of remifentanil for achieving the best anesthesia by observing the hemodynamic changes according to the effect site concentration of remifentanil. METHODS: 36 patients, who corresponded with the ASA physical status classification 1 and 2 and who were from 20 to 70 years old, were the subjects of this study. They were randomly classified into three groups according to the effect site concentration of remifentanil. Propofol 4microgram/ml was infused continuously, and remifentanil was continuously infused for each group to achieve an effect site concentration of 4 ng/ml, 6 ng/ml, and 8 ng/ml, respectively. Rocuronium 0.5 mg/kg was used. The arterial blood pressures and heart rates were measured before induction of anesthesia, before endotracheal intubation, after endotracheal intubation and after insertion of a suspension laryngoscope. RESULTS: In comparison with the other groups, the 4 ng/ml remifentanil group was able to prevent acute elevation of blood pressure and heart rate. CONCLUSIONS: For total intravenous anesthesia using propofol and remifentanil, 4 ng/ml of remifentanil is proposed to be the effect site concentration that is able to stably maintain blood pressure and heart rate during laryngeal microscopic surgery.

The Effect of Doxapram Hydrochloride on the Ventilation Responses during Total Intravenous Anesthesia by Laryngeal Mask Airway / 대한마취과학회지

BACKGROUND: Intravenous anesthetics causes depression of ventilatory response to hypercapnea. Doxapram stimulates ventilation via peripheral and central chemoreceptors. This study was aimed to evaluate the effect of doxapram on ventilation during total intravenous anesthesia (TIVA). METHODS: 60 patients undergoing operation under spontaneous ventilation via laryngeal mask airwaywere randomly divided into 3 groups: Control group received 5% dextrous infusion, D-2 group received doxapram injection of 1 mg/kg followed by continuous infusion of 2 mg/kg/hr, and D-4 group received doxapram injection of 2 mg/kg followed by continuous infusion of 4 mg/kg/hr. Anesthesia was induced and maintained with propofol and remifentanil. Respiratory rate, tidal volume (VT) and arterial carbon dioxide tension (PaCO2) were measured before and 15 min after induction of anesthesia, 0(15 min after start of operation), 1, 2, 3, 5, 15, 30, 45, and 60 min after start of doxapram infusion during TIVA. RESULTS: VT was significantly increased 1 min after start of doxapram infusion and returned to the value of pre-doxapram infusion immediately. In D-4 group, VT was significantly (P < 0.05) increased again 5 min after doxapram infusion compared with the value of pre-doxapram infusion and control group. PaCO2 was decreased 1 min after start of doxapram infusion and then increased again 2 min after doxapram infusion. In D-4 group, the degree of increase of PaCO2 was significantly (P < 0.05) less than those of D-2 group. CONCLUSIONS: Doxapram injection of 2 mg/kg followed by continuous infusion of 4 mg/kg/hr improved the depression of ventilatory response during TIVA.

The Role of Opioid Receptor on the Analgesic Action of Intrathecal Sildenafil in Rats / 대한통증학회지

BACKGROUND: Intrathecal sildenafil has produced antinociception by increasing the cGMP through inhibition of phosphodiesterase 5. Spinal opioid receptor has been reported to be involved in the modulation of nociceptive transmission. The aim of this study was to examine the role of opioid receptor in the effect of sildenafil on the nociception evoked by formalin injection. METHODS: Rats were implanted with lumbar intrathecal catheters. Formalin testing was used as a nociceptive model. Formalin-induced nociceptive behavior (flinching response) was observed. To clarify the role of the opioid receptor for the analgesic action of sildenafil, naloxone was administered intrathecally 10 min before sildenafil delivery, and formalin was then injected 10 min later. RESULTS: Intrathecal sildenafil produced dose-dependent suppression of flinches in both phases during the formalin test. Intrathecal naloxone reversed the analgesic effect of sildenafil in both phases. CONCLUSIONS: Sildenafil is active against the nociceptive state that's evoked by a formalin stimulus, and the opioid receptor is involved in the analgesic action of sildenafil at thespinal level.

Antinociceptive Effects of Intrathecal Melatonin on Formalin: and Thermal-induced Pain in Rats / 대한통증학회지

BACKGROUND: It has been known that melatonin is involved in the modulation of nociceptive transmission. However, the effect of melatonin administered spinally has not been examined. Therefore, we examined the effect of melatonin on the formalin-induced or thermal-induced nociception at the spinal level. METHODS: Intrathecal catheter was inserted into the subarachnoid space of male Sprague-Dawley rats. Pain was assessed by formalin test (induced by injection of 50microliter of a 5% formalin solution to the hindpaw) or Hot-Box test (induced by radiant heat application to the hindpaw). The effect of intrathecal melatonin was examined on flinching behavior in the formalin test or withdrawal response in Hot-Box test. RESULTS: Intrathecal melatonin produced a limited, but dose-dependent reduction of the flinching response during phase 1 and 2 in the formalin test. In addition, melatonin delivered at evening also decreased the flinching response in both phases of the formalin test. Melatonin restrictively increased the withdrawal latency in Hot-Box test. CONCLUSIONS: These results suggest that melatonin is active against the formalin- and thermal-induced nocicpetion at the spinal level, but the effect is limited.

Comparison of the Effects on Increase of Heart Rate and Blood Pressure between Tracheal Intubation and Desflurane Inhalation during Propofol Anesthesia / 대한마취과학회지

BACKGROUND: This study was undertaken to compare the hemodynamic effects between desflurane inhalation and endotracheal intubation, and to evaluate the intensity of airway irritation by desflurane inhalation of high concentration. METHODS: Twenty adult patients with ASA 1 were enrolled in this study. Radial artery was catheterized and heart rate (HR) and mean arterial pressure (MAP) were measured throughout the study. Anesthesia was induced by propofol and effect site concentration of propofol was maintained at 4microgram/ml using target controlled infusor (TCI). Peak HR and MAP following tracheal intubation were recorded and inhalation of 12 vol% desflurane was started after HR and MAP had been returned to pre-intubation value. The HR, MAP, inspiratory (Fi) and end-tidal fraction (Et) were observed after desflurane inhalation for 10 minutes. RESULTS: The HR and MAP were significantly increased after tracheal intubation and desflurane inhalation, and the peak hemodynamic change after desflurane inhalation was significantly delayed as compared to tracheal intubation. The maximal HR change from baseline after tracheal intubation or desflurane inhalation was not different, but maximal MAP change was significantly lower during desflurane inhalation compared with tracheal intubation. The maximal change of HR and MAP when end-tidal fraction of desflurane had been reached 6 vol% was lower than that of tracheal intubation or desflurane inhalation. CONCLUSIONS: Despite of propofol administration required for general anesthesia, the HR and MAP were significantly increased during desflurane inhalation of high concentration. In particular, the extent of HR increase during desflurane inhalation was similar to that by tracheal intubation.

Effects of Alfentanil on Hemodynamic and Catecholamine Responses to Laryngoscopy and Endobronchial Intubation in the Elderly / 대한구급학회지

BACKGROUND: Endobronchial intubation should elicit significant circulatory responses. We examined the effects of alfentanil on hemodynamic and catecholamine responses to endobronchial intubation in elderly patients. METHODS: A total of 60 patients aged over 60 years requiring endobronchial intubation were randomized into three groups of 20 patients each. Anesthesia was induced with thiopental 4~6 mg/kg followed by saline (placebo) or alfentanil 10 or 30microgram/kg given as a bolus over 30 s. Succinylcholine 1 mg/kg was given for neuromuscular block. Laryngoscopy and intubation were performed 1 min later. RESULTS: The intubation significantly increased systolic arterial pressure and heart rate. The maximum pressure changes from pre-intubation values in both alfentanil groups (58+/-27 and 33+/-30 mm Hg in 10 and 30microgram/kg, respectively) were significantly lower compared with that of 83+/-35 mm Hg in the control group. The tachycardiac response was not significantly affected by alfentanil 10microgram/kg, but attenuated by alfentanil 30microgram/kg. The plasma norepinephrine concentrations were increased, which was not affected by alfentanil 10microgram/kg, but was significantly attenuated by alfentanil 30microgram/kg. Both doses of alfentanil abolished the increase of plasma epinephrine concentrations. Three patients in the 30microgram/kg group received ephedrine for hypotension. CONCLUSIONS: This study showed that endobronchial intubation elicited significant pressor response, and that alfentanil 30microgram/kg is more efficacious in attenuating the hemodynamic and catecholamine responses, although potential hypotension warrants a caution of its use, in elderly patients.

Vocal Cord Paralysis after the Coronary Artery Bypass Graft: A Case Report / 대한구급학회지

Surgical trauma has long been recognized as the most common cause of unilateral and bilateral vocal cord paralysis. We experienced a case of bilateral vocal cord paralysis after off-pump coronary artery bypass graft. The patient was repeated intubation and extubation after operation in surgical intensive care unit. Fiberoptic bronchoscopy revealed bilateral vocal cord paralysis in the patient. The patient recovered after permanent tracheotomy. We reported a case of vocal cord paralysis after coronary artery bypass graft.

Re-expansion Pulmonary Edema after Chest Tubing: A Case Report / 대한구급학회지

Re-expansion pulmonary edema (RPE) is a rare complication associated with the treatment of collapsed lung caused by pneumothorax, atelectasis, pleural effusion in which a large amount of air or effusion fluid is evacuated. In general RPE is resulted from more than 3 days of lung collapse and application of high negative intrapleural pressure. However, it is reported that RPE could be developed despite the collapse period is short and negative pressure suction is not performed. It also has been known that the rate of reexpansion is more important than amount of evacuated air, or collapse period in the development of RPE. Seventeen-year-old female was undergone suture hemostasis for liver laceration, in which RPE was occurred after closed thoracostomy for pleural effusion on postoperative-27 day. We present a case report with review of related articles.

Antinociceptive Effects of Intrathecal Metabotropic Glutamate Receptor Compounds and Morphine in Rats / 대한통증학회지

BACKGROUND: Spinal metabotropic glutamate receptors (mGluRs) and opioid receptors are involved in the modulation of nociception. Although opioid receptors agonists are active for pain, the effects of the compounds for the mGluRs have not been definitely investigated at the spinal level. We examined the effects of the intrathecal mGluR compounds and morphine in the nociceptive test, and then we further clarified the role of the spinal mGluRs. In addition, the nature of the pharmacological interaction after the coadministration of mGluRs compounds with morphine was determined. METHODS: Catheters were inserted into the intrathecal space of male SD rats. For the induction of pain, 50microl of 5% formalin solution or a thermal stimulus was applied to the hindpaw. An isobolographic analysis was used for the evaluation of the drug interaction. RESULTS: Neither group I mGluR compounds nor group III mGluR compounds produced any antinociceptive effect in the formalin test. The group II mGluR agonist (APDC) had little effect on the formalin-induced nociception. The group II mGluR antagonist (LY 341495) caused a dose-dependent suppression of the phase 2 flinching response on the formalin test, but it did not reduce the phase 1 response of the formalin test nor did it increase the withdrawal latency of the thermal stimulus. Isobolographic analysis revealed a synergistic interaction after the intrathecal delivery of a LY 341495-morphine mixture. CONCLUSIONS: These results suggest that group II mGluRs are involved in the facilitated processing at the spinal level, and the combination of LY 341495 with morphine may be useful to manage the facilitated pain state.