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.     

Modulation of remifentanil-induced analgesia,hyperalgesia, and tolerance by small-dose ketamine in humans

Adding a small dose of ketamine to opioids may increase the analgesic effect and prevent opioid-induced hyperalgesia and acute tolerance to opioids. In this randomized, double-blinded, placebo-controlled crossover study, we investigated the effect of remifentanil combined with small concentrations of ketamine on different experimental pain models. Pain detection thresholds to single and repeated IM electrical stimulation and to repeated transcutaneous electrical stimulation, pressure pain tolerance threshold, and sedative, respiratory, and cardiovascular side effects were assessed in 14 healthy volunteers. Saline, remifentanil alone, and remifentanil combined with ketamine at target plasma concentrations of 50 or 100 ng/mL were administered in four study sessions. The ketamine infusion was started after baseline testing at a constant target concentration. Remifentanil was started after testing with ketamine alone at an initial target concentration of 1 ng/mL and then increased to 2 ng/mL and decreased to 1 ng/mL. The last test series were started 10 min after discontinuation of remifentanil. Acute remifentanil-induced hyperalgesia and tolerance were detected only by the pressure pain test and were not suppressed by ketamine. Remifentanil alone induced significant analgesia with all pain tests. Ketamine further increased the remifentanil effect only on IM electrical pain. Remifentanil at a 2 ng/mL target concentration induced a slight respiratory depression that was antagonized by ketamine. We conclude that ketamine effects on opioid analgesia are pain-modality specific. IMPLICATIONS: Coadministration of ketamine and morphine for pain relief is still controversial. Our experimental pain study with volunteers showed that ketamine enhances opioid analgesia without increasing sedation and reduces respiratory depression. Opioid-induced hyperalgesia and tolerance were not affected by ketamine and depended on the type of nociceptive stimulus. This may explain the conflicting results on opioid tolerance in previous studies.     

Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine

BACKGROUND: It has been reported that mu-opioid receptor activation leads to a sustained increase in glutamate synaptic effectiveness at the N-methyl-D-aspartate (NMDA) receptor level, a system associated with central hypersensitivity to pain. One hypothesis is that postoperative pain may result partly from the activation of NMDA pain facilitatory processes induced by opiate treatment per se. The authors tested here the effectiveness of the opiate analgesic fentanyl for eliciting a delayed enhancement in pain sensitivity. METHODS: The consequences of four bolus injections (every 15 min) of fentanyl (20-100 microg/kg per injection, subcutaneously) on immediate (for several hours) and long-term (for several days) sensitivity to nociceptive stimuli in the rat (paw-pressure vocalization test) were evaluated. The effects of the combination of the NMDA-receptor antagonist ketamine (10 mg/kg, subcutaneously) with fentanyl also were assessed. RESULTS: Fentanyl administration exhibited a biphasic time-dependent effect: first, an early response (for 2-5 h) associated with a marked increase in nociceptive threshold (analgesia), and second, a later response associated with sustained lowering of the nociceptive threshold (5 days for the longest effect) below the basal value (30% of decrease for the maximal effect) indicative of hyperalgesia. The higher the fentanyl dose used, the more pronounced was the fentanyl-induced hyperalgesia. Ketamine pretreatment, which had no analgesic effect on its own, enhanced the earlier response (analgesia) and prevented the development of long-lasting hyperalgesia. CONCLUSIONS: Fentanyl activates NMDA pain facilitatory processes, which oppose analgesia and lead to long-lasting enhancement in pain sensitivity.     

Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia

Opioids administered during surgery may be beneficial by preempting postoperative pain or detrimental by causing acute tolerance. We used a stable model of hyperalgesia in volunteers to test whether acute opioid exposure also results in such pain sensitization over a period of hours in humans. Ten healthy volunteers were studied. Areas of mechanical hyperalgesia and allodynia were induced by topical capsaicin application plus intermittent heating. Computer-controlled IV remifentanil infusion was titrated to a targeted plasma concentration that reduced pain report to noxious heat by 70% and was maintained at this level for 60-100 min. Areas of hyperalgesia and allodynia were measured during and after remifentanil infusion. Remifentanil (targeted concentration of 3.1 +/- 1.2 ng/mL) reduced areas of hyperalgesia and allodynia by 33% +/- 31% and 65% +/- 28%, respectively, during infusion (P < 0.05). Areas of hyperalgesia and allodynia continuously enlarged 4 h after remifentanil was stopped, to 180% +/- 47% and 180% +/- 86%, respectively. This study demonstrates that acute opioid exposure enhances hypersensitivity for hours after exposure. If applicable to the surgical setting, this could increase the dose of opioid required for postoperative analgesia and enhance, rather than inhibit, postoperative pain.     

Remifentanil tolerance and hyperalgesia: short‐term gain,long‐term pain?

The unique pharmacology of remifentanil makes it a popular intra‐operative analgesic. Short‐acting opioids like remifentanil have been associated with acute opioid tolerance and/or opioid‐induced hyperalgesia, two phenomena which have different mechanisms and are pharmacologically distinct. Clinical studies show heterogeneity of remifentanil infusion regimens, durations of infusion, maintenance of anaesthesia, cumulative dose of remifentanil and pain measures, which makes it difficult to draw conclusions about the incidence of acute tolerance or hyperalgesia. However, it appears that intra‐operative remifentanil infusion rates of above 0.25 μg.kg^?1.min^?1 are associated with higher postoperative opioid consumption, suggesting tolerance. Infusion rates greater than 0.2 μg.kg^?1.min^?1 are characterised by lower mechanical/pressure/cold/pain thresholds, which suggests hyperalgesia. The use of concurrent multimodal analgesia, especially N‐methyl‐D‐aspartate receptor antagonists, may be an effective preventive strategy. The clinical significance and long‐term consequences of these entities is still uncertain.     

Long-lasting Hyperalgesia Induced by Fentanyl in Rats: Preventive Effect of Ketamine

Background: It has been reported that [mu]-opioid receptor activation leads to a sustained increase in glutamate synaptic effectiveness at the N-methyl-D-aspartate (NMDA) receptor level, a system associated with central hypersensitivity to pain. One hypothesis is that postoperative pain may result partly from the activation of NMDA pain facilitatory processes induced by opiate treatment per se. The authors tested here the effectiveness of the opiate analgesic fentanyl for eliciting a delayed enhancement in pain sensitivity.

Methods: The consequences of four bolus injections (every 15 min) of fentanyl (20-100 [mu]g/kg per injection, subcutaneously) on immediate (for several hours) and long-term (for several days) sensitivity to nociceptive stimuli in the rat (paw-pressure vocalization test) were evaluated. The effects of the combination of the NMDA-receptor antagonist ketamine (10 mg/kg, subcutaneously) with fentanyl also were assessed.

Results: Fentanyl administration exhibited a biphasic time-dependent effect: first, an early response (for 2-5 h) associated with a marked increase in nociceptive threshold (analgesia), and second, a later response associated with sustained lowering of the nociceptive threshold (5 days for the longest effect) below the basal value (30% of decrease for the maximal effect) indicative of hyperalgesia. The higher the fentanyl dose used, the more pronounced was the fentanyl-induced hyperalgesia. Ketamine pretreatment, which had no analgesic effect on its own, enhanced the earlier response (analgesia) and prevented the development of long-lasting hyperalgesia.     

Experimental Cutaneous Pain Thresholds and Tolerance in Clinical Analgesia with Epidural Morphine

Ten patients experiencing significant analgesia from repealed low-dose morphine injections via an indwelling epidural catheter were studied. One group (n=5) with acute, postoperative pain was tested for changes in experimental cutaneous pain thresholds with and without clinical morphine analgesia. Three of these patients received intravenous naloxone. The analgesia was reversed in two. There was no significant alteration in any cutaneous modality, including pain, although the postoperative deep pain was relieved. This discrepancy might be explained by the existence of separate subpopulations of opiate receptors at the spinal cord level, which differentiate nociceptive input from the skin and from deep body structures. The other group (n = 5) of cancer pain patients with a permanent epidural catheter was monitored for long-term changes in clinical pain. Signs of tolerance were not seen with an observation period up to 6 weeks.     

The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance

Perioperative opioids increase postoperative pain and morphine requirement, suggesting acute opioid tolerance. Furthermore, opioids elicit N-methyl-D-aspartate (NMDA)-dependent pain hypersensitivity. We investigated postfentanyl morphine analgesic effects and the consequences of NMDA-receptor antagonist (ketamine) pretreatment. The rat nociceptive threshold was measured by the paw-pressure vocalization test. Four fentanyl boluses (every 15 min) elicited a dose-dependent (a) increase followed by an immediate decrease of the nociceptive threshold and (b) reduction of the analgesic effect of a subsequent morphine administration (5 mg/kg): -15.8%, -46.6%, -85.1% (4 x 20, 4 x 60, 4 x 100 microg/kg of fentanyl, respectively). Ketamine pretreatment (10 mg/kg) increased the fentanyl analgesic effect (4 x 60 microg/kg), suppressed the immediate hyperalgesic phase, and restored the full effect of a subsequent morphine injection. Fentanyl also elicited a delayed dose-dependent long-lasting decrease of the nociceptive threshold (days) that was prevented by a single ketamine pretreatment before fentanyl. However, a morphine administration at the end of the fentanyl effects restored the long-lasting hyperalgesia. Repeated ketamine administrations were required to obtain a complete preventive effect. Although ketamine had no analgesic effect per se at the dose used herein, our results indicate that sustained NMDA-receptor blocking could be a fruitful therapy for improving postoperative morphine effectiveness. IMPLICATIONS: Fentanyl-induced analgesia is followed by early hyperalgesia (hours), acute tolerance to the analgesic effects of morphine, and long-lasting hyperalgesia (days). All these phenomena are totally prevented by repeated administrations of the NMDA-receptor antagonist, ketamine, simultaneously with fentanyl and morphine administration.     

Nitrous oxide revisited: evidence for potent antihyperalgesic properties

BACKGROUND: Although opioids are unsurpassed analgesics for surgery, they also induce an N-methyl-D-aspartate-dependent enhancement of postoperative hyperalgesia. Because nitrous oxide (N2O) has anti-N-methyl-D-aspartate properties, the purpose of this study was to evaluate nitrous oxide ability to prevent such an opioid-induced hyperalgesia in rats. METHODS: First, preventive effects of 50/50% N2O-O2 on the development of delayed hyperalgesia observed after inflammatory pain (hind paw carrageenan injection on D0) were examined for several days. Second, the ability of nitrous oxide (10-40%) to limit opioid-induced hyperalgesia induced by fentanyl was evaluated in nonsuffering rats. Third, antihyperalgesic effects of various nitrous oxide concentrations (20-50%) were assessed in both inflammatory and incisional pain models in fentanyl-treated rats (4 x 100 microg/kg subcutaneously). Finally, the analgesic effect of a single dose of morphine was evaluated 24 h after fentanyl administration and nitrous oxide (D0) to assess its preventive effect on acute morphine tolerance in both nonsuffering and hind paw-incised rats. RESULTS: When applied on D0, nitrous oxide reduced delayed hyperalgesia induced by inflammation. Exposure to nitrous oxide on D0 also reduced opioid-induced hyperalgesia in nonsuffering rats in a dose-dependent manner. In fentanyl-treated rats with inflammatory or incisional pain, nitrous oxide strongly limited both magnitude and duration of hyperalgesia. Moreover, nitrous oxide exposure on D0 opposed development of acute tolerance to analgesic effects of morphine administered on D1 in both nonsuffering and incised fentanyl-treated rats. CONCLUSIONS: Nitrous oxide, an N-methyl-D-aspartate receptor antagonist, prevented the enhancement of pain sensitivity induced by both nociceptive inputs and fentanyl and opposed acute morphine tolerance. Results suggest that perioperative nitrous oxide use reduces exaggerated postoperative pain and morphine consumption.     

Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers

BACKGROUND: Although the preclinical literature suggests that cannabinoids produce antinociception and antihyperalgesic effects, efficacy in the human pain state remains unclear. Using a human experimental pain model, the authors hypothesized that inhaled cannabis would reduce the pain and hyperalgesia induced by intradermal capsaicin. METHODS: In a randomized, double-blinded, placebo-controlled, crossover trial in 15 healthy volunteers, the authors evaluated concentration-response effects of low-, medium-, and high-dose smoked cannabis (respectively 2%, 4%, and 8% 9-delta-tetrahydrocannabinol by weight) on pain and cutaneous hyperalgesia induced by intradermal capsaicin. Capsaicin was injected into opposite forearms 5 and 45 min after drug exposure, and pain, hyperalgesia, tetrahydrocannabinol plasma levels, and side effects were assessed. RESULTS: Five minutes after cannabis exposure, there was no effect on capsaicin-induced pain at any dose. By 45 min after cannabis exposure, however, there was a significant decrease in capsaicin-induced pain with the medium dose and a significant increase in capsaicin-induced pain with the high dose. There was no effect seen with the low dose, nor was there an effect on the area of hyperalgesia at any dose. Significant negative correlations between pain perception and plasma delta-9-tetrahydrocannabinol levels were found after adjusting for the overall dose effects. There was no significant difference in performance on the neuropsychological tests. CONCLUSIONS: This study suggests that there is a window of modest analgesia for smoked cannabis, with lower doses decreasing pain and higher doses increasing pain.     

Fentanyl enhancement of carrageenan-induced long-lasting hyperalgesia in rats: prevention by the N-methyl-D-aspartate receptor antagonist ketamine

BACKGROUND: Tissue damage may produce hyperalgesia, allodynia, and persistent pain. The authors recently reported that fentanyl elicits analgesia but also activates N-methyl-D-aspartate-dependent pain facilitatory processes opposing analgesia. In nonsuffering rats, this leads to a long-lasting enhancement in pain sensitivity. The current study assessed whether fentanyl could amplify carrageenan-induced hyperalgesia. METHODS: First, rats were injected once with carrageenan in a hind paw, with fentanyl (60 or 100 microg/kg each given four times at 15-min intervals [4 x 60 or 4 x100]) or saline. Second, rats were injected with carrageenan twice without fentanyl (7-day interval), with the second injection either in the previously injected paw or in the other paw. Third, rats were injected twice with carrageenan in the same hind paw: the first ketamine injection was given (10 mg/kg each given three times at 5-h intervals) with or without fentanyl (4 x 60 microg/kg), and second injection was given without ketamine or fentanyl. The consequences of treatments on long-term hyperalgesia were examined by the paw-pressure vocalization test. RESULTS: The long-lasting hyperalgesia induced by the first carrageenan injection was dose-dependently enhanced in both duration and magnitude in 4 x 60 or 4 x 100 microg/kg fentanyl-treated rats: 5 or 10 days, respectively, as compared with 2 days in saline-treated rats. Hyperalgesia observed in the hind paw contralateral to the first carrageenan injection was enhanced in fentanyl-treated rats. The second carrageenan injection, performed in any hind paw, induced an exaggerated hyperalgesia, especially in fentanyl-treated rats. Pretreatment with ketamine totally prevented the carrageenan- and fentanyl-induced enhancement of the long-lasting hyperalgesia. CONCLUSION: Central sensitization in inflammatory pain states is reinforced by an opiate treatment, which could be prevented by N-methyl-D-aspartate receptors blockade.     

Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing major digestive surgery

BACKGROUND: As a broader definition of preemptive analgesia, preventive analgesia aims to prevent the sensitization of central nervous system, hence the development of pathologic pain after tissular injury. To demonstrate benefits from preventive treatment, objective measurement of postoperative pain such as wound hyperalgesia and persistent pain should be evaluated. The current study assessed the role and timing of epidural analgesia in this context. METHODS: In a randomized, double-blinded trial, 85 patients scheduled to undergo neoplastic colonic resection were included. All the patients received a thoracic epidural catheter, systemic ketamine at a antihyperalgesic dose, and general anesthesia. Continuous infusion of analgesics belonging to the same class was administered by either intravenous or epidural route before incision until 72 h after surgery. Patients were allocated to four groups to receive intraoperative intravenous lidocaine-sufentanil-clonidine or epidural bupivacaine-sufentanil-clonidine followed postoperatively by either intravenous (lidocaine-morphine-clonidine) or epidural (bupivacaine-sufentanil-clonidine) patient-controlled analgesia. Postoperative pain scores (visual analog scale), analgesic consumption, wound area of punctuate hyperalgesia, residual pain, and analgesics needed from 2 weeks until 12 months were recorded. RESULTS: Analgesic requirements, visual analog scale scores, and area of hyperalgesia were significantly higher in the intravenous treatment group (intravenous-intravenous), and more patients reported residual pain from 2 weeks until 1 yr (28%). Although postoperative pain measurements did not differ, postoperative epidural treatment (intravenous-epidural) was less effective to prevent residual pain at 1 yr (11%; P = 0.2 with intravenous-intravenous group) than intraoperative one (epidural-epidural and epidural-intravenous groups) (0%; P = 0.01 with intravenous-intravenous group). CONCLUSION: Combined with an antihyperalgesic dose of ketamine, intraoperative epidural analgesia provides effective preventive analgesia after major digestive surgery.     

Nitrous Oxide Revisited: Evidence for Potent Antihyperalgesic Properties

Background: Although opioids are unsurpassed analgesics for surgery, they also induce an N-methyl-d-aspartate-dependent enhancement of postoperative hyperalgesia. Because nitrous oxide (N2O) has anti-N-methyl-d-aspartate properties, the purpose of this study was to evaluate nitrous oxide ability to prevent such an opioid-induced hyperalgesia in rats.

Methods: First, preventive effects of 50/50% N2O-O2 on the development of delayed hyperalgesia observed after inflammatory pain (hind paw carrageenan injection on D0) were examined for several days. Second, the ability of nitrous oxide (10-40%) to limit opioid-induced hyperalgesia induced by fentanyl was evaluated in nonsuffering rats. Third, antihyperalgesic effects of various nitrous oxide concentrations (20-50%) were assessed in both inflammatory and incisional pain models in fentanyl-treated rats (4 x 100 [mu]g/kg subcutaneously). Finally, the analgesic effect of a single dose of morphine was evaluated 24 h after fentanyl administration and nitrous oxide (D0) to assess its preventive effect on acute morphine tolerance in both nonsuffering and hind paw-incised rats.

Results: When applied on D0, nitrous oxide reduced delayed hyperalgesia induced by inflammation. Exposure to nitrous oxide on D0 also reduced opioid-induced hyperalgesia in nonsuffering rats in a dose-dependent manner. In fentanyl-treated rats with inflammatory or incisional pain, nitrous oxide strongly limited both magnitude and duration of hyperalgesia. Moreover, nitrous oxide exposure on D0 opposed development of acute tolerance to analgesic effects of morphine administered on D1 in both nonsuffering and incised fentanyl-treated rats.     

Ketamine improves the management of exaggerated postoperative pain observed in perioperative fentanyl-treated rats

BACKGROUND: Although opioids are unsurpassed analgesics, experimental and clinical studies suggest that opioids activate N-methyl-d-aspartate pronociceptive systems leading to pain hypersensitivity and short-term tolerance. Because it is difficult in humans to differentiate pain from hyperalgesia during the postoperative period, the authors performed experimental studies with fentanyl using the rat incisional pain model for evaluating relations between hyperalgesia and short-term tolerance. Because N-methyl-d-aspartate receptor antagonists oppose both pain hypersensitivity and tolerance induced by opioids, the authors examined the capability of ketamine for improving exaggerated postoperative pain management. METHODS: During halothane anesthesia, a hind paw plantar incision was performed in rats receiving four fentanyl subcutaneous injections (100 microg/kg per injection, every 15 min). In some groups, three subcutaneous ketamine injections (10 mg/kg per injection, every 5 h) were performed in saline- or fentanyl-treated rats. One day after surgery, the analgesic effect of morphine (2 mg/kg subcutaneous) was tested. Analgesia, mechanical hyperalgesia, tactile allodynia, and pain score were assessed for several days using the paw pressure vocalization test, the von Frey application test, and the postural disequilibrium test. RESULTS: Fentanyl induced analgesia but also produced exaggerated postoperative pain as indicated by the enhancement of hyperalgesia, allodynia, and weight-bearing decrease after hind paw plantar incision. Ketamine pretreatment prevented such a fentanyl-induced enhancement of postoperative pain and improved its management by morphine. CONCLUSIONS: By opposing postoperative pain hypersensitivity and subsequent short-term tolerance induced by perioperative opioid use, ketamine not only improves exaggerated postoperative pain management but also provides better postoperative rehabilitation.     

Long-term changes in the antinociceptive potency of morphine or dexmedetomidine after a single treatment

Acute tolerance develops after a single administration of opiate or alpha(2)-adrenergic agonists, but the characteristics of the delayed type of acute tolerance have not been analyzed in acute and inflammatory thermal pain tests. We investigated the long-term changes in the antinociceptive potency of morphine (10 mg/kg) injected intraperitoneally and the alpha(2)-adrenoceptor agonist dexmedetomidine (150 microg/kg intraperitoneally) on acute heat pain (tail-flick test) sensitivity and on carrageenan-induced inflammatory thermal hyperalgesia (paw withdrawal test) after a second injection 7 days later. The first treatment did not influence the baseline values on Day 8 in either test. In the tail-flick test, the antinociceptive potency of morphine, but not that of dexmedetomidine, was significantly decreased after repeated administration, suggesting a delayed type of acute tolerance to morphine. In contrast, the antihyperalgesic effect of morphine in the paw withdrawal test did not change after repeated injection, whereas the potency of dexmedetomidine was increased on Day 8. There were significant differences between the inflamed and noninflamed sides on Day 1 but not on Day 8, revealing an increased potency of the drugs on the inflamed side. There was no sign of cross-tolerance between the two drugs in either pain test. These data indicate long-term changes in the antinociceptive potency of morphine or dexmedetomidine after single treatment in different heat pain tests.     

Continuous physostigmine combined with morphine-based patient-controlled analgesia in the postoperative period

BACKGROUND: Recently, new drugs and techniques for the treatment of postoperative pain were introduced, with the goal of enhancing opiates' analgesia while minimizing their side-effects. Cholinergic agents play an antinociceptive role, but their clinical use is quite limited, due to side-effects. Physostigmine is a cholinesterase inhibitor, which crosses the blood-brain barrier and elevates brain acetylcholine level. Physostigmine can produce analgesia by itself, and enhance opiate analgesia; but these effects are of short duration following bolus administration. METHODS: We compared pain intensity and morphine consumption in two postoperative treatment groups: One group received continuous physostigmine infusion combined with morphine-based patient-controlled analgesia (PCA), and the other received PCA alone. Cholinergic anti-inflammatory pathways have recently been described. We therefore also compared changes in proinflammatory cytokine production in the two pain management groups. RESULTS: Continuous infusion of physostigmine combined with morphine-based PCA in the postoperative period significantly reduced opiate consumption, and enhanced the analgesic response. Patients in the physostigmine group also exhibited reduced ex-vivo production of the proinflammatory cytokine, IL-1beta. At the same time, physostigmine increased nausea and vomiting, mostly in the first 2 h of the postoperative period. CONCLUSIONS: Physostigmine combined with morphine in the postoperative period reduced morphine consumption, enhanced analgesia, and attenuated production of the proinflammatory cytokine, IL-1beta. This latter finding may account for the decreased pain observed in this group; this cytokine is known to mediate basal pain sensitivity and induce hyperalgesia in inflammatory conditions. Taking into account the other potential beneficial effects of physostigmine, we suggest that a continuous infusion of physostigmine should be considered as a useful component in multimodal postoperative analgesia.     

Potentiation of systemic morphine analgesia in humans by proglumide, a cholecystokinin antagonist

Proglumide, a cholecystokinin antagonist, potentiates analgesia produced in rats by morphine and endogenous opiates, and appears to reverse tolerance in rats to opiate analgesia. Therefore, proglumide and other cholecystokinin antagonists may be clinically valuable. We have tested proglumide's possible opiate analgesic potentiating effects by examining, in volunteers, the effects of morphine and proglumide on human pain visual analogue scale responses to 45-51 degrees C skin temperature stimuli. Proglumide (50-100 micrograms intravenously) potentiated both the magnitude and duration of analgesia produced by small doses of morphine. This study provides indirect evidence for a cholecystokinin-opiate interaction in humans. Therefore, cholecystokinin antagonists such as proglumide may serve to potentiate exogenous or endogenous opiate action.     

Lack of Analgesia by Oral Standardized Cannabis Extract on Acute Inflammatory Pain and Hyperalgesia in Volunteers

Background: Cannabinoid-induced analgesia was shown in animal studies of acute inflammatory and neuropathic pain. In humans, controlled clinical trials with [DELTA]9-tetrahydrocannabinol or other cannabinoids demonstrated analgesic efficacy in chronic pain syndromes, whereas the data in acute pain were less conclusive. Therefore, the aim of this study was to investigate the effects of oral cannabis extract in two different human models of acute inflammatory pain and hyperalgesia.

Methods: The authors conducted a double-blind, crossover study in 18 healthy female volunteers. Capsules containing [DELTA]9-tetrahydrocannabinol-standardized cannabis extract or active placebo were orally administered. A circular sunburn spot was induced at one upper leg. Heat and electrical pain thresholds were determined at the erythema, the area of secondary hyperalgesia, and the contralateral leg. Intradermal capsaicin-evoked pain and areas of flare and secondary hyperalgesia were measured. Primary outcome parameters were heat pain thresholds in the sunburn erythema and the capsaicin-evoked area of secondary hyperalgesia. Secondary measures were electrical pain thresholds, sunburn-induced secondary hyperalgesia, and capsaicin-induced pain.

Results: Cannabis extract did not affect heat pain thresholds in the sunburn model. Electrical thresholds (250 Hz) were significantly lower compared with baseline and placebo. In the capsaicin model, the area of secondary hyperalgesia, flare, and spontaneous pain were not altered.     

Cyclooxygenase-2 inhibition potentiates morphine antinociception at the spinal level in a postoperative pain model

BACKGROUND AND OBJECTIVES: After peripheral inflammatory stimuli, spinal cord cyclooyxgenase-2 (COX-2) mRNA and protein levels increase, whereas COX-1 is unchanged. In animal models of inflammatory pain, intrathecal COX-2 selective inhibitors suppress hyperalgesia. However, the role of spinal COX-2 inhibition in postoperative pain is not well elucidated. This study investigates whether a water-soluble COX-2 selective inhibitor, L-745337, can modify allodynic responses in a rat model of postoperative pain. METHODS: Allodynia was induced in the left plantar hindpaw by surgical incision. Animals then received intrathecal (0-80 micro g) or subcutaneous (0-30 mg/kg) L-745337 coadministered with intrathecal morphine (0-2 nmol). Reduction of mechanical allodynia (increased withdrawal threshold) was quantified with calibrated von Frey hairs. RESULTS: L-745337 alone, whether intrathecal or systemic, had no effect on withdrawal threshold. When intrathecal L-745337 at doses of 40 to 80 micro g was combined with a subthreshold dose (0.5 nmol) of morphine, withdrawal thresholds were increased in a dose-dependent manner. Adding 80 micro g L-745337 to 1 nmol morphine produced an antiallodynic effect greater than that of morphine at twice the dose. Subcutaneous L-745337, up to 30 mg/kg combined with intrathecal morphine resulted in the same antiallodynic response as morphine alone. CONCLUSION: These results suggest a spinal interaction of COX-2 inhibition with opiate analgesia may allow a reduction of postoperative pain with lower doses of opiate.     

Ketamine Improves the Management of Exaggerated Postoperative Pain Observed in Perioperative Fentanyl-treated Rats

Background: Although opioids are unsurpassed analgesics, experimental and clinical studies suggest that opioids activate N-methyl-d-aspartate pronociceptive systems leading to pain hypersensitivity and short-term tolerance. Because it is difficult in humans to differentiate pain from hyperalgesia during the postoperative period, the authors performed experimental studies with fentanyl using the rat incisional pain model for evaluating relations between hyperalgesia and short-term tolerance. Because N-methyl-d-aspartate receptor antagonists oppose both pain hypersensitivity and tolerance induced by opioids, the authors examined the capability of ketamine for improving exaggerated postoperative pain management.

Methods: During halothane anesthesia, a hind paw plantar incision was performed in rats receiving four fentanyl subcutaneous injections (100 [mu]g/kg per injection, every 15 min). In some groups, three subcutaneous ketamine injections (10 mg/kg per injection, every 5 h) were performed in saline- or fentanyl-treated rats. One day after surgery, the analgesic effect of morphine (2 mg/kg subcutaneous) was tested. Analgesia, mechanical hyperalgesia, tactile allodynia, and pain score were assessed for several days using the paw pressure vocalization test, the von Frey application test, and the postural disequilibrium test.

Results: Fentanyl induced analgesia but also produced exaggerated postoperative pain as indicated by the enhancement of hyperalgesia, allodynia, and weight-bearing decrease after hind paw plantar incision. Ketamine pretreatment prevented such a fentanyl-induced enhancement of postoperative pain and improved its management by morphine.