The current recommendations regarding maximum doses of local anesthetics presented in textbooks, or by the responsible pharmaceutical companies, are not evidence based (ie, determined by randomized and controlled studies). Rather, decisions on recommending certain maximum local anesthetic doses have been made in part by extrapolations from animal experiments, clinical experiences from the use of various doses and measurement of blood concentrations, case reports of local anesthetic toxicity, and pharmacokinetic results. The common occurrence of central nervous system toxicity symptoms when large lidocaine doses were used in infiltration anesthesia led to the recommendation of just 200 mg as the maximum dose, which has remained unchanged for more than 50 years. In most cases, there is no scientific justification for presenting exact milligram doses or mg/kg doses as maximum dose recommendations. Instead, only clinically adequate and safe doses (ranges) that are block specific are justified, taking into consideration the site of local anesthetic injection and patient-related factors such as age, organ dysfunctions, and pregnancy, which may influence the effect and the pharmacokinetics of the local anesthetic. Epinephrine in concentrations of 2.5 to 5 microg/mL should be added to the local anesthetic solution when large doses are administered, providing there are no contraindications for the use of epinephrine. As a rule, conditions (eg, end-stage pregnancy, high age in epidural, or spinal block) or diseases (uremia) that may increase the rate of the initial uptake of the local anesthetic are indications to reduce the dose in comparison to one normally used for young, healthy, and nonpregnant adults. On the other hand, the reduced clearance of local anesthetics associated with renal, hepatic, and cardiac diseases is the most important reason to reduce the dose for repeated or continuous administration. The magnitude of the reduction should be related to the expected influence of the pharmacodynamic or pharmacokinetic change.

We reported earlier that preincisional paravertebral block (PVB) provides significant immediate postoperative analgesia after breast cancer surgery. In the same patients (n = 60), a 1-yr follow-up was performed to find out whether PVB could also reduce the prevalence of postoperative chronic pain. The follow-up consisted of a 14-day symptom diary and telephone interviews 1, 6, and 12 mo after surgery. The 14-day consumption of analgesics was similar in the 30 PVB and the 30 control patients. However, 1 mo after surgery, the intensity of motion-related pain was lower (P = 0.005) in the PVB group. Six months after surgery, the prevalence of any pain symptoms (P = 0.029) was lower in the PVB group. Finally, at 12 mo after surgery, in addition to the prevalence of pain symptoms (P = 0.003) and the intensity of motion-related pain (P = 0.003), the intensity of pain at rest (P = 0.011) was lower in the PVB group. These findings were independent of whether or not axillary dissection had been performed. The incidence of neuropathic pain was low (two and three patients in the PVB and control groups, respectively). In addition to providing acute postoperative pain relief, preoperative PVB seems to reduce the prevalence of chronic pain 1 yr after breast cancer surgery.

The same dose of intravenous oxycodone and morphine administered by PCA pump was needed for immediate postoperative analgesia. The two drugs appear to be equipotent.

Paravertebral block (PVB) seems to decrease postoperative pain and postoperative nausea and vomiting (PONV) after breast surgery, but the studies have not been placebo controlled. We studied 60 patients scheduled for breast cancer surgery randomly given single-injection PVB at T3 with bupivacaine 5 mg/mL (1.5 mg/kg) or saline before general anesthesia. The patient and attending investigators were blinded; the PVB or the sham block was performed behind a curtain by an anesthesiologist not involved in the study. The patients given PVB with bupivacaine needed 40% less IV opioid medication (primary outcome variable) in the postanesthesia care unit, had a longer latency to the first opioid dose, and had less pain at rest after 24 h than the control patients (P < 0.01). They also had less PONV in the postanesthesia care unit (P < 0.05), were less sedated until 90 min (P < 0.05), and performed better in the digit symbol substitution test at 90 min and the ocular coordination test 60-120 min after surgery (P < 0.05). The average peak bupivacaine plasma concentration was 750 ng/mL. One patient had bilateral convulsions immediately after bupivacaine injection. We conclude that PVB before general anesthesia for breast cancer surgery reduced postoperative pain, opioid consumption, and occurrence of PONV and improved recovery from anesthesia.

The antinociceptive effects of dexmedetomidine, a highly selective new alpha 2-adrenoceptor agonist, were evaluated in rats after intrathecal, intraperitoneal and subcutaneous administration. Antinociception was tested using the tail-flick method. Both 3 and 6 micrograms of intrathecal dexmedetomidine produced maximal antinociception within 10 min. The effect lasted for up to 6 hr. The smaller dose of 1.5 micrograms produced a mean antinociception of 50% (of the maximum possible effect, MPE%) which lasted for about 2 hr. Subcutaneous atipamezole, a specific alpha 2-adrenergic antagonist completely abolished the antinociception produced by intrathecal dexmedetomidine. When given intraperitoneally, dexmedetomidine produced on average a 50% antinociceptive effect with the highest dose of 60 micrograms/kg. The lower doses of 10 and 30 micrograms/kg were ineffective. After subcutaneous administration a maximal effect was achieved with 120 micrograms/kg, a 70% effect, on average, with 60 micrograms/kg and a short lasting effect of 60% with 30 micrograms/kg. In conclusion, dexmedetomidine is a very potent antinociceptive agent when given intrathecally to rats.

Inhalation anesthetics activate and cannabinoid agonists inhibit TWIK-related acid-sensitive K ϩ channels (TASK)-1 two-pore domain leak K ϩ channels in vitro. Many neuromodulators, such as noradrenaline, might also manifest some of their actions by modifying TASK channel activity. Here, we have characterized the basal behavioral phenotype of TASK-1 knockout mice and tested their sensitivity to the inhalation anesthetics halothane and isoflurane, the ␣ 2 adrenoreceptor agonist dexmedetomidine, and the. TASK-1 knockout mice had a largely normal behavioral phenotype. Male, but not female, knockout mice displayed an enhanced acoustic startle response. The knockout mice showed increased sensitivity to thermal nociception in a hot-plate test but not in a tail-flick test. The analgesic, sedative, and hypothermic effects of WIN55212-2 (2-6 mg/kg s.c.) were reduced in TASK-1 knockout mice. These results implicate TASK-1-containing channels in supraspinal pain pathways, in particular those modulated by endogenous cannabinoids. TASK-1 knockout mice were less sensitive to the anesthetic effects of halothane and isoflurane than wild-type littermates, requiring higher anesthetic concentrations to induce immobility as reflected by loss of the tail-withdrawal reflex. Our results support the idea that the activation of multiple background K ϩ channels is crucial for the high potency of inhalation anesthetics. Furthermore, TASK-1 knockout mice were less sensitive to the sedative effects of dexmedetomidine (0.03 mg/kg s.c.), suggesting a role for the TASK-1 channels in the modulation of function of the adrenergic locus coeruleus nuclei and/or other neuronal systems.

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The administration of pregabalin reduced postoperative opioid consumption after cardiac surgery reduced the incidence of confusion on the first postoperative day and increased time to extubation when compared with placebo. Three months after operation, patients in the pregabalin group experienced less pain during movement.