Noritaka Imamachi

Continuous local anesthetic infusion through ultrasound-guided rectus sheath catheters

To the Editor, Although epidural analgesia is a gold standard technique for postoperative abdominal analgesia, its use is sometimes limited due to perioperative anticoagulant therapy and undesirable complications such as hypotension. Rectus sheath (RS) blocks can provide alternative analgesia after midline abdominal surgery. This ultrasound-guided technique has recently gained popularity owing to fewer complications and a higher success rate. Since the duration of the RS block is limited by single injection, it is necessary to develop longer lasting analgesic methods for smooth postoperative recovery. A few attempts using RS catheters have been reported, including continuous administration of a large volume (42 mL hr) of local anesthetic. However, continuous high-dose local anesthetic infusion may induce local anesthetic systemic toxicity. We report cases in which continuous low-dose local anesthetic infusion through ultrasound-guided RS catheters showed effective postoperative midline abdominal analgesia. Written consent for publication was obtained from each patient.

The non-NMDA glutamate receptor antagonist CNQX augments lidocaine antinociception through a spinal action in rats.

UNLABELLED Non-NMDA glutamate receptor antagonists produce antinociceptive effects, but the antinociceptive interaction between non-NMDA glutamate receptor antagonists and local anesthetics has not been demonstrated. We designed this study to evaluate the antinociceptive effects of a non-NMDA glutamate receptor antagonist and its interaction with lidocaine in rats. Intrathecal catheters were implanted at the L4-5 level in rats. The tail flick (TF) and colorectal distension (CD) tests were used to assess somatic and visceral antinociceptive effects, respectively. The TF latency and CD threshold were measured before and for 180 min after the intrathecal administration of lidocaine (20-100 micrograms), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (0.4-4.0 micrograms), a combination of CNQX (0.2-0.6 microgram) and lidocaine (10-30 micrograms), or isotonic sodium chloride solution. The TF latency and CD threshold were converted to the percent maximal possible effect (%MPE). To determine synergistic interaction, isobolographic analysis was used. Lidocaine or CNQX increased %MPEs in both the TF and CD tests. The coadministration of CNQX 0.4 microgram and lidocaine 20 micrograms, which had no effect by alone, significantly increased %MPEs in the TF and CD tests for 30 min and 10 min, respectively. Isobolographic analysis revealed the synergistic antinociception of CNQX and lidocaine in the TF test. Motor impairment was not observed after that combination. We conclude that CNQX and lidocaine produce synergistic analgesia on somatic and visceral pain at the spinal level. IMPLICATIONS We investigated the antinociceptive effects of 6-cyano-7-nitroquinoxaline-2,3-dione and its interaction with lidocaine at the spinal level in rats. Intrathecal 6-cyano-7-nitroquinoxaline-2,3-dione produced both somatic and visceral antinociception, and its coadministration with lidocaine showed synergistic antinociceptive effects.

Effects of Intrathecal κ-Opioid Receptor Agonist on Morphine-Induced Itch and Antinociception in Mice.

Abstract The &mgr;-opioid receptor (MOR) agonist–induced itch is a significant issue associated with analgesic therapies. Research suggested that systemically administered &kgr;-opioid receptor (KOR) agonists inhibit intrathecal morphine–induced itch in primates. However, serious adverse effects induced by systemically administered KOR agonists may restrict their usefulness in humans. We investigated the effects of intrathecal KOR agonists on intrathecal morphine–mediated itch and antinociception in mice. Mice received intrathecal injections of one of the following drugs: morphine (0.1–1.0 nmol), the selective KOR agonist TRK-820 100 pmol, the combination of morphine 0.3 nmol + TRK-820 (10–100 pmol), and 5 &mgr;L of saline. One hour after intraperitoneal administration of the selective KOR antagonist nor-binaltorphimine 1.0 &mgr;mol, the effect of TRK-820 100 pmol on intrathecal morphine 0.3 nmol–induced scratching was tested. Total numbers of scratches after intrathecal injection were analyzed. After observing scratching behavior, sedation level was evaluated subjectively. Nociceptive threshold was determined by tail immersion test with intrathecal injections of the following agents: morphine (0.1–1.0 nmol), TRK-820 (10–100 pmol), morphine 0.1 nmol + TRK-820 10 pmol, and 5 &mgr;L of saline. Intrathecal TRK-820 dose-dependently inhibited intrathecal morphine-induced scratching compared with that in the saline group. Intraperitoneal nor-binaltorphimine completely inhibited the antiscratching effect of intrathecal TRK-820 100 pmol. The combination of morphine 0.3 nmol and TRK-820 did not alter the sedation score compared with that in the morphine 0.3 nmol group. Morphine 0.1 nmol + TRK-820 10 pmol significantly produced greater thermal antinociceptive effects than morphine 0.1 nmol. We demonstrated that intrathecal KOR agonists exert antipruritic effects on intrathecal morphine–induced itch without affecting sedation. The combination of intrathecal morphine and intrathecal KOR agonists produces more potent antinociceptive effects against a thermal stimulus compared with morphine alone.

Gabapentin augments the antihyperalgesic effects of diclofenac sodium through spinal action in a rat postoperative pain model.

BACKGROUND: Gabapentin and nonsteroidal antiinflammatory drugs (NSAIDs) attenuate postoperative pain and neuropathic pain in humans. The combination of gabapentin and NSAIDs is effective for postoperative pain and enhances functional recovery after surgery. Intrathecal administration of gabapentin or NSAIDs inhibits hyperalgesia in a rat postoperative pain model. However, there is no information on the effects of intrathecal administration of a combination of gabapentin and NSAIDs. We therefore investigated the effects of intrathecal administration of gabapentin and NSAIDs in a rat model of postoperative pain. METHODS: Rats were prepared for intrathecal catheters under halothane anesthesia. Two days after catheterization, gabapentin (4, 40, or 400 &mgr;g per 20 &mgr;L of saline), diclofenac sodium, a nonselective cyclooxygenase inhibitor (2, 20, or 200 &mgr;g per 20 &mgr;L of 6% glucose), 20 &mgr;L saline, 20 &mgr;L 6% glucose, and a combination of gabapentin and diclofenac (40 &mgr;g gabapentin + 20 &mgr;g diclofenac and 4 &mgr;g gabapentin + 2 &mgr;g diclofenac per 20 &mgr;L 6% glucose) were injected intrathecally. We performed a hindpaw incision 30 minutes after injection. Each group consisted of 6 rats. The mechanical threshold was measured to evaluate secondary hyperalgesia using von Frey filaments before intrathecal catheterization and at 2 hours, and 1, 3, 5, and 7 days after paw incision. RESULTS: Gabapentin 400 &mgr;g attenuated mechanical hyperalgesia for 7 days compared with the control group. Diclofenac 200 &mgr;g inhibited hyperalgesia for 5 days compared with the control group. The 40 &mgr;g gabapentin + 20 &mgr;g diclofenac group had a significantly reduced secondary hyperalgesic response in 2 hours and 1 day compared with 40 &mgr;g gabapentin and 20 &mgr;g diclofenac, respectively. The 4 &mgr;g gabapentin + 2 &mgr;g diclofenac group had a significantly reduced secondary hyperalgesic response in 2 hours and 1 day compared with 2 &mgr;g diclofenac. The withdrawal threshold on the contralateral paw did not change compared with the preincision threshold. CONCLUSION: Intrathecal administration of gabapentin and diclofenac in combination reduced secondary hyperalgesia at doses having no antihyperalgesic effects when given individually. Our results suggest that gabapentin and diclofenac have an important role in postoperative pain reduction at the spinal level, and that gabapentin augments the antihyperalgesic effects of diclofenac through action in the spinal cord.

Spinal anesthesia with tetracaine in 7.5% or 0.75% glucose in adolescents and adults.

To examine whether adolescents and adults might develop different anesthetic distribution and hemodynamic consequences after spinal injection of 0.5% tetracaine in 7.5% or 0.75% glucose, we studied 100 ASA I or II patients who were scheduled for elective surgery to the lower limb and fulfilled the following criteria: age between 13 and 16 yr (Adolescent group, n = 40) or between 25 and 74 yr (Adult group, n = 60); height between 155 and 180 cm; and body mass index between 18 and 32 kg/m2. Patients in each group were then randomly divided into two equal subgroups to receive spinal anesthesia with 0.5% tetracaine in either 7.5% or 0.75% glucose with 0.125% phenylephrine at the L3-4 interspace. With patients in the supine horizontal position, neural block was assessed by cold, pinprick, and touch sensation and a modified Bromage scale after the injection of the study drug. The 7.5% glucose solution produced a significantly higher and faster spread of blockade in adolescents than in adults. In contrast, there were no differences in the levels of three sensory modalities between the two age groups after the 0.75% glucose solution, which produced a lower spread of blockade than the 7.5% glucose solution in either age group. Adolescents given the 0.75% glucose solution developed a smaller maximum decrease in systolic pressure than those given the heavier solution. We conclude that adolescents may develop an extensive level of blockade more easily and quickly than adults after intrathecal hyperbaric tetracaine, but that the difference may be reduced by using a less heavy solution.

Prophylactic Pentazocine Reduces the Incidence of Pruritus After Cesarean Delivery Under Spinal Anesthesia With Opioids: A Prospective Randomized Clinical Trial.

BACKGROUND: The incidence of pruritus after cesarean delivery under spinal anesthesia with opioids is high, ranging from 50% to 100%. Pruritus is difficult to prevent; however, pentazocine has been shown to be an effective treatment. Despite this, the prophylactic effect of pentazocine on pruritus has not been defined. This randomized double-blind trial aimed to evaluate the effect of intraoperative IV pentazocine on the incidence of opioid-induced pruritus within the first 24 hours after administration of neuraxial opioids. METHODS: We obtained institutional review board approval and written informed consent from the 122 patients (American Society of Anesthesiologists [ASA] physical status II; aged 20–40 years) scheduled for elective cesarean delivery who were included in this study. Spinal anesthesia was performed with 10 mg of 0.5% hyperbaric bupivacaine, 10 &mgr;g of fentanyl, and 100 &mgr;g of morphine. After delivery of the baby and placenta, the parturient women were randomized to intravenously receive 15 mg (1 mL) of pentazocine or 1 mL of saline. All women received postoperative analgesia with the epidural infusion of 0.15% levobupivacaine. The presence of pruritus within the first 24 hours after intrathecal administration of opioids was recorded, and severity of itch, numerical rating scale (NRS) for pain, and adverse effects were also recorded at the time of the arrival on the ward, as well as 3, 6, 12, and 24 hours after the intrathecal administration of opioids. RESULTS: A total of 119 women completed the study. IV pentazocine reduced the overall incidence of pruritus within the first 24 hours compared to IV saline, with an estimated relative risk of 69% (95% confidence interval [CI], 52%, 90%; P = .007). IV pentazocine also reduced the severity of pruritus. The incidence of nausea and vomiting was not significantly different. There were no significant differences in postoperative NRS scores. CONCLUSIONS: A single 15-mg dose of IV pentazocine after delivery can reduce both the incidence and severity of pruritus in women who have received subarachnoid opioids during cesarean delivery.

Reply to Dr Ruan.

To the Editor: We read with great interest the article by Sakakihara and colleagues, entitled “Effects of intrathecal κ-opioid receptor agonist on morphine-induced itch and antinociception in mice,” published in Regional Anesthesia and Pain Medicine. They describe the rationale of their study, “Research suggested that systemically administered κ-opioid receptor (KOR) agonists inhibit intrathecal morphine-induced itch in primates. However, serious adverse effects induced by systemically administered KOR agonists may restrict their usefulness in humans.” The authors demonstrated that intrathecal KOR agonists exert antipruritic effects on intrathecal morphineinduced itch without affecting sedation, and that combination of intrathecal morphine and intrathecal KOR agonists produces more potent antinociceptive effects against a thermal stimulus when compared with morphine alone. Nearly 3 decades ago, Pfeiffer and colleagues suggested that agonism of the KOR elicits dysphoric and psychotomimetic effects in humans. They reasoned that, in humans, μ agonists produce euphorigenic actions which seem to be opposed to the dysphoric effects of the κ agonist (ie, the endogenous opioid systems associated with μ and κ receptors may serve opposite functions in processes affecting emotional and perceptual experiences). In the paper by Pfeiffer et al, the psychotomimetic effects which subjects experienced included racing thoughts, feelings of body distortion, disturbances in the perception of space and time, abnormal visual experiences such as moving lines or walls or color phenomena, and uncontrolled laughter. We question how, and if, such psychotomimetic experience is manifested in the murine model of Sakakihara et al using intrathecal KOR agonists along with intrathecal morphine. Further, the antipruritic effect of κ agonists may involve peripheral KOR as well. μ-Opioid receptor (MOR) and KOR are expressed in the skin and central nervous system (CNS). μ-Opioid receptor and KOR mediate different effects. Activation of MOR inhibits pain, whereas activation of KOR inhibits itch. κ-Opioid receptors participate in the pathophysiology of pruritus not only by their expression in the CNS but also by their presence in the skin. Phan and colleagues suggested that the application of KOR agonists as systemic, and probably also topical, agents is a promising therapeutic approach to chronic pruritus. Despite many observations and treatments, it is extremely difficult, if not impossible, to differentiate peripheral KOR effects from activity within the CNS. Phan and colleagues further suggested that pruritus might arise from an imbalance of the MOR and KOR system activity in either the skin or CNS. We previously encountered a case of intractable itching in a 56-year-old woman, being treated for failed back surgery syndrome, while undergoing an outpatient epidural hydromorphone infusion trial. Our patient had been taking longstanding oxycodone extended-release 40 mg twice a day, before her epidural infusion trial, without experiencing any itching, nor did she experience any itching with oral methadone at 20 mg twice a day after the hydromorphone epidural infusion trial. Yet, she experienced intractable pruritus while receiving a minimal dose of hydromorphone epidural infusion (0.72 mg daily during a 7-day trial). We performed a focused literature review and hypothesized that the centrally located MOR plays a major role in opioidinduced pruritus, whereas κ-opioid activity antagonizes opioid-induced pruritus. Because psychotomimetic effects are centrally mediated, one would intuit that central KOR plays a most dominant role, if not an exclusive one. In this regard, intrathecal κ agonist infusion in humans may potentially (at least in theory) lead to dysphoric and psychotomimetic effects. Thus, we question the clinical utility of centrally administering κ-receptor agonist in humans. However, the work of Sakakihara et al showing improved analgesia and reduced itching in mice, when intrathecal KOR agonists and morphine (MOR agonists) are coadministered is not only enlightening but also deserving of further investigation.