Igor Kissin

Postoperative Pain After Inguinal Herniorrhaphy with Different Types of Anesthesia

In a randomized, double-blind study, postoperative pain was assessed in 36 patients undergoing inguinal herniorrhaphy with three types of anesthesia: general (thiopental-nitrous oxide-halothane); general with the addition of local (infiltration of the abdominal wall with 0.25% bupivacaine along the line of the proposed incision); and spinal (0.5% bupivacaine). The severity of constant incisional pain, movement-associated incisional pain, and pain upon pressure applied to the surgical wound using an algometer was assessed with a visual analogue self-rating method at 24 h, 48 h, and 10 days after surgery. The addition of local anesthesia significantly decreased the intensity of all types of postoperative pain. This effect was especially evident with constant incisional pain that disappeared almost completely 24 h after surgery. With pain caused by pressure on the site of the surgical incision, the pain score difference between general and general plus local anesthesia was obvious even 10 days after the surgery (with 0.4-kg/cm2 pressure, the pain scores were 16 ± 3 vs 2 ± 1, P < 0.01). The difference in postoperative pain scores between spinal and general anesthesia groups indicated that spinal anesthesia also decreases the pain intensity. However, this decrease is less pronounced than that seen with the addition of local anesthesia: movement-associated pain scores 24 h after surgery were 72 ± 5 in the general anesthesia group, 40 ± 6 in the spinal anesthesia group, and 16 ± 3 in the general plus local anesthesia group (with P < 0.002 between the groups).Our results indicate that postoperative pain after inguinal herniorrhaphy can be significantly decreased if the surgery is performed with the use of local or spinal anesthesia. We hypothesize that neural blockade, by preventing nociceptive impulses from entering the central nervous system during and immediately after surgery, suppresses the formation of the sustained hyperexcitable state in the central nervous system that is responsible for the maintenance of postoperative pain.

Rapid development of tolerance to analgesia during remifentanil infusion in humans.

Studies in experimental animals have demonstrated a rapidly developing acute tolerance to the analgesic effect of opioids administered by continuous IV infusion.The aim of the present study was to determine whether acute tolerance plays an important role in the analgesic effect of remifentanil provided by IV infusion to humans. The analgesic effect of remifentanil, infused at a constant rate of 0.1 [micro sign]g [center dot] kg-1 [center dot] min-1 for 4 h, was evaluated by measuring pain tolerance with thermal (2[degree sign]C water) and mechanical (pressure) noxious stimulations in 13 paid volunteers. The constant-rate infusion of remifentanil resulted in a threefold increase in pain tolerance with both tests. After reaching its maximum in 60-90 min, the analgesic effect of remifentanil began to decline despite the constant-rate infusion, and after 3 h of infusion, it was only one fourth of the peak value. A comparative rate in the development of acute tolerance measured in terms of time to 50% recovery during infusion was 129 +/- 27 min (mean +/- SD) with the cold water test and 138 +/- 39 min with the pressure test. We conclude that the development of tolerance should be included in the calculations for target-controlled infusions. Implications: Our study shows that tolerance to analgesia during remifentanil infusion is profound and develops very rapidly. The administration of opioids during anesthesia based on target-controlled infusions should include corrections for the development of tolerance. (Anesth Analg 1998;86:1307-11)

PREEMPTIVE EFFECT OF FENTANYL AND KETAMINE ON POSTOPERATIVE PAIN AND WOUND HYPERALGESIA

The aim of this study was to test the hypothesis that the induction and maintenance of anesthesia with the use of fentanyl or ketamine reduces postoperative pain and wound hyperalgesia beyond the period when these effects can be explained by the direct analgesic action of these drugs. Twenty-seven patients scheduled for elective hysterectomy were investigated in a double-blind, randomized study. Patients were divided into three groups. In the fentanyl group, anesthesia was induced with fentanyl 5 micrograms/kg combined with thiopental 3 mg/kg and maintained with isoflurane and fentanyl 0.02 microgram.kg-1.min-1. In the ketamine group, anesthesia was induced with ketamine 2 mg/kg in combination with thiopental 3 mg/kg and maintained with isoflurane and ketamine 20 micrograms.kg-1.min-1. In the control group, anesthesia was induced with thiopental 5 mg/kg and maintained with isoflurane only. Patients in all three groups received identical postoperative pain treatment. The intensity of spontaneous incisional pain and movement-associated pain was measured with a visual analog self-rating method. The surgical wound hyperalgesia was assessed by measuring pain threshold to pressure on the wound by using an algometer, and also by measuring the intensity of pain to suprathreshold pressure on the wound with the visual analog self-rating method. Forty-eight hours after surgery, the pain threshold was 0.90 +/- 0.06 kg in controls, 1.69 +/- 0.19 kg (P < 0.001) in the fentanyl group, and 1.49 +/- 0.15 kg (P < 0.01) in the ketamine group.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of pre-incisional infiltration of tonsils with bupivacaine on the pain following tonsillectomy under general anesthesia.

&NA; The aim of the present study was to test the hypothesis that blockade of nociceptive input with bupivacaine during tonsillectomy can decrease pain beyond the immediate postoperative period. Fourteen patients between the ages of 6 and 18 years scheduled for tonsillectomy (with or without adenoidectomy) were randomly divided into two groups. The patients of both groups received 0.006 mg/kg atropine and anesthesia was induced by inhalation of halothone. Atracurium 0.5 mg/kg was used for myorelaxation. After oral intubation anesthesia was maintained with isoflurane plus nitrous oxide 67% in oxygen. In the bupivacaine group, 5 min before incision the tonsillar fossae were infiltrated with 0.25% bupivacaine with epinephrine (1 : 200,000). In the control group, the tonsillar fossae were infiltrated with normal saline with epinephrine (1 : 200,000). All patients received morphine 0.07 mg/kg (in the recovery room) and oral elixir with codeine 0.05 mg/kg plus acetaminophen 5 mg/kg every 4 h. Pain assessments were made using the visual analog (100 mm scale) self‐rating method. Two types of pain were assessed: constant incisional pain and pain caused by drinking 100 ml of water. In the bupivacaine group, the constant pain score on the second day after surgery was 19 ± 6 compared to 74 ± 8 in the saline group (P < 0.0002). By the 4–5th day after surgery almost no constant pain occurred in the bupivacaine group, but the pain score remained at the 40–60 level in the saline group. The difference in pain intensity on swallowing between the bupivacaine and saline groups was present even on the 10th postoperative day (1 ± 1 vs. 14 ± 5, P < 0.05). The results indicate that pre‐incisional infiltration of the tonsils with bupivacaine markedly decreased the intensity of pain following tonsillectomy well beyond the immediate postoperative period. An explanation for the long‐lasting pain relief might be that neural blockade prevents nociceptive impulses from entering the central nervous system during and immediately after surgery and thus suppresses formation of the sustained hyperexcitable state that is responsible for the maintenance of postoperative pain.

Depth of anesthesia and bispectral index monitoring.

In a comprehensive review on monitoring anesthesia, Stanski (1) concluded that both specific defined stimuli and specific responses are needed to assess anesthetic depth. He stated that no unifying clinical measure of anesthetic depth spans all classes of anesthetic drugs and that clinical measures

The effect of ketamine on opioid-induced acute tolerance : can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations?

Ketamine administered intraoperatively in very small doses reduces postoperative opioid consumption. We suggest that this effect is the result of attenuation of acute tolerance to the analgesic effect of opioids. We sought to demonstrate that acute tolerance induced by alfentanil infusion can be attenuated by a dose of ketamine that is too small to produce a direct antinociceptive effect. The experiments were conducted in rats with the use of an infusion algorithm designed to maintain a constant plasma level of the opioid for 4 h. The degree of acute tolerance was determined on the basis of decline in the level of analgesia measured with a tail compression test. Ketamine (10 mg/kg) did not change the baseline pain threshold and did not increase the peak of alfentanil-induced analgesia. At the same time, it attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion. These effects were similar to those observed with dizocilpine (0.1 mg/kg). The development of acute tolerance to analgesia induced by the infusion of an opioid can be attenuated by ketamine administered in doses that are not large enough to provide a direct antinociceptive effect. Therefore, ketamine has the potential to reduce opioid consumption even in subanalgesic doses. Implications Ketamine attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion.

The Development of New Analgesics Over the Past 50 Years: A Lack of Real Breakthrough Drugs

Fifty-nine drugs identified as analgesics were introduced from 1960 to 2009 and remain in use. Seven can be regarded as having novel molecular targets; however, only one, sumatriptan, was sufficiently effective to motivate the introduction of many similar drugs acting at the same target (triptans). Publication productivity in the area of pain grew exponentially during this period. Pain-related publications on morphine were dominant among other analgesics. Very intensive research efforts directed at diverse molecular targets related to pain mechanisms produced thousands of publications, but those efforts have not yet yielded new analgesics with sufficient effectiveness to change the share of publications on opioids or nonsteroidal antiinflammatory drugs. Morphine and aspirin, introduced for the treatment of pain more than a century ago, continue to dominate biomedical publications despite their limited effectiveness in many areas (e.g., neuropathic pain) and multiple serious adverse effects. The present assessment reveals the lack of real breakthroughs in analgesic drug development despite intense research efforts. Possible factors contributing to the apparent drought of novel analgesics are discussed.

Acute tolerance in morphine analgesia: continuous infusion and single injection in rats.

This study aimed to determine whether the decline of the analgesic effect of morphine with a continuous infusion or that after a single injection correlates with the changes in brain concentration of morphine. The analgesic effect of morphine and its brain and serum concentrations were determined with a continuous 8-h infusion at a constant rate and after a single subcutaneous injection of the agent. The analgesic effect was determined by measuring the threshold of motor response to noxious stimulation. Brain and serum concentrations of morphine were detected by radioimmunoassay with the use of 125I-labeled morphine. With the constant-rate (4 mg.kg-1.h-1, intravenous) morphine infusion, the peak of analgesia could not be maintained: the increase in the pain threshold at 2 h was 1,003 g and at 8h was 286 g (a decrease in analgesia by 72%, P less than 0.0002). At the same time, the brain morphine concentration tended to increase, to 278 ng/g at 2 h and 329 ng/g at 8 h. After the single morphine injection (6 mg/kg, subcutaneous), recovery from analgesia occurred at a much faster rate than did the decrease in morphine brain concentration; the decrease in pain threshold was 79% at 90 vs. 30 min after the injection (P less than 0.0001), and the corresponding decrease in brain concentration was 28% (NS). The absence of correlation between analgesia and morphine brain concentration both with the constant-rate morphine infusion and after the single injection suggests the development of acute tolerance, which is pharmacodynamic in nature.

Ketamine enhances local anesthetic and analgesic effects of bupivacaine by peripheral mechanism: a study in postoperative patients.

Patients with unilateral (n = 14) and bilateral (n = 4) herniorrhaphy participated in this study. With bilateral herniorrhaphy, at the end of the surgery, the wound was infiltrated with a solution of bupivacaine 0.5% and ketamine 0.3% on one side and a solution of bupivacaine 0.5% only, on the other. With unilateral herniorrhaphy, the patients were randomly assigned to one of two groups (n = 7). One group at the end of the surgery received the infiltration with a solution of bupivacaine 0.5% and ketamine 0.3%, the other group received the infiltration with a solution of bupivacaine 0.5% only. The duration of the local anesthetic (response to a von Frey filament) and postoperative analgesic (time to mild spontaneous pain) effects of the infiltrations, as well as wound pain threshold 24 h after surgery (pressure algometry), were determined. In patient with unilateral herniorrhaphy, the addition of ketamine for wound infiltration enhanced the duration of infiltration anesthesia (206 +/- 76 versus 343 +/- 108 min, P < 0.02) and analgesia (240 +/- 45 versus 420 +/- 151 min, P < 0.03). Similar enhancement of the local anesthetic effect was observed in patients with bilateral herniorrhaphy. The increase in pain threshold to pressure on the wound with the addition of ketamine was evident in bilateral herniorrhaphy patients and also with a combination of bilateral and unilateral results (1.39 +/- 0.40 versus 2.35 +/- 0.92 kg, P < 0.02). In the group of five volunteers, the subcutaneous infiltration with 0.3% ketamine produced a local anesthetic effect lasting only 10-20 min. The results indicate that ketamine acting via a peripheral mechanism can profoundly enhance anesthetic and analgesic actions of a local anesthetic administered for infiltration anesthesia.

Calcium entry blockers: uses and implications for anesthesiologists.

Calcium Entry Blockers: Uses and Implications for Anesthesiologists J G Reves;Igor Kissin;William Lell;Steve Tosone; Anesthesiology