P. H. Rosenberg

Maximum recommended doses of local anesthetics: A multifactorial concept

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 μg/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.

Driving ability in cancer patients receiving long-term morphine analgesia

When given in single doses to healthy volunteers, opioid analgesics impair reaction time, muscle coordination, attention, and short-term memory sufficiently to affect driving and other skilled activities. Despite the increasing use of oral morphine daily, little is known about the effect of long-term opioid therapy on psychomotor performance. To examine the effects of continuous morphine medication, psychological and neurological tests originally designed for professional motor vehicle drivers were conducted in two groups of cancer patients who were similar apart from experience of pain. 24 were on continuous morphine (mean 209 mg oral morphine daily) for cancer pain; and 25 were pain-free without regular analgesics. Though the results were a little worse in the patients taking morphine, there were no significant differences between the groups in intelligence, vigilance, concentration, fluency of motor reactions, or division of attention. Of the neural function tests, reaction times (auditory, visual, associative), thermal discrimination, and body sway with eyes open were similar in the two groups; only balancing ability with closed eyes was worse in the morphine group. These results indicate that, in cancer patients receiving long-term morphine treatment with stable doses, morphine has only a slight and selective effect on functions related to driving.

Preincisional paravertebral block reduces the prevalence of chronic pain after breast surgery.

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.

Controlled release injectable liposomal gel of ibuprofen for epidural analgesia.

The epidural administration is used commonly in the treatment of pain. Nonsteroidal anti-inflammatory drugs, especially ibuprofen, would have potential in epidural use. Like many epidurally useful drugs it, however, has a short duration of action, which is a limiting factor. To improve epidural pain treatment, a long-acting, single-dose gel injection is being developed. In the present study, the possibility of using liposomal systems to control the release and dural permeation of ibuprofen was investigated in vitro. Liposomal solutions of ibuprofen.Na (20 mg/ml) were prepared by high-pressure homogenization from egg phosphatidylcholine. The liposomal gel consisted of poloxamer 407 and the liposomal solution. No signs in the 1H-NMR spectroscopy of line broadenings or chemical shifts were observed. The liposomal formulations were reproducible and stable. Ibuprofen release in phosphate buffer, pH 7.4, at 37 degrees C from the liposomal solution and the liposomal gel were prolonged significantly compared with their respective solution and gel controls. The liposomal gel controlled ibuprofen release and dural permeation in vitro and showed a permeation pattern favourable for maintaining constant drug levels. The liposomal poloxamer gel represents a new formulation approach to increase the local epidural availability of ibuprofen. It appeared to be a promising injectable controlled-release drug delivery system.

Single-injection paravertebral block before general anesthesia enhances analgesia after breast cancer surgery with and without associated lymph node biopsy.

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.

Postdischarge symptoms after ambulatory surgery: first-week incidence, intensity, and risk factors.

Minor sequelae, such as pain, nausea, and drowsiness, often occur in surgical outpatients in the immediate postdischarge period. In this prospective, observational study was defined the daily incidence and intensity of several symptoms during the first week after surgery and determined predictive factors of minor morbidity. In two similar mixed ambulatory surgery units, 3910 patients received a questionnaire to grade daily the intensity of predefined symptoms on a 4-point scale. Multinomial logistic regression was used to analyze risk factors, with adults and children as separate groups. Of these patients, 2754 (70%) responded. Patients experienced numerous minor sequelae during the first week after ambulatory surgery. Symptoms were common (up to 86% of all patients) on the initial days after surgery and were still reported by 24% of adults on the postoperative Day 7. In adults, pain was the most common symptom and, in comparison with other symptoms, was more often moderate or severe. Drowsiness was most common in children. Younger adults, older children, and women were more prone to experience minor morbidity. Longer duration of surgery led to increased likelihood of pain and nausea in all patients and increased the risk of several other symptoms in adults.

Controlled Release of Lidocaine from Injectable Gels and Efficacy in Rat Sciatic Nerve Block

AbstractPurpose. Methods of delaying the action of local anesthetics are important, since short duration of action limits their use in the treatment of postoperative and chronic pain. The present study evaluated the use of low-viscosity gels in prolonging the release of lidocaine. Methods. Release of lidocaine from 2% lidocaine-HC1 containing methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), sodiumcarboxymethyl cellulose (CMC), and poloxamer 407 (PO) gels was studied in phosphate buffer, pH 7.4, at 37°C. Commercial metylcellulose gel (MCcom) served as control. The in vivo efficacy of the respective gel formulations were evaluated in rats. The gel was injected into the vicinity of the sciatic nerve and nociception and motor function were tested. Results. The cumulative amount of lidocaine released during 8 hr was slowest from the PO gel, followed by the CMC, HPMC and MC gels. The antinociceptive effect was not prevented by the motor block and lasted longest with the PO gel. Good linear and rank order correlation was obtained between in vitro and in vivoresults. The microscopic examination of the tissue samples revealed only mild or no irritation of the skeletal muscle tissue by the PO, HPMC, and CMC gels. Conclusions. Based on these results poloxamer gel proved to be the most promising carrier for lidocaine.

Comparison of analgesic efficacy of oxycodone and morphine in postoperative intravenous patient-controlled analgesia

Background: Morphine has been the standard opioid in patient‐controlled analgesia (PCA). Oxycodone, the analgesic potency of which in i.v. administration has been suggested to be slightly greater than that of morphine, has not yet been studied for its efficacy in PCA.

Efficacy of epidural blood patch for postdural puncture headache

This prospective investigation was conducted to evaluate the efficacy of different volumes of epidural blood patch (EBP) for treatment of postdural puncture headache (PDPH) in 81 consecutive patients. In the first part of the investigation (Study part I), 10 ml of blood was injected for EBP in 28 patients. In the second randomized part of the investigation (Study part II), the patients were allocated to receive for EBP either 10 ml (27 patients) or 10–15 ml (26 patients), according to the height of the patient. The procedure was considered initially successful if PDPH disappeared completely during the 2–h recovery room follow–up. To evaluate the long–term success, a questionnaire was mailed to all patients. The EBP performed 3.7± 2.9 days following the dural puncture was initially successful in 88–96% of the patients in the different study groups. In the questionnaire, only 50–68% of the patients reported that PDPH had disappeared immediately without recurrence. In 16–36% of the patients the PDPH returned at lesser intensity and in 14–17% PDPH was reported to have continued, disappearing gradually in all patients. Despite this, 87% of all patients were satisfied with the EBP treatment. There were no statistically significant differences between the groups. The results indicate that a larger, height–adjusted volume of blood for EBP in adults does not produce a better effect on PDPH compared to a standard 10–ml volume. Despite the excellent initial effect (91%) seen in our patients, a permanent effect of the blood patch was only achieved in 61%.

Postoperative pain relief and bupivacaine plasma levels during continuous interscalene brachial plexus block

Interscalene brachial plexus block was performed on 40 patients for prophylactic pain relief after shoulder surgery. A dose of 1.25 mg/kg of 0.5%, bupivacaine was injected for the block (Group 1) and continued with an infusion of 0.25%, bupivacaine 0.25 mg/kg/h (Group 2). If the postoperative analgesia was insufficient, the patients received i.m. oxycodone 0.15 mg/kg. In Group 1, one patient managed without oxycodone supplementation during the 24‐h observation period compared with eight patients in Group 2 [P < 0.01). The rest of the patients received 3.8 ± 1.6 doses (Group 1) and 2.5 ± 1.2 doses (Group 2) of oxycodone (P < 0.05). At 30 min, the mean bupivacaine plasma concentration was 1.0 pg/ml in Group 1 and 0.9 pg/ ml in Group 2. The mean plasma level of bupivacaine increased from 0.7 μg/ml after 180 min to 1.1 μg/ml (P < 0.01) after 24 h of infusion, providing some evidence of accumulation during infusion. The dizziness and confusion experienced by three patients could be associated with the local anaesthetic, as they obtained relief after the infusion was stopped.