Analgesia produced by normal doses of opioid antagonists alone and in combination with morphine

In a recent study [30] it was reported that naloxone, at doses normally employed for opioid antagonism, produced a dose-dependent analgesia in BALB/c mice in the formalin test. We report here that another opioid antagonists, naltrexone, also produces analgesia under these conditions. Female BALB/c mice were injected subcutaneously with naltrexone (0.01-1.0 mg/kg) or saline alone and tested for analgesia using the formalin test. Naltrexone produced a statistically significant dose-dependent analgesia, with an ED50 of 0.05 mg/kg and almost total analgesia at doses of 0.1 mg/kg or greater. To determine the relationship between naloxone analgesia and better documented forms of opioid analgesia, BALB/c mice were injected with naloxone or saline following the administration of a pre-determined ED50 for morphine and tested for analgesia using the tail-flick and formalin tests. Naloxone antagonized morphine analgesia in the tail-flick test at both doses used (0.3 and 10 mg/kg). In the formalin test, however, naloxone attenuated morphine analgesia at the lower doses (0.1 and 0.3 mg/kg) and potentiated morphine analgesia at the highest dose (10 mg/kg). The implications of this finding are discussed.     

Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats.

Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence. This study investigated the site of action of the paradoxical effects of naltrexone and the generality of this effect. The potential of ultra-low doses of naltrexone to influence morphine-induced analgesia was investigated in tests of nociception. Administration of intrathecal (0.05 and 0.1 ng) or systemic (10 ng/kg i.p.) naltrexone augmented the antinociception produced by an acute submaximal dose of intrathecal (5 microg) or systemic (7.5 mg/kg i.p.) morphine in the tail-flick test. Chronic intrathecal (0.005 and 0.05 ng) or systemic (10 ng/kg) naltrexone combined with morphine (15 microg i.t.; 15 mg/kg i.p.) over a 7-day period inhibited the decline in morphine antinociception and prevented the loss of morphine potency. In animals rendered tolerant to intrathecal (15 microg) or systemic (15 mg/kg) morphine, administration of naltrexone (0.05 ng i.t.; 10 and 50 ng/kg i.p.) significantly restored the antinociceptive effect and potency of morphine. Thus, in ultra-low doses, naltrexone paradoxically enhances morphine analgesia and inhibits or reverses tolerance through a spinal action. The potential of naltrexone to influence morphine-induced reward was also investigated using a place preference paradigm. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference. These effects of naltrexone on morphine-induced reward may have implications for chronic treatment with agonist-antagonist combinations.     

Addition of ultralow dose naloxone to postoperative morphine PCA: unchanged analgesia and opioid requirement but decreased incidence of opioid side effects

Ultralow doses of naloxone (0.001-0.1 microg/kg) produce analgesia in animal models. However, no clinical study has evaluated the combination of ultralow dose naloxone and morphine using patient-controlled analgesia (PCA). This randomized, double blind controlled study sought to determine if the combination of ultralow dose naloxone and morphine in PCA solutions affects opioid requirements, analgesia, and side effects. Two-hundred and sixty-five patients (18-65 years old) undergoing operations were randomized to receive PCA morphine 1 mg/ml (n=129) or PCA morphine 1 mg/ml plus naloxone 0.6 microg/ml (n=136). We evaluated the numbers of supplemental rescue doses, the cumulative dose of each PCA solution, pain intensity, pain relief, and opioid side effects during the first 24 h after surgery. We found that opioid requirements did not differ significantly between groups. The morphine+naloxone group on average required 0.07 mg more morphine (95% CI -1.1 to 1.3) during the 24 h than the morphine group. Pain intensity levels were also similar in both groups. The morphine+naloxone group had 0.06 units lower (95% CI -0.5 to 0.4) pain intensity levels than the morphine group. The morphine+naloxone group had a lower incidence of nausea and pruritus than the morphine group (P=0.01 for both symptoms). However, the incidence of vomiting, time to tolerate fluids, sedation, and urinary retention were similar between groups (all P values >0.1). The combination of ultralow dose naloxone and morphine in PCA does not affect analgesia or opioid requirements, but it decreases the incidence of nausea and pruritus.     

Mu-opioid receptor up-regulation and functional supersensitivity are independent of antagonist efficacy

Chronic opioid antagonist treatment up-regulates opioid receptors and produces functional supersensitivity. Although opioid antagonists vary from neutral to inverse, the role of antagonist efficacy in mediating the chronic effects of opioid antagonists is not known. In this study, the effects of two putative inverse agonists (naltrexone, naloxone) and a putative neutral antagonist (6beta-naltrexol) were examined. Initially, peak effect (40 min, naltrexone and naloxone; 70 min, 6beta-naltrexol) and relative potency to antagonize morphine analgesia were determined (relative potencies = 1, 2, and 16, 6beta-naltrexol, naloxone, and naltrexone, respectively). Next, mice were infused for 7 days with naloxone (0.1-10 mg/kg/day), naltrexone (10 or 15 mg s.c. pellet), or 6beta-naltrexol (0.2-20 mg/kg/day), and spinal micro-opioid receptor density was examined, or morphine analgesia dose-response studies were conducted. All antagonists up-regulated mu-opioid receptors (60-122%) and induced supersensitivity (1.8-2.0-fold increase in morphine potency). There were no differences in antagonist potency to produce up-regulation or supersensitivity. These data suggest that opioid antagonist-induced mu-opioid receptor up-regulation and supersensitivity require occupancy of the receptor and that antagonist efficacy is not critical. Finally, the ED(50) to precipitate withdrawal jumping was examined in morphine-dependent mice. Naltrexone, naloxone, and 6beta-naltrexol produced withdrawal jumping, although potencies relative to 6beta-naltrexol were 211, 96, and 1, respectively. Thus, antagonist potency to precipitate opioid withdrawal was related to inverse agonist efficacy. Overall, the estimated relative potency of the opioid antagonists was a function of the outcome measured, and inverse agonist activity was not required for mu-opioid receptor up-regulation and supersensitivity.     

Comparison between intravenous morphine versus fentanyl in acute pain relief in drug abusers with acute limb traumatic injury

BACKGROUND: Rapid and effective pain relief in acute traumatic limb injuries (ATLI) is one of the most important roles of emergency physicians. In these situations, opioid addiction is an important concern because of the dependency on opioids. The study aims to compare the effectiveness of intravenous (IV) fentanyl versus morphine in reducing pain in patients with opioid addiction who suffered from ATLI. METHODS: In this double-blind randomized clinical trial, 307 patients with ATLI, who presented to the emergency department (ED) from February 2016 to April 2016, were randomly divided into two groups. One group (152 patients) received 0.1 mg/kg IV morphine. The other group (155 patients) received 1 mcg/kg IV fentanyl. Patients’ demographic data, pain score at specific intervals, vital signs, side effects, satisfaction and the need for rescue analgesia were recorded. RESULTS: Eight patients in the morphine group and five patients in the fentanyl group were excluded. Pain score in the fentanyl group had a significant decrease at 5-minute follow-up (P value=0.00). However, at 10, 30, and 60-minute follow-ups no significant differences were observed between the two groups in terms of pain score reduction. The rescue analgesia was required in 12 (7.7%) patients in the fentanyl group and in 48 (31.6%) patients in the morphine group (P value=0.00). No significant difference was observed regarding side effects, vital signs and patients’ satisfaction between the two groups. CONCLUSION: Fentanyl might be an effective and safe drug in opioid addicts suffering from ATLI.     

The combination of low dose of naloxone and morphine in PCA does not decrease opioid requirements in the postoperative period

The continuous infusion of low doses of naloxone has been reported to decrease postoperative opioid requirements and opioid side effects. However, there is no study that evaluates the effectiveness of the combination of a low dose of naloxone and morphine using patient-controlled analgesia (PCA). This prospective, randomized double-blind controlled study sought to determine if the combination of a low dose of naloxone and morphine in a PCA solution decreases postoperative opioid requirements and pain intensity. One hundred sixty-six patients (18-65 years old) undergoing operations of less than 3 h duration with an American Society of Anesthesiologist physical status I or II were randomized to receive PCA morphine 1 mg/cc plus normal saline or PCA morphine 1 mg/cc plus naloxone 6 microg/cc. Initial PCA settings were 0.5 cc per demand with a lockout time of 10 min. The numbers of 2.5 cc supplemental rescue doses and the cumulative dose of each solution were recorded in the first 24 h after the surgical procedure. Pain intensity and opioid side effects were evaluated every 10 min in the post-anesthesia care unit and every 4 h afterwards. Patient satisfaction was assessed at the end of the 24 h of observation. The morphine+naloxone group had more treatment failures (P=0.0001), higher opioid requirements (P=0.0097), greater pain intensity (P=0.04), less pain relief (P=0.004), and less satisfaction (P=0.01) than the morphine group. The incidence of side effects was similar in both groups (P=0.3). Contrary to previous reports, adding low doses of naloxone to a morphine PCA solution increases opioid requirements and pain.     

A subanalgesic dose of morphine eliminates nalbuphine anti-analgesia in postoperative pain.

The agonist-antagonist kappa-opioid nalbuphine administered for postoperative pain produces greater analgesia in females than in males. In fact, males administered nalbuphine (5 mg) experience pain greater than those receiving placebo, suggesting the existence of an anti-analgesic effect. These sexually dimorphic effects on postoperative pain can be eliminated by coadministration of a fixed ratio of the prototypical opioid receptor antagonist naloxone with nalbuphine, implying a role for opioid receptors in the anti-analgesic as well as analgesic effects of nalbuphine. In the present study, we further evaluated the role of opioid receptors in the sex-specific effects on pain produced by nalbuphine by coadministering a dose of morphine low enough that it does not produce analgesia. After extraction of bony impacted third molar teeth, nalbuphine (5 mg) was administered alone or in combination with either of 2 low doses of morphine (2 mg or 4 mg). Both doses of morphine reversed nalbuphine-induced anti-analgesia in males, but only the lower dose (2 mg) reached statistical significance. Neither dose affected nalbuphine-induced analgesia in females, and when administered alone in either males or females, morphine (2 mg) had no analgesic effect. Though not observed in females, the effect of morphine in males argues that, like naloxone, low-dose morphine may act as an anti-analgesia opioid receptor antagonist. PERSPECTIVE: Previously, we reported that the nalbuphine produces both analgesic and anti-analgesic effects and that the opioid antagonist naloxone can enhance nalbuphine analgesia by selectively antagonizing the anti-analgesic effect. Here we show that morphine, given in a subanalgesic dose, reverses nalbuphine-induced anti-analgesia in males, perhaps by a similar mechanism.     

NMDA receptor antagonist MK-801 blocks non-opioid stress-induced analgesia in the formalin test.

The analgesic effect of a 3-min swim stress was assessed using the formalin test. Male Swiss mice were injected i.p. with naloxone (0.1 or 1.0 mg/kg), MK-801 (0.075 mg/kg) or saline 15 min prior to swimming in water maintained at 20 degrees C or 32 degrees C. The mice were then injected with 20 microliters of 5% formalin into the plantar surface of 1 hind paw and pain behaviour (time spent licking the injected paw) was continuously monitored during the subsequent 10 min. Swim stress produced a significant reduction in pain behaviour at both 20 degrees C and 32 degrees C. MK-801 completely blocked the analgesia produced by both the 20 degrees C and 32 degrees C swim. At a dose of 0.1 mg/kg, naloxone partially antagonized the analgesia produced by the 32 degrees C swim but did not affect the analgesia produced by the 20 degrees C swim. Naloxone at a dose of 1.0 mg/kg had no effect on swim stress-induced analgesia. Neither MK-801 nor 0.1 mg/kg naloxone altered baseline pain behaviour, although 1.0 mg/kg naloxone did significantly reduce it. It is unlikely that the effect of MK-801 on swim stress-induced analgesia is due to an interaction with an opioid mechanism, as MK-801 had no effect on morphine analgesia. These results suggest that the analgesia produced by the 20 degrees C swim stress in the formalin test is non-opioid in nature and mediated via the NMDA receptor, whereas the 32 degrees C swim stress-induced analgesia has both an opioid and non-opioid component.     

The glycine/NMDA receptor antagonist (+)-HA966 enhances the peripheral effect of morphine in neuropathic rats

Systemic opioid dosing until adequate analgesia in neuropathic pain may involve intolerable and untreatable side effects. Peripheral opioid receptor mechanisms may participate in the antinociceptive effect of systemic morphine. We evaluated the effect of peripherally injected morphine alone, and the ability of the functional antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor complex (+)-HA966 to modulate the antinociceptive effect of peripheral morphine in a rat model of neuropathic pain. Mononeuropathy was induced by placing four ligatures around the common sciatic nerve. Experiments were performed 2 weeks after the nerve ligature, when the pain-related behavior reached a stable maximum. Rats received injections of either subcutaneous (+)-HA966 (2.5mg/kg) or saline administered 20 min before morphine (50-150 microg injected into the nerve-injured hindpaw). The antinociceptive effect was tested against mechanical (vocalization threshold to hindpaw pressure) or thermal (struggle latency to hindpaw immersion into a 46 degrees C hot water bath) stimuli. In both tests, morphine alone (100-150 microg) produced antinociception. Pretreatment with (+)-HA966 did not potentiate the analgesic effectiveness of the two highest doses of morphine, but it did produce analgesia when combined with a low dose of morphine (50 microg), which did not produce analgesia by itself. These effects were reversed by intraplantar naloxone methiodide (50 microg injected into the nerve-injured hindpaw) indicating a peripherally opioid-mediated mechanism of action. The present studies suggested that combined administration of glycine/NMDA receptor antagonists, and peripherally acting morphine may be an interesting approach in the treatment of neuropathic pain.     

Effects of N-methyl-D-aspartate receptor antagonists on acute morphine-induced and l-methadone-induced antinociception in mice.

Although N-methyl-D-aspartate (NMDA) receptor antagonists clearly attenuate the development of tolerance to the antinociceptive effects of opioids, it is not clear whether they also alter acute opioid-induced antinociception. The present study was designed to assess NMDA/opioid interactions in C57BL/6 mice by examining various NMDA receptor antagonists of different selectivity in combination with the mu opioid receptor agonists morphine and l-methadone. A mouse hot plate procedure was used to assess the effects of morphine (0.1 to 10.0 mg/kg) and l-methadone (0.1 to 5.6 mg/kg) alone and after pretreatment with the competitive NMDA receptor antagonist LY235959 (0.1 to 1.0 mg/kg), the glycine site NMDA receptor antagonist R(+)-HA-966 (10.0 to 56.0 mg/kg), or the polyamine site and NR2B selective NMDA receptor antagonist ifenprodil (3.2 to 10.0 mg/kg). Morphine and l-methadone produced dose- and time-dependent increases in 56 degrees C hot plate latencies. At the doses tested, the NMDA receptor antagonists produced no effect on hot plate latencies. However, when these drugs were combined with morphine, latency to respond to the hot plate was significantly increased from morphine alone. Combinations of the NMDA receptor antagonist LY235959 and l-methadone produced similar increases in hot plate latencies; however, combinations of l-methadone with R(+)-HA-966 or ifenprodil did not increase hot plate latencies compared with l-methadone alone. These results suggest that a range of NMDA receptor antagonists potentiate morphine-induced antinociception, although the potentiation of l-methadone might be specific to the antagonist examined. PERSPECTIVE: The inclusion of low-dose NMDA receptor antagonists to opioids might be beneficial for the treatment of acute pain by enhancing the antinociceptive effects of the opioid.     

Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability

Recent preclinical and clinical studies have demonstrated that cotreatments with extremely low doses of opioid receptor antagonists can markedly enhance the efficacy and specificity of morphine and related opioid analgesics. Our correlative studies of the cotreatment of nociceptive types of dorsal-root ganglion neurons in vitro and mice in vivo with morphine plus specific opioid receptor antagonists have shown that antagonism of Gs-coupled excitatory opioid receptor functions by cotreatment with ultra-low doses of clinically available opioid antagonists, e.g. naloxone and naltrexone, markedly enhances morphine's antinociceptive potency and simultaneously attenuates opioid tolerance and dependence. These preclinical studies in vitro and in vivo provide cellular mechanisms that can readily account for the unexpected enhancement of morphine's analgesic potency in recent clinical studies of post-surgical pain patients cotreated with morphine plus low doses of naloxone or nalmefene. The striking consistency of these multidisciplinary studies on nociceptive neurons in culture, behavioral assays on mice and clinical trials on post-surgical pain patients indicates that clinical treatment of pain can, indeed, be significantly improved by administering morphine or other conventional opioid analgesics together with appropriately low doses of an excitatory opioid receptor antagonist.     

Efficacy and safety profile of a single dose of hydromorphone compared with morphine in older adults with acute,severe pain: A prospective,randomized, double-blind clinical trial

Background: Older adults (ie, those aged ≥65 years) are the fastest growing segment of the US population, with an estimated ~71 million expected by 2030. Over the past 10 years, there has been an 11% increase in the number of emergency department (ED) visits by older adults, and pain is their most common chief complaint.Objective: The goal of this study was to compare weight-based IV hydromorphone and IV morphine in adults aged ≥65 years presenting to the ED with acute, severe pain.Methods: This was a prospective, randomized, double-blind clinical trial of older adults with acute, severe pain at an adult, urban academic ED. Patients were randomly allocated to receive a single dose of 0.0075-mg/kg IV hydromorphone or 0.05-mg/kg IV morphine. The primary outcome was the between-group difference in decrease in pain from baseline to 30 minutes after the medications were infused. Patients' degree of pain was measured on a numerical rating scale (NRS) where “0” was defined as “no pain” and “10” was defined as “the worst pain possible.” Adverse effects, pain reduction at 10 minutes and 2 hours postbaseline, patient evaluations of satisfaction and pain relief at 30 minutes postbaseline, and use of additional analgesics and antiemetics were tracked as secondary outcomes.Results: A total of 194 patients were randomized to treatment; 183 patients (hydromorphone group, n = 93; morphine group, n = 90 [overall mean (SD) age, 75 (8) years]) had sufficient data for analysis at the primary end point of 30 minutes postbaseline. The mean decrease in pain from baseline to 30 minutes in patients allocated to IV hydromorphone was 3.8 versus 3.3 NRS units in patients allocated to IV morphine. This difference of 0.5 NRS unit (95% CI, ?0.2 to 1.3) was neither clinically nor statistically significant. A majority of patients in both groups (57.0% randomized to hydromorphone and 58.9% randomized to morphine) failed to achieve a ≥50% reduction in pain within 30 minutes of treatment. The incidence of adverse effects from baseline to 30 minutes was not statistically different in the 2 groups.Conclusions: A single dose of IV hydromorphone at 0.0075 mg/kg was neither clinically nor statistically different from IV morphine at 0.05 mg/kg for the treatment of acute, severe pain at 30 minutes postbaseline in these older adults in the ED. The incidence of adverse effects was not statistically different. Our data suggest that hydromorphone and morphine in the doses given had similar efficacy and safety profiles in these older adults. Neither regimen provided ≥50% pain relief for the majority of patients. Future investigations of acute pain management in older adults should examine the efficacy and safety of higher initial (loading) doses of opioids titrated at frequent intervals until adequate analgesia is achieved.     

Pharmacological characterization of nalorphine, a kappa 3 analgesic.

Nalorphine is an unusual opiate. Whereas low doses of nalorphine antagonize morphine analgesia, higher nalorphine doses are analgesic, with ED50 values (95% CL) of 13.4 (11.5, 15.8) mg/kg in the writhing and 39.5 (26.6, 60.1) mg/kg in the tail-flick assay. Although nalorphine analgesia is sensitive to naloxone, implying an opioid mechanism, neither beta-funaltrexamine, naltrindole nor nor-binaltorphomine antagonized nalorphine analgesia in the tail-flick assay at doses which reversed equianalgesic doses of their respective selective agonists. Nalorphine and the kappa 3 opiate naloxone benzoylhydrazone demonstrated analgesic cross-tolerance regardless of whether the mice were treated chronically with either nalorphine or naloxone benzoylhydrazone. Animals tolerant to nalorphine were not tolerant to either morphine or U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(pyrrolindinyl)-cyclohexyl]- benzeneacetamide). Furthermore, nalorphine retained its analgesic potency in animals tolerant to U50,488H. Nalorphine exerts its analgesia predominantly through supraspinal mechanisms. Against systemically administered nalorphine, the opiate antagonist WIN44,441 ([2,6,11S-(-)-1-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6, 11-trimethyl-2,6-methano-e-benazocine-11-yl)-3-pentanone methylsulfonate) reversed nalorphine analgesia 1500-fold more potently when administered i.c.v. (ID50, 0.1 ng) than when given intrathecally (ID50,159 ng). Together these results indicate that nalorphine analgesia in the tail-flick assay does not involve mu, delta or the U50,488H-sensitive kappa 1 receptor and strongly suggest a role for supraspinal kappa 3 receptors.     

Intracerebroventricular physostigmine-induced analgesia: enhancement by naloxone, beta-funaltrexamine and nor-binaltorphimine and antagonism by dynorphin A (1-17)

The antinociceptive action (tail-flick test) of physostigmine given i.c.v. to mice was enhanced by the administration intrathecally (i.t.) of narcotic antagonists. Doses, i.t., as low as 0.1 fentog of naloxone, 0.25 ng of beta-funaltrexamine and 0.1 ng of nor-binaltorphimine enhanced physostigmine, 2 micrograms i.c.v., analgesia. These doses of opioid antagonists did not inhibit spinal mu receptors or kappa receptor agonist-induced analgesia as assessed by absence of effect on Tyr-D-Ala2-N-MePhe4-Gly-ol5 or U50,488H i.t. analgesia. Enhancing effects of the opioid antagonists were interpreted to indicate that i.c.v. physostigmine-induced analgesia was mediated spinally by an endogenous opioid which had an antagonistic effect. This putative opioid antagonist was postulated to be dynorphin A (1-17). Thus, i.t. administration of small doses of less than 10 pg of dynorphin was shown to antagonize the analgesic action of physostigmine, i.c.v. Furthermore, this effect of dynorphin was attenuated by the doses of naloxone, beta-funaltrexamine or nor-binaltorphimine which were effective in enhancing physostigmine-induced analgesia. We concluded that physostigmine given i.c.v. had two actions, the first produced analgesia and the second activated a system which had an antianalgesic effect. Evidence indicated that the latter effect was mediated by dynorphin A (1-17). This concept of dynorphin action may be the basis for some of the unusual findings of the analgesic action of naloxone in other situations and support the concept for a descending dynorphin A (1-17)-mediated antianalgesic system.     

Sublingual buprenorphine for acute renal colic pain management: a double-blind, randomized controlled trial

Background

The aim of this study was to compare the efficacy and safety of sublingual buprenorphine with intravenous morphine sulfate for acute renal colic in the emergency department.

Methods

In this double-dummy, randomized controlled trial, we enrolled patients aged 18 to 55 years who had a clinical diagnosis of acute renal colic. Patients received either 2 mg sublingual buprenorphine with an IV placebo, or 0.1 mg/kg IV morphine sulfate with a sublingual placebo. Subjects graded their pain with a standard 11-point numeric rating scale (NRS) before medication administration and 20 and 40 minutes after that. The need for rescue analgesia and occurrence of side effects were also recorded in the two groups.

Results

Of 69 patients analyzed, 37 had received buprenorphine, and 32 had taken morphine. Baseline characteristics were similar in both groups. NRS pain scores were reduced across time by administration of both buprenorphine (from 9.8 to 5.22 and then 2.30) and morphine (from 9.78 to 4.25 and then 1.8), significantly (P <0.0001). The two regimens did not differ significantly for pain reduction (P?=?0.260). Dizziness was more frequently reported by the buprenorphine group (62.1% versus 37.5%, P <0.05) but other adverse effects observed within 40 minutes were similar in the two groups.

Conclusions

Sublingual buprenorphine (2 mg) is as effective as morphine sulfate (0.1 mg/kg) in acute renal colic pain management.     

Is there an ideal morphine dose for prehospital treatment of severe acute pain? A randomized,double-blind comparison of 2 doses

Study objective

We aimed to determine the best intravenous morphine titration protocol by comparing 2 protocols for prehospital treatment of patients with severe acute pain.

Methods

Eligible patients with a numerical rating scale (NRS) score of 60/100 or higher were randomlyallocated to receive either 0.05 mg/kg morphine then 0.025 mg/kg every 5 minutes (group A) or 0.1 mg/kg morphine then 0.05 mg/kg every 5 minutes (group B) intravenously. The protocol-defined primary outcome measure was the percentage of patients with pain relief (with a NRS score of 30/100 or lower) 30 minutes after the first injection.

Results

A total of 106 consecutive patients were randomized. Thirty minutes after the injection, 66% of the patients in group A had an NRS of 30 or lower vs 76% of those in group B (P = .25). Ten minutes after the injection, 17% of the patients in group A had an NRS score of 30 or lower vs 40% of those in group B, (odds ratio, 3.4; 95% confidence interval, 1.3-8.8; P < .01). Patients in group B were significantly more satisfied with their analgesia. In addition, there were no serious complications in either group. However, patients in group B did experience almost twice the incidence of adverse effects overall and in particular 4times the level of emesis, although neither of these observations were statistically significant. Using univariate and multivariate analysis, only an initial NRS score of 100 was an independent predictive factor for failure of analgesia (odds ratio, 0.125; 95% confidence interval, 0.02-0.68; P < .05).

Conclusion

The high-dose morphine regimen showed a similar analgesic response pattern to the low-dose one in severe acute pain in a prehospital setting. Patients in the high-dose group were more likely to experience pain relief 10 minutes after the injection. In the interests of achieving rapid pain relief, an initial dose of 0.05 mg/kg should no longer be recommended for treating severe acute pain in a prehospital setting. Another important message arising from our study is that a regimented dose of morphine, with an initial dose and strictly administered lower doses at regular intervals, is safe in the prehospital setting.     

Interaction of mu-opioid receptor agonists and antagonists with the analgesic effect of buprenorphine in mice.

Buprenorphine is a potent opioid analgesic with partial agonistic properties at mu-opioid receptors. This study investigated the interaction potential with several full mu-agonists in the tail-flick test in mice. We further examined the reversibility of buprenorphine antinociception by different mu-opioid receptor antagonists. Combination of buprenorphine with morphine, oxycodone, hydromorphone and fentanyl in the analgesic dose range resulted in additive or synergistic effects. When given after the decline of the acute buprenorphine effect, both morphine and fentanyl also showed full efficacy. A moderate antagonistic effect according to the partial mu-agonistic properties of buprenorphine was only seen when high doses exceeding the therapeutic dose ranges were combined. Under these conditions antinociception of morphine was reduced to the effect of buprenorphine alone. Prophylactic administration of naloxone (10 mg/kg i.v.), naltrexone (1 mg/kg i.v.) and clocinnamox (5 mg/kg s.c.) fully and persistently blocked the antinociception of a high dose of buprenorphine. An established effect of buprenorphine was less sensitive, although repeated administration of naloxone induced complete antagonism, as did the irreversible antagonist clocinnamox under prophylactic and curative treatment conditions. Our results suggest that the antinociceptive effect of buprenorphine is mainly, if not exclusively, mediated by activation of mu-opioid receptors. They confirm clinical experience that in the analgesic dose range a switch between buprenorphine and full mu-agonists is possible without loss of analgesic efficacy and without a refractory period between the termination of buprenorphine analgesia and the onset of action of the new mu-opioid treatment. Antinociception of buprenorphine is sensitive towards mu-opioid receptor antagonists and incomplete inhibition can be improved by increasing the dose or repetitive dosing.     

极小剂量纳洛酮增强电针的镇痛作用但不影响电针对吗啡戒断症状的抑制作用

目的:纳洛酮(naloxone,NX)是一种阿片受体拮抗剂,应用于大鼠,在1～10mg/kg范围内能对抗吗啡镇痛和电针(electroacupuncture,EA)镇痛。但有人报道,极小剂量NX可加强吗啡镇痛。本工作观察极小剂量NX是否能加强大鼠电针镇痛,及电针对大鼠吗啡戒断的抑制作用。方法:选用成年雄性SD大鼠,分两批进行实验。第一批以辐射热甩尾阈(TFL)作为大鼠痛阈指标,检测腹腔注射(i.p.)NX10ng/kg对2Hz EA和100Hz EA镇痛效应的影响。第二批在慢性吗啡依赖大鼠模型上,以体重丢失作为吗啡戒断反应指标,观察i.p NX 10 ng/kg对 2Hz EA和 100Hz EA抑制 NX(lmg/kg,i.p.)诱发的体重丢失的影响。结果:(1)EA之前10分钟 i.p. NX 10 ng/kg,不仅能显著增强2Hz EA的镇痛作用(P<0.05),而且可使其镇痛效应延长至120分钟;同样剂量NX对100 Hz EA的镇痛效应无明显影响(P>0.05)。(2)EA之前10分钟i.p. NX 10 ng/kg,对两种频率EA抑制吗啡戒断大鼠体重丢失的效应均无显著影响。结论:极小剂量的NX能增强和延长2Hz EA的镇痛作用,该发现可能具有临床应用意义。极小剂量的NX未能影响EA抑制吗啡戒断大鼠体重丢失的作用,这可能与吗啡戒断状态下阿片受体的功能改变有关。     

Acute supersensitivity to the discriminative stimulus effects of naltrexone in pigeons

The ability of acute morphine injections to augment discriminative stimulus effects and rate-decreasing effects of opioid antagonists was examined in pigeons trained to discriminate among i.m. injections of morphine (5.6 mg/kg), saline and naltrexone (10.0 mg/kg). A single injection of 10.0 or 32.0 mg/kg of morphine 24 hr before naltrexone produced 3- and 10-fold decreases, respectively, in the dose of naltrexone required for complete generalization. When morphine (10.0-100.0 mg/kg) was administered 48 hr before naltrexone, pigeons were not more sensitive to naltrexone as a discriminative stimulus but continued to be more sensitive to the rate-decreasing effects of naltrexone. Conditions that produced the largest increase in sensitivity to the discriminative stimulus effects of naltrexone (32.0 mg/kg of morphine 24 hr before the session) also increased sensitivity to the discriminative stimulus effects and rate-decreasing effects of naloxone, but did not affect the discriminative stimulus effects of diprenorphine, nalorphine or morphine. Increases in sensitivity to the discriminative stimulus effects of naltrexone and naloxone after single injections of morphine approached in magnitude the increases reported previously in pigeons treated chronically (once/daily) with large doses of morphine. However, the lack of generalization to naltrexone after pretreatment with still larger doses of morphine, as well as the failure of nalorphine and diprenorphine to substitute for naltrexone as discriminative stimuli under conditions in which sensitivity to naltrexone was increased, support the view that naltrexone does not produce its discriminative stimulus effects in nondependent animals exclusively through an opioid antagonistic action. The results suggest that morphine induced, acute supersensitivity to the discriminative stimulus effects of naltrexone differs from the supersensitivity to antagonists observed during chronic morphine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral and preemptive opioid antinociception in a mouse visceral pain model

Recent studies suggest that opioids can produce analgesia through peripheral mechanisms following inflammation of peripheral tissue. This study examined whether opioids administered prior to inflammation can produce antinociception by peripheral mechanisms in a model of visceral pain. Mice were injected intraperitoneally (i.p.) with 1% acetic acid to evoke abdominal writhing, a standard model of visceral pain. The number of writhes that occurred during 30 min after acetic acid were determined. Intraperitoneal injection of morphine sulfate (60, 90, 100 or 120 microg/0.3 ml) or the peripherally acting opioid loperamide (0.12, 0.36, 1.2 or 3.6 mg/0.3 ml) given 5 min after acetic acid decreased writhing in a dose-dependent fashion. Morphine (100 microg) produced an 70% attenuation in the number of writhes while loperamide (1.2 mg) decreased writhing by 56%. These antinociceptive effects were blocked by pretreatment with the opioid receptor antagonists naloxone (10 mg/kg) and its quarternary version naloxone methiodide (10 mg/kg). To determine whether opioids produced preemptive antinociception via peripheral mechanisms, mice received i.p. injections of morphine (1, 5, and 10 microg/0.3 ml) or vehicle 5 min before acetic acid. Doses of 5 and 10 microg morphine inhibited the number of writhes by 51 and 93%, respectively. The highest dose (10 microg) was ineffective when given intravenously 5 min before acetic acid, suggesting that antinociception following i.p. administration was acting via peripheral mechanisms. These data demonstrate that low doses of opioids, given before or after acetic acid, produce visceral antinociception through peripheral mechanisms. This may be clinically relevant for the management of postoperative abdominal pain.