Guy Simonnet

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

Background It has been reported that &mgr;-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 &mgr;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. Conclusions Fentanyl activates NMDA pain facilitatory processes, which oppose analgesia and lead to long-lasting enhancement in pain sensitivity.

Opioid-induced hyperalgesia

INTRODUCTION It is well recognized that opioids are the analgesics of choice for the treatment of moderate to severe pain. However, a large number of clinical studies have reported that opioids can unexpectedly elicit hyperalgesia (enhanced responses to noxious stimulation) and allodynia (pain elicited by normal innocuous stimuli) [1–8]. Opioid-induced hyperalgesia has also been reported in animal experimental models [9–17]. This pain hypersensitivity has been classified as abnormal pain [16,18] as opposed to physiological (or normal) pain associated with nociception. Physiological pain has an important function in the preservation of an organism since it is an essential warning device that alerts the organism of impending danger from actual or potentially injurious stimuli in the environment. Does this suggest that there are good and bad pains, i.e. normal or abnormal pain? From a clinical viewpoint, the response is probably yes, if pain is only considered as a simple sensory system. However, pain is also a motivational process inducing a coordinated set of behavioral changes that serves to remember danger, some behaviors being facilitated and others inhibited. In this respect, pain sensitivity may be the result of a balance between the activity of inhibitory (antinociceptive) and facilitatory (pronociceptive) circuitries within the CNS with regard to the environmental state. If the main function of antinociceptive systems is to reduce pain during threatening situations as pain may compromise defensive behavior, it has been argued [19] that the function of pronociceptive systems might be that of motivating recuperative behaviors that would be adaptive for maintaining preservation of the organism when signals for safety succeed to threats. From an adaptive viewpoint, one hypothesis is that a pain hypersensitivity state is a normal step following defensive analgesia associated with the recruitment of endogenous antinociceptive systems. Since it is unlikely that evolution has selected mechanisms that are only activated by endogenous antinociceptive systems such as opioid systems, it might be suggested that delayed hyperalgesia following the use of exogenous opioids is a normal rather than an abnormal pain. In this review, we will first examine experimental evidences which indicate that exogenous opioids simultaneously activate both inhibitory and facilitatory pain systems leading to a long-lasting enhancement in pain sensitivity after analgesia. Second, we will assess the possible role of such an enhancement in pain sensitivity in the development of both tolerance to the analgesic effect of opioids and pain chronicisation processes.

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 × 20, 4 × 60, 4 × 100 &mgr;g/kg of fentanyl, respectively). Ketamine pretreatment (10 mg/kg) increased the fentanyl analgesic effect (4 × 60 &mgr;g/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.

Acute tolerance associated with a single opiate administration: involvement of N-methyl-D-aspartate-dependent pain facilitatory systems.

Mechanisms underlying the development of acute tolerance to the analgesic effect of opiates were investigated. In the rat tail-flick test, administration of naloxone (1 mg/kg, s.c.) 40 min after heroin (1 mg/kg, s.c.) was shown to induce hyperalgesia, indicative of a short-onset, opiate-activated pain facilitatory systems masking the opiate analgesia. Pretreatment with the N-methyl-D-aspartate receptor antagonist dizocilpine maleate blocked, in a dose-dependent manner, the naloxone-induced hyperalgesia and potentiated the heroin-induced analgesia. Using a schedule of two successive injections of 1 mg/kg heroin, acute tolerance was indicated by a marked reduction (-52%) in analgesia induced by the second dose. After pretreatment with dizocilpine maleate, the acute tolerance was abolished and the analgesic effects of both injections of heroin were strongly potentiated. These observations indicate that acute tolerance appears after the first exposure to opiates and stems from opiate activation of N-methyl-D-aspartate-dependent pain facilitatory systems.

Evidence for opiate-activated NMDA processes masking opiate analgesia in rats.

The acute interaction between opioid receptors and N-methyl-D-aspartate (NMDA) receptors on nociception was examined in rats using tail-flick and paw-pressure vocalisation tests. When injected at various times (1 to 6 h) after morphine (5 to 20 mg/kg, i.v.) or fentanyl (4x40 microgram/kg, i.v.), the opioid receptor antagonist naloxone (1 mg/kg, s.c.) not only abolished the opiate-induced increase in nociceptive threshold, but also reduced it below the basal value (hyperalgesia). The noncompetitive NMDA receptor antagonist MK-801 (0.15 or 0.30 mg/kg, s.c.) prevented the naloxone-precipitated hyperalgesia and enhanced the antinociceptive effects of morphine (7.5 mg/kg, i.v.) and fentanyl (4x40 microgram/kg, i.v.). These results indicate that the antinociceptive effects of morphine and fentanyl, two opiate analgesics widely used in humans in the management of pain, are blunted by concomitant NMDA-dependent opposing effects which are only revealed when the predominant antinociceptive effect is sharply blocked by naloxone. This study provides new rationale for beneficial adjunction of NMDA receptor antagonists with opiates for relieving pain by preventing pain facilitatory processes triggered by opiate treatment per se.

Opiate tolerance to daily heroin administration : An apparent phenomenon associated with enhanced pain sensitivity

From a classical viewpoint, tolerance to analgesic effects of opiates refers to the decreased effectiveness of a given opiate following its repeated use. Despite much research, it has not been conclusively demonstrated in vivo that functional changes observed at the opioid receptor level in the responsiveness to opiates account for development of tolerance. An alternative hypothesis is that opioid receptors remain operative following repeated opiate administration but that opioid receptor activation rapidly induces a prolonged increase in pain sensitivity which opposes the predominant opiate analgesic effect following repeated opiate administration. We recently showed that a single heroin administration induces an enhanced pain sensitivity for several days, a phenomenon which is prevented by the non-competitive N-methyl-D aspartate receptor antagonist MK-801. Herein we report that repeated once-daily heroin injections induced a gradual lowering of the nociceptive threshold which progressively masked a sustained heroin analgesic functional effect. MK-801 prevented such opiate-induced allodynia and thereby prevented development of an apparent decrease in the effectiveness of heroin. These results indicate that intermittent heroin administration induced a persistent increase in the basal pain sensitivity which, if not taken into account gives the impression of less analgesia, i.e. apparent tolerance.

Characterization of rat spinal cord receptors to FLFQPQRFamide, a mammalian morphine modulating peptide: a binding study

An in vitro binding assay, using 125I-YLFQPQRFamide, a newly synthetized iodinated analog of FLFQPQRFamide, in which Phe1 (F) has been substituted by a Tyr (Y), was developed to demonstrate and characterize putative binding sites of this brain morphine modulating peptide. This radioligand bound in a time-dependent manner to rat spinal cord membrane preparation. This binding was dose-dependent, saturable and reversible. Both kinetic data and saturation measured at equilibrium lead to the existence of a homogenous population of high affinity binding sites with a Kd value of 0.09-0.1 nM and a maximal capacity Bmax of 14.5 +/- 2 fmol/mg protein. Results of competition experiments show that both FLFQPQRFamide and its analog YLFQPQRFamide had a similar capacity to inhibit the 125I-YLFQPQRFamide binding, suggesting that this radioiodinated analog is a good tool to study binding characteristics of FLFQPQRFamide receptors. The related octadecapeptide AGEGLSSPFWSLAAPQRFamide, another mammalian morphine modulating peptide competes for radioligand binding with similar potency. Our results also show that mu, delta and kappa opiate receptor agonists as well as the antagonist naloxone were not able to affect binding either in presence or in absence of 120 mM NaCl. Together, these data demonstrate that FLFQPQRFamide does not function as an endogenous opiate receptor antagonist and that is capacity to reduce opiate-induced analgesia is supported by specific binding sites.

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 &mgr;g/kg each given four times at 15-min intervals [4 × 60 or 4 ×100]) 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 × 60 &mgr;g/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 × 60 or 4 × 100 &mgr;g/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.

Supplementing Desflurane-remifentanil Anesthesia with Small-dose Ketamine Reduces Perioperative Opioid Analgesic Requirements

Relative large-dose intraoperative remifentanil could lead to the need for more postoperative analgesics. Intraoperative N-methyl-d-aspartate receptor antagonists, such as ketamine, decrease postoperative opioid use. We therefore tested the hypothesis that intraoperative small-dose ketamine improves postoperative analgesia after major abdominal surgery with remifentanil-based anesthesia. Fifty patients undergoing abdominal surgery under remifentanil-based anesthesia were randomly assigned to intraoperative ketamine or saline (control) supplementation. The initial ketamine dose of 0.15 mg/kg was followed by 2 &mgr;g · kg−1 · min−1. In both groups, desflurane was kept constant at 0.5 minimum alveolar anesthetic concentration without N2O, and a remifentanil infusion was titrated to autonomic responses. All patients were given 0.15 mg/kg of morphine 30 min before the end of surgery. Pain scores and morphine consumption were recorded for 24 postoperative h. Less of the remifentanil was required in the Ketamine than in the Control group (P < 0.01). Pain scores were significantly larger in the Control group during the first 15 postoperative min but were subsequently similar in the two groups. The Ketamine patients required postoperative morphine later (P < 0.01) and received less morphine during the first 24 postoperative h: 46 mg (interquartile range, 34–58 mg) versus 69 mg (interquartile range, 41–87 mg, P < 0.01). No psychotomimetic symptoms were noted in either group. In conclusion, supplementing remifentanil-based anesthesia with small-dose ketamine decreases intraoperative remifentanil use and postoperative morphine consumption without increasing the incidence of side effects. Thus, intraoperative small-dose ketamine may be a useful adjuvant to intraoperative remifentanil.

Long‐lasting increased pain sensitivity in rat following exposure to heroin for the first time

Acute dependence, defined as a precipitation of somatic signs by an antagonist, may occur after a single administration of an opiate drug. Because hyperalgesia is a consistent sign of the withdrawal syndrome, we tested the effectiveness of heroin, an opiate used by addicts, to induce pain facilitation even after a first exposure to the drug. In opiate‐naive rats, subcutaneous injection of heroin induced analgesia followed by allodynia, a decrease in pain threshold. This latter phenomenon was observed in the absence of noxious stimuli and lasted several days. An N‐methyl‐d‐aspartate (NMDA) receptor antagonist, MK‐801 prevented such long‐lasting allodynia. These results suggest that allodynia is an early sign reflecting neural plasticity associated with the development of dependence.