Antinociceptive Effects Of Fentanyl Research Articles

24. Divalent Vaccination to Protect Against the Cardiopulmonary and Antinociceptive Effects of Fentanyl, Oxycodone, and Their Mixture in Male Rats

24. Divalent Vaccination to Protect Against the Cardiopulmonary and Antinociceptive Effects of Fentanyl, Oxycodone, and Their Mixture in Male Rats

Pre-treatment with Tandospirone attenuates fentanyl-induced respiratory depression without affecting the analgesic effects of fentanyl in rodents

Opioid analgesics are widely used to treat acute, postoperative, and chronic pain. However, opioid receptor activation can result in severe respiratory depression. In this study, we demonstrated that Tandospirone (TS), a selective serotonin-1A receptor partial agonist, is effective against opioid-induced respiratory depression. Fentanyl was used to establish a respiratory depression model in rodents. We observed the effects of TS on respiratory depression in rats by using plethysmographic recordings and arterial oxygen saturation. In addition, we evaluated the effects of TS on fentanyl-induced sedation and analgesia by using the loss of righting reflex (LORR) and hot-plate tests, respectively. Rats (n = 5) were treated with TS or saline 5 min prior to fentanyl administration. TS [2 mg/kg, intravenous (i.v.)] dose-dependently attenuated fentanyl-induced respiratory depression versus saline + fentanyl group. Furthermore, pre-treatment with TS (2 mg/kg, i.v.) increased arterial oxygen saturation to 76.5 ± 2.0% at 5 min after fentanyl injection, compared with 35.9 ± 2.5% in saline pre-treated rats (P < 0.001), whereas the time to induction of LORR (P > 0.99) and duration of LORR (P = 0.95) did not differ between the “TS + fentanyl” and “saline + fentanyl” group. The antinociceptive effect of fentanyl was not affected by the administration of TS (P = 0.99) in mice (n = 10). In conclusion, we found that TS, a novel non-benzodiazepine anxiolytic/antidepressant drug, could attenuate severe fentanyl-induced respiratory depression and did not affect the analgesic/sedative effect of fentanyl. The clinical application of TS could significantly improve pain management.

Receptor Mechanisms in Nicotinic Enhancement of Opioid Antinociception

The use of prescription opioids for pain management can be limited by their adverse behavioral effects, which usually are not measured in the initial preclinical assessment of established or novel candidate analgesics. Recently, we have developed a protocol for concurrently assessing the antinociceptive effects of drugs (an indicator of analgesic promise) and their ability to decrease rates of operant behavior (an indicator of unwanted behavioral effects). Under these procedures, nicotine has been shown to augment the antinociceptive, but not the rate‐decreasing, effects of opioid analgesics with an inverse relationship to efficacy at the m‐opioid receptor‐ e.g., nicotine‐induced enhancement of nalbuphine&gt;oxycodone&gt;fentanyl. The present study was designed to further elucidate nicotinic‐opioid interactions by exploring the role of nicotinic receptor efficacy in the nicotinic augmentation of opioid antinociception. Male squirrel monkeys (n=4) lever‐pressed under a fixed ratio (FR) 10 schedule of 20% (v/v) condensed milk reinforcement. A 30‐s timeout (TO) period followed either the completion of the FR 10 or the elapse of 20‐s (limited hold (LH) 20). During the 30‐s TO, the distal portion of the monkey’s tail was immersed in 35, 50, 52, or 55°C water, and the latency to remove the tail was recorded. Dose response functions for tail‐withdrawal latency and decreases in response rate were generated for the high efficacy m‐opioid agonist fentanyl and the low efficacy m‐agonist nalbuphine alone and in the presence of nicotinic agonists reported to have high or intermediate efficacy‐‐epibatidine (0.00056 mg/kg) or varenicline (0.032 mg/kg), respectively. Fentanyl dose‐dependently increased tail‐withdrawal latencies at all water temperatures and, concomitantly, decreased rates of responding. Nalbuphine did not significantly decrease response rate, and increased tail‐withdrawal latencies at 50 and 52°C, but not at 55°C. Neither epibatidine nor varenicline significantly modified the rate decreasing effects of any of the opioids or the antinociceptive effects of fentanyl. However, the antinociceptive potency of nalbuphine was markedly enhanced by epibatidine (up to ~70‐fold) and only slightly increased by varenicline. The present results add to previous findings with nicotine, showing that nicotinic enhancement of opioid antinociception is inversely related to m‐opioid efficacy. They also extend those findings to suggest that such adjuvant effects are more robustly produced by nicotinic full agonists (nicotine, epibatidine) than a partial agonist (varenicline). In conjunction with previous reports, these findings support the idea that nicotinic agonists may be clinically useful as adjuvants for opioid analgesia.Support or Funding InformationDA035857 and Harvard Medical School Livingston Fellowship

The Effect of Benfotiamine on Mu-opioid Receptor Mediated Antinociception in Experimental Diabetes

Diabetic neuropathy is a prevalent, disabling disorder. Currently, the only treatments available to patients with diabetic neuropathy are glucose control and pain management. B vitamin present neuroprotective effects, which are suggested to be related to their analgesic action in various models of neuropathic pain. According to our literature knowledge there is no report about antinociceptive effects of thiamine as benfotiamine and opioids together in diabetic mice. The purpose of this study was to determine the effects of benfotiamine on the antinociception produced by mu-opioid receptor agonist fentanyl in diabetic mice. The effects of benfotiamine on antinociception produced by fentanyl in diabetic mice were studied in 4 groups. Antinociceptive effect was determined with tail flick, hot plate and formalin test. Our results showed that, mu-opioid agonist fentanyl in benfotiamine applied diabetic group caused more potent antinociceptive effect than in diabetic group without benfotiamine treatment. In brief benfotiamine supplement in diet did not bring out antinociceptive effect itself, but during development of STZ diabetes, benfotiamine replacement increased the antinociceptive effect of fentanyl in mice tail-flick test. This effect is probably due to the replacement of benfotiamine efficiency occurring in diabetes mellitus. Finally, we suppose that oral benfotiamine replacement therapy may be useful to ameliorate analgesic effect of mu-opioid agonists on neuropathic pain in diabetic case.

Differential alternation of the antinociceptive effect of narcotic analgesics on the inflammatory pain state

Antinociceptive effect of narcotic analgesics, fentanyl, oxycodone and methadone in inflammatory pain state was described in the von Frey filament test using the complete Freund's adjuvant (CFA)-induced mouse inflammatory pain model. After the i.pl. injection of CFA, mechanical allodynia (decrease of mechanical threshold) was observed in ipsilateral paw. The antinociceptive effect of fentanyl and oxycodone injected s.c. against mechanical allodynia in inflammatory pain state was reduced bilaterally at 1 day after CFA pretreatment. However, the antinociceptive effect of methadone injected s.c. against mechanical allodynia in inflammatory pain state was reduced unilaterally at 1 day after CFA pretreatment. Moreover, the reduction of the antinociceptive effect of methadone in ipsilateral paw on inflammatory pain state was smaller than those of fentanyl or oxycodone. In conclusion, the alternation of the antinociceptive effect of narcotic analgesics in inflammatory pain state is variable among the narcotic analgesics used.

Opioid chronopharmacology: influence of timing of infusion on fentanyl&amp;rsquo;s analgesic efficacy in healthy human volunteers

Chronopharmacology studies the effect of the timing of drug administration on drug effect. Here, we measured the influence of 4 timing moments on fentanyl-induced antinociception in healthy volunteers. Eight subjects received 2.1 μg/kg intravenous fentanyl at 2 pm and 2 am, with at least 2 weeks between occasions, and 8 others at 8 am and 8 pm. Heat pain measurements using a thermode placed on the skin were taken at regular intervals for 3 hours, and verbal analog scores (VAS) were then obtained. The data were modeled with a sinusoid function using the statistical package NONMEM. The study was registered at trialregister.nl under number NTR1254. A significant circadian sinusoidal rhythm in the antinociceptive effect of fentanyl was observed. Variations were observed for peak analgesic effect, duration of effect, and the occurrence of hyperalgesia. A peak in pain relief occurred late in the afternoon (5:30 pm) and a trough in the early morning hours (5:30 am). The difference between the peak and trough in pain relief corresponds to a difference in VAS of 1.3–2 cm. Only when given at 2 am, did fentanyl cause a small but significant period of hyperalgesia following analgesia. No significant changes were observed for baseline pain, sedation, or the increase in end-tidal CO2. The variations in fentanyl’s antinociceptive behavior are well explained by a chronopharmacodynamic effect originating at the circadian clock in the hypothalamus. This may be a direct effect through shared pathways of the circadian and opioid systems or an indirect effect via diurnal variations in hormones or endogenous opioid peptides that rhythmically change the pain response and/or analgesic response to fentanyl.

Magnesium modifies fentanyl-induced local antinociception and hyperalgesia

Fentanyl-induced hyperalgesia and antinociception after systemic administration has been shown in previous clinical and experimental studies. However, there is very little evidence regarding the local possible effects of fentanyl. The purpose of this study was to assess whether local (intraplantar) fentanyl administration can produce antinociception and hyperalgesia. In addition, we examined the effects of magnesium, N-methyl-D-aspartate receptor antagonist, on possible changes produced by fentanyl. The paw withdrawal latencies to radiant heat stimuli were measured to assess the thermal nociceptive actions. Intraplantar administration of fentanyl caused time and dose-dependent increase in the paw withdrawal latencies (antinociception). Coinjection of magnesium with fentanyl markedly enhanced the antinociception. However, fentanyl also markedly decreased paw withdrawal latencies 24 h after intraplantar administration (hyperalgesia). In the presence of magnesium, hyperalgesia after fentanyl administration was not observed. Consequently, following the fentanyl administration, local hyperalgesia after antinociception is a negative effect in pain treatment. Magnesium may not only prevent the hyperalgesia but also enhance antinociceptive effect of fentanyl.

The analgesic efficacy of partial opioid agonists is increased in mice with targeted inactivation of the α 2A-adrenoceptor gene

α 2A-Adrenoceptors mediate the antinociceptive effects of α 2-adrenoceptor agonists in mice, and analgesic synergism between noradrenergic and opioidergic mechanisms has been reported to be lacking in mice devoid of functional α 2A-adrenoceptors. We investigated whether the antinociceptive actions of opioid agonists with different efficacy would be altered in mice with targeted inactivation of the α 2A-adrenoceptor gene (α 2A-KO mice). The antinociceptive effects of fentanyl, morphine, buprenorphine and tramadol were assessed using conventional tail-flick and hot-plate assays. Antinociceptive responses to fentanyl were unaltered in the α 2A-KO animals. Morphine analgesia was slightly accentuated in the tail-flick test. The naloxone-sensitive antinociceptive responses to both tested weak partial agonists were very markedly accentuated in both tests. For example, after 40 mg/kg tramadol administration, the tramadol-induced prolongation of tail-flick latency was 86 ± 6% of the maximal possible effect (MPE) in α 2A-KO and 22 ± 2% of MPE in control mice; prolongation of hot-plate latency was 93 ± 5% of MPE in α 2A-KO mice and 8 ± 2% of MPE in the controls ( P < 0.001 for both). The effects of α 2A-KO were mimicked by pretreatment of wild-type control mice with the α 2-adrenoceptor antagonists, atipamezole and yohimbine; the apparent efficacy of tramadol and buprenorphine now approached that of morphine and fentanyl. Other behavioural effects of the tested opioid agonists were not similarly influenced by α 2A-KO. Antagonists of α 2A-adrenoceptors may offer a novel mechanism to augment the antinociceptive actions of partial opioid agonists.

Low doses of nitroparacetamol or dexketoprofen trometamol enhance fentanyl antinociceptive activity

We have reported that subeffective doses of the nonsteroidal anti-inflammatory drug (NSAID) dexketoprofen trometamol enhances μ-opioid receptor agonist fentanyl antinociception. The aim of this study was to assess if this effect can also be observed with other new cyclooxygenase-inhibitors such as nitroparacetamol, and in responses to high intensity electrical stimulation (wind-up). Single motor units were recorded in male Wistar rats under α-chloralose anaesthesia. The antinociceptive effect of fentanyl was studied alone and in the presence of subeffective doses of dexketoprofen trometamol or nitroparacetamol. In responses to noxious mechanical stimulation, the potency of fentanyl was enhanced by more than threefold in the presence of the NSAIDs and no significant recovery was observed after 45 min. The opioid antagonist naloxone and the α 2-adrenoceptor antagonist atipamezol did not reverse the effect. The enhancement of the effect of fentanyl in wind-up was lower though significant. We conclude that the co-administration of subeffective doses of new cyclooxygenase-inhibitors and the μ-opioid receptor agonist fentanyl should be considered as a potential pain therapy.

Prevention of fentanyl-induced delayed pronociceptive effects in mice lacking the protein kinase Cγ gene

It has recently been reported in several nociceptive models of rats that the antinociceptive effect of fentanyl, an opioid analgesic widely used in the management of per-operative pain, was followed by paradoxical delayed hyperalgesia dependent on N-methyl-D-aspartate (NMDA) mechanisms. Events upstream of the NMDA receptor, especially the activation of the protein kinase Cγ (PKCγ), have been involved in the persistence of pain states associated with central sensitisation. In order to evaluate the contribution of the PKCγ in early and delayed fentanyl nociceptive responses, we studied these effects in knock-out mice deficient in such a protein. We found that fentanyl antinociception was followed by the spontaneous appearance of prolonged hyperalgesia in the paw pressure and formalin tests, and allodynia in the Von Frey paradigm. In PKCγ deficient mice, an enhancement of the early fentanyl antinociceptive effects was observed, as well as a complete prevention of the fentanyl delayed hyperalgesic/allodynic effects. Finally, naloxone administration in mice that had recovered their pre-fentanyl nociceptive threshold, precipitated hyperalgesia/allodynia in wild-type but not in mutant mice. This study identifies the PKCγ as a key element that links opioid receptor activation with the recruitment of opposite systems to opioid analgesia involved in a physiological compensatory pain enhancement.

Prolonged Analgesia After Epidural Injection of a Poorly Soluble Salt of Fentanyl

Epidurally administered fentanyl is commonly used in postoperative pain management. The onset of action is rapid, but the duration of analgesia is short. In this study we examined the hypothesis that a poorly soluble salt of fentanyl (fentanyl pamoate) would create a depot of the drug in the epidural space and thus provide prolonged analgesia. The dose-response relationship and duration of analgesic action of epidural fentanyl citrate (FC) and fentanyl pamoate (FP) were studied in white male Sprague-Dawley rats. Somatic and visceral nociceptive stimulation (tail flick and colorectal distension, respectively) were used to test the analgesic effects of the drugs. The calculated dose producing 100% of the maximum possible effect (100% MPE) for FP was 31 micrograms toward somatic and 33 micrograms toward visceral noxious stimulation, and for FC it was 3 micrograms toward both stimulations. The antinociceptive effects were similar, with 31 micrograms of FP and 3 micrograms of FC. The areas under the time-response curves (AUC) were significantly higher with FP than with FC when high doses (5 micrograms of FC or 50 micrograms of FP) were used, but with doses expected to produce 100% MPE, differences between the study drugs were not observed in the duration of analgesia. We conclude that the duration of antinociceptive effect of fentanyl can be prolonged when administered as a poorly soluble salt.

Synergism between the antinociceptive effects of intrathecal midazolam and fentanyl on both A δ and C somatosympathetic reflexes

The interaction between the antinociceptive effects of fentanyl and midazolam, administered intrathecally (i.t.), was examined in dogs. Midazolam 1 mg (i.t.) depressed the A δ and C fibre mediated somatosympathetic reflexes to 68.3 and 85.2% of control values and then reduced the subsequent doses of fentanyl (i.t.) required to abolish these reflexes by 50%. After midazolam (1 mg, i.t.) the ED 25,50,75 values for fentanyl were markedly less than the theoretical predicted additive values. This indicates synergism between the effects of fentanyl and midazolam.