Low Doses Of Naloxone Research Articles

Effect of Low-Dose Naloxone Infusion on Fentanyl Requirements in Critically Ill Children

Sedating critically ill patients often involves prolonged opioid infusions causing opioid tolerance. Naloxone has been hypothesized to limit opioid tolerance by decreasing adenylate cyclase/cyclic adenosine monophosphate activation. The study purpose was to investigate the effect of low-dose naloxone on the maximum cumulative daily fentanyl dose in critically ill children. We conducted a double-blinded, randomized, placebo-control trial from December 2002 through July 2004 in a university PICU. We enrolled 82 children age 1 day to 18 years requiring mechanical ventilation and fentanyl infusions anticipated to last for >4 days were eligible for enrollment. Those receiving additional oral analgesia or sedation, having a history of drug dependence or withdrawal, or having significant neurologic, renal, or hepatic disease were excluded. In addition to fentanyl infusions, patients received low-dose naloxone or placebo infusions. Medications were adjusted using the Modified Motor Activity Assessment Scale. Withdrawal was monitored using the Modified Narcotic Withdrawal Scale. Intervention was a low-dose naloxone infusion (0.25 microg/kg per hour) and the main outcome variable was the maximum cumulative daily fentanyl dose (micrograms per kilogram per day). There was no difference in the maximum cumulative daily fentanyl dose between patients treated with naloxone (N = 37) or those receiving placebo (N = 35). Adjustment for the starting fentanyl dose also failed to reveal group differences. Total fentanyl dose received throughout the study in the naloxone group (360 microg/kg) versus placebo (223 microg/kg) was not statistically different. Placebo patients trended toward fewer rescue midazolam boluses (10.7 vs 17.8), lower total midazolam dose (11.6 mg/kg vs 23.9 mg/kg), and fewer rescue fentanyl boluses (18.5 vs 23.9). We conclude that administration of low-dose naloxone (0.25 microg/kg per hour) does not decrease fentanyl requirements in critically ill, mechanically ventilated children.

(213) Low-dose intrathecal naloxone to enhance intrathecal morphine analgesia in the treatment of refractory severe chronic low back pain

(213) Low-dose intrathecal naloxone to enhance intrathecal morphine analgesia in the treatment of refractory severe chronic low back pain

A Study of Naloxone Effect on Urinary Retention in the Patient Receiving Morphine Patient-Controlled Analgesia

The purpose of the study was to compare urinary retention rates following orthopaedic surgery in patients who received low-dose intravenous naloxone while receiving morphine patient-controlled analgesia with patients who did not receive naloxone. Randomized controlled trial without blinding. There were 97 participants consenting to the study, 45 were randomly assigned to a control group and 52 assigned to an experimental group. Forty-three patients in the control group and 47 in the experimental group (90 total) completed the study protocol. Postoperative urinary residuals were lower, patients voided more frequently, and fewer catheterizations were needed when given low-dose naloxone while receiving morphine patient-controlled analgesia. At the same time, naloxone in small doses was found to have negligible effect on overall patient pain control.

Effects of low-dose naloxone on opioid therapy in pediatric patients: a retrospective case-control study

To develop novel therapies that prevent opioid tolerance in critically ill children we examined the effects of low-dose naloxone infusions on patients' needs for analgesia or sedation. Matched case-control study in a pediatric intensive care unit at a university children's hospital. We compared 14 pediatric ICU patients receiving low-dose naloxone and opioid infusions with 12 matched controls receiving opioid infusions. Opioid analgesia and sedative requirements were assessed as morphine- and midazolam-equivalent doses, respectively. No differences were observed between groups in opioid doses at baseline or during naloxone, but in the postnaloxone period opioid doses tended to be lower in the naloxone group. Compared to baseline the naloxone group required more opioids during naloxone but fewer opioids after naloxone. Total sedative doses were comparable at baseline in both groups, with no differences in the postnaloxone period. The naloxone group required less sedation after naloxone but sedation doses were unchanged in controls. The two groups did not differ in pain scores, sedation scores, or opioid side effects. Naloxone did not reduce the need for opioid during the infusion period but tended to reduce opioid requirements in the postnaloxone period without additional need for sedation. Randomized clinical trials may examine the effects of low-dose naloxone on opioid tolerance and side effects in pediatric ICU patients requiring prolonged opioid analgesia.

Does naloxone alone increase resuscitation rate during cardiopulmonary resuscitation in a rat asphyxia model?

Cardiac arrest was induced with asphyxia to identify if naloxone alone increases resuscitation rate during cardiopulmonary resuscitation in a rat asphyxia model. The animals were randomized into either a saline group (Sal-gro, treated with normal saline 1 ml iv, n = 8), a low-dose naloxone group (treated with naloxone 0.5 mg/kg iv, n = 8), or a high-dose naloxone group (HN-gro, treated with naloxone 1 mg/kg iv, n = 8) in a blinded fashion during resuscitation. At the end of 10 minutes of asphyxia, cardiopulmonary resuscitation was started, and each drug was administered at the same time. The rate of restoration of spontaneous circulation was seen in 1 of 8, 3 of 8, and 7 of 8 animals in the Sal-gro, LN-gro, and HN-gro, respectively. The rate of restoration of spontaneous circulation in HN-gro was significantly higher than that in Sal-gro ( P < .05). Naloxone (1 mg/kg) alone can increase resuscitation rate following asphyxial cardiac arrest in rats.

Role of κ- and δ-opioid receptors in the antinociceptive effect of oxytocin in formalin-induced pain response in mice

Oxytocin has been implicated in the modulation of somatosensory transmission such as nociception and pain. The present study investigates the effect of oxytocin on formalin-induced pain response, a model of tonic continuous pain. The animals were injected with 0.1 ml of 1% formalin in the right hindpaw and the left hindpaw was injected with an equal volume of normal saline. The time spent by the animals licking or biting the injected paw during 0–5 min (early phase) and 20–25 min (late phase) was recorded separately. Oxytocin (25, 50, 100 μg/kg, i.p.) dose dependently decreased the licking/biting response, both in the early as well as the late phases. The antinociceptive effect of oxytocin (100 μg/kg, i.p.) was significantly attenuated in both the phases by a higher dose of the non-selective opioid receptor antagonist naloxone (5 mg/kg, i.p.), MR 2266 (0.1 mg/kg, i.p.), a selective κ-opioid receptor antagonist and naltrindole (0.5 mg/kg, i.p.), a selective δ-opioid receptor antagonist but not by a lower dose of naloxone (1 mg/kg, i.p.) or β-funaltrexamine (2.5 μg/mouse, i.c.v.), a selective μ-opioid receptor antagonist. Nimodipine, a calcium channel blocker (1 and 5 mg/kg, i.p.) produced a dose-dependent analgesic effect. The antinociceptive effect of oxytocin was significantly enhanced by the lower dose of nimodipine (1 mg/kg, i.p.) in both the phases. Chronic treatment with oxytocin (100 μg/kg/day, i.p. daily for 7 days) did not produce tolerance in both the phases of formalin-induced pain response. The results thus indicate that oxytocin displays an important analgesic response in formalin test; both κ- and δ-opioid receptors as well as voltage-gated calcium channels seem to be involved in the oxytocin-induced antinociception.

Unlimited Access to Heroin Self-Administration: Independent Motivational Markers of Opiate Dependence

The goal of the present study was to develop and validate an animal model of unlimited access to intravenous heroin self-administration combined with responding for food and water to characterize the transition to drug dependence. Male Wistar rats were allowed to lever press for heroin (60 microg/kg/0.1 ml infusion/s; fixed ratio 1; 20-s time out) and nosepoke for food and water in consecutive, daily 23-h sessions. Daily heroin intake increased over days, reaching significance by Day 14. Drug-taking increased across the circadian cycle, reflected as increases in both the nocturnal peak and diurnal nadir of heroin intake. Changes in the circadian pattern of food intake and meal patterning preceded and paralleled the changes in heroin intake. By Day 7, the circadian amplitude of feeding was blunted. Nocturnal intake decreased because rats consumed smaller and briefer meals. Diurnal intake increased due to increased meal frequency, whereas total daily food intake decreased. To control for time or experience in the self-administration boxes as a possible confound, rats with saline (no drug) tethers were tested and did not display significant changes in food intake pattern. Body weight gain slowed slightly in heroin rats relative to saline controls. Separate groups of rats revealed that significant physical dependence as measured by physical signs of opiate withdrawal following a naloxone injection (1.0 mg/kg, subcutaneous (s.c.)) was reached by Day 14. Significant increases in heroin intake could be produced using low doses of naloxone (0.003-0.03 mg/kg, s.c.) on days 28-31 of heroin access. After 6 weeks of heroin self-administration, rats injected with buprenorphine (0, 0.01, 0.04, and 0.2 mg/kg, s.c.) showed a dose-dependent reduction in heroin intake. Changes in the pattern of drug and food intake in the present unlimited heroin access model may serve as independent motivational markers for the transition to a drug-dependent state.

The Roles of the Opioidergic System and Nitric Oxide in the Analgesic Effect of Venlafaxine

The noradrenalin and serotonin re-uptake inhibitor venlafaxine has an analgesic effect that is independent of its antidepressant activity; however, the mechanism of this effect remains to be elucidated. This study was performed to investigate the possible roles of the opioidergic system and nitric oxide (NO) pathway in the analgesic effect of venlafaxine. Eighty Wistar rats of both sexes were allocated to 10 groups. The hot plate test was used to assess the antinociceptive/analgesic effect. The temperature of the hot plate was adjusted to 52.5+/-1 degrees C, the cut-off period was set to be 50 sec; licking of the hind paw was used as a sign of pain perception. Venlafaxine alone (25 mg/kg) showed marked analgesic activity (p<0.05). N-omega-nitro-L-arginine (L-NOARG) alone (20 mg/kg) and naloxone alone (2 mg/kg and 4 mg/kg) showed no analgesic activity (p>0.05). Coadministration of low-dose naloxone (2 mg/kg) and both doses of L-NOARG (20 and 40 mg/kg) with venlafaxine (25 mg/kg) did not modify the analgesic effect but high-dose naloxone (4 mg/kg) decreased it significantly (p<0.05). In conclusion, these results suggest that the opioidergic system but not the NO pathway has a role in the analgesic effect of venlafaxine.

Endogenous opioid-mediated antinociception in cholestatic mice is peripherally, not centrally, mediated

Cholestasis is associated with naloxone reversible antinociception and opiate receptor antagonists are used clinically to treat pruritus. Pain and pruritus are closely interrelated and opioids modulate both sensations. Therefore, we undertook a series of experiments to characterize opioid-mediated antinociception in cholestasis and determine if it occurs inside or outside the CNS. Antinociception scores to both thermal and mechanical stimuli were determined in mice with cholestasis due to bile duct resection vs sham controls. Cholestatic mice demonstrated significant antinociception to both stimuli compared to controls, which was reversible by the opiate receptor antagonist naloxone. The experiments were repeated with a naloxone derivative, which does not cross the blood-brain-barrier (i.e. naloxone methiodide) with similar results, indicating an opioid antinociceptive effect mediated outside of the CNS. Experiments with intraplantar injections of low dose naloxone methiodide confirmed that cholestasis-associated antinociception occurs at the level of cutaneous nerve endings. These findings were supported by findings of increased dermal met-enkephalin expression in cholestatic mice. Cholestasis in mice is associated with antinociception due to local effects of endogenous opioids (i.e. met-enkephalin) at the level of sensory nerve endings. These findings may have direct implications in the management of cholestasis associated pruritus.

Activation of Naloxone-Sensitive and -Insensitive Inhibitory Systems in a Human Pain Model

We investigated naloxone effects in a model of electrically induced pain and hyperalgesia. In a double-blind, placebo-controlled, cross-over study, 15 volunteers underwent four 150-minute sessions of high-current-density electrical stimulation of their forearms. After 60 minutes, naloxone or placebo was given intravenously (increasing plasma concentrations of 0.1, 1, and 10 ng/mL; 30 minutes each) in 3 of the 4 sessions. Pain ratings and areas of mechanical hyperalgesia were assessed at regular intervals during all sessions. The low doses of naloxone did not cause any significant change of pain rating of areas of hyperalgesia. In terms of intrasession effects, pain ratings and areas of hyperalgesia significantly decreased during the sessions to 62% (pain rating), 70% (area of punctuate hyperalgesia), and 82% (area of allodynia) of the initial values. Naloxone (10 ng/ml) reversed these decreases. In terms of between-session effects, the time course of pain ratings remained constant from session to session. In contrast, the areas of punctate hyperalgesia successively decreased to 60% of initial value at the fourth repetition. The session effect was not reversed by naloxone. High-current-density electrical stimulation provokes central sensitization, but in addition inhibitory systems are activated that are only partly naloxone-sensitive. Perspective Endogenous inhibitory systems are of major importance for clinical pain conditions, but are not reflected in traditional human pain models. Here we show activation of a naloxone-sensitive short-term and a naloxone-insensitive long-term inhibitory system in a new model of electrically induced pain and hyperalgesia.

Context- and cue-conditioned potentiation of acute morphine dependence and withdrawal

Single morphine injections induce a state of acute opioid dependence measured by an increase in naloxone potency to precipitate withdrawal. Repeated morphine exposure (daily/weekly intervals) results in further potentiation of naloxone potency, perhaps due to conditioning mechanisms. The current study tested the hypothesis that previously neutral stimuli could elicit a conditioned potentiation of the withdrawal response following acute bolus injections of morphine. Rats trained on an FR-15 schedule for food received five morphine injections (5.6 mg/kg) at daily intervals. Four hr after morphine injection on Conditioning Days (first 4 days), naloxone (1 mg/kg)-induced suppression of responding was paired either with operant context only, or with a tone/light conditioned stimulus (CS). On Test Day low dose naloxone (0.001–0.33 mg/kg) given 4-h post-morphine preceded the operant session. Rats exposed to naloxone repeatedly in the operant context without CS (Paired-Context Only) showed an increase in naloxone potency on Test Day relative to Unpaired Controls that received all morphine and naloxone in the home cage at a different time of day than operant testing. Rats exposed to the tone/light CS on Conditioning Days also showed a significant increase in naloxone potency relative to Unpaired Controls when the CS was represented on Test Day (Paired-CS), but not when the CS was omitted on the Test Day (Paired-CS/Test Context). Thus, conditioning processes appear to play a significant role in the early development of opioid dependence and withdrawal.

Low-dose naloxone on the side reduces adverse effects of morphine

Low-dose naloxone on the side reduces adverse effects of morphine

Low-dose naloxone on the side reduces adverse effects of morphine

Low-dose naloxone on the side reduces adverse effects of morphine

Low-dose naloxone does not improve morphine-induced nausea, vomiting, or pruritus

Objective We tested the hypothesis that low-dose naloxone delivered with intravenous (IV) bolus morphine to emergency department patients in pain would reduce nausea. Methods Randomized, double-blind, placebo-controlled trial. Patients receiving 0.10 mg/kg morphine IV bolus rated pain, nausea, and pruritus on 100-mm visual analog scales at enrollment and 20 minutes. Patients were randomized to 0.25 μg/kg naloxone or equal volume placebo administered with IV morphine. Results One hundred thirty-one enrolled, 99 (76%) treated according to protocol with sufficient data for analysis. At 20 minutes the difference between groups (naloxone-placebo) was 1 mm (95% CI [confidence interval], −9 to 11) for nausea, 1 mm (95% CI, −3 to 3) for pruritus, 4% (95% CI, −1 to 9) for vomiting, and 0% (95% CI, −5 to 5) for rescue antiemetics. Pain was significantly reduced in both groups. Conclusion Addition of 0.25 μg/kg naloxone to bolus morphine does not improve nausea, pruritus, vomiting, or reduce use of rescue antiemetics when administered to emergency department patients in pain.

Isradipine and dextromethorphan in methadone-maintained humans under a naloxone discrimination procedure

In seven methadone-maintained human participants trained to distinguish between a low dose of naloxone (0.15 mg/70 kg, i.m.; i.e., Drug A) and placebo (i.e., Drug B) under an instructed novel-response drug discrimination procedure, the calcium channel blocker isradipine (0–10 mg/70 kg, p.o.; N=7) and the N-methyl- d-aspartic acid (NMDA) receptor antagonist dextromethorphan (0–60 mg/70 kg, p.o.; N=6) were tested each alone and in combination with the training dose of naloxone. Isradipine alone produced some naloxone- and novel-appropriate responding, minimal changes in self-reports and decreases in blood pressure. Dextromethorphan alone produced some novel-appropriate responding and minimal changes in self-reports and vital signs. When combined with naloxone, isradipine significantly attenuated naloxone-occasioned responding, without increasing novel-appropriate responding, and attenuated naloxone-induced increases in opioid receptor antagonist ratings and ratings measuring sedation. Dextromethorphan significantly attenuated naloxone-appropriate responding, increased novel-appropriate responding, and enhanced naloxone's effects on ratings of dysphoric effects. These results suggest that isradipine attenuates and dextromethorphan enhances some of the behavioral effects of naloxone in opioid-dependent humans.

Effects of Ondansetron or Naloxone Patient-Controlled Analgesia on Postoperative Analgesia and Side Effects

Background: Opioid delivered by PCA (patient-controlled analgesia) is effective at relieving pain after surgery, but it is associated with side effects, such as nausea, vomiting, pruritus, respiratory depression, and urinary retention. The purpose of this study was to compare fentanyl-related side effects and the quality of analgesia when naloxone or ondansetron was added to IV PCA regimen. Methods: Ninety patients undergoing lumbar laminectomy were enrolled in this study. General anesthesia was maintained with 50% and enflurane. In the recovery room patients received a 1/kg bolus of fentanyl, and addition normal saline 2 ml (group C), ondansetron 4 mg (group O), or naloxone 0.04 mg (group N). Simultaneously intravenous fentanyl PCA with normal saline (group C), ondansetron 4 mg (group O), or naloxone 0.36 mg (group N) was commenced. Pain scores and side effects were assessed on postoperative days (PODs) 0, 1, and 2 using a VAS (visual analogue scale). Results: The incidences of vomiting in the groups C, O, and N were 13.2%, 13.2%, and 3.3%, respectively. The VAS scores for nausea on PODs 0 and 1 in group N were significantly lower than in group C. The VAS scores for sedation on POD 0 in group N was lower than in group C, and on POD 2 lower than in group O. No differences in the VAS for pain and urinary retention were observed between the three groups. Conclusions: Low-dose naloxone with IV fentanyl PCA is effective at reducing opioid-related nausea and sedation without attenuating the quality of analgesia.

What’s New in the Management of Pain in Children

What’s New in the Management of Pain in Children

Dose ratio is important in maximizing naloxone enhancement of nalbuphine analgesia in humans

The analgesic effect of kappa partial agonist opioids (i.e. nalbuphine, pentazocine and butorphanol) is significantly greater in women. Recent evidence suggests that this sexual dimorphism may result from a naloxone-sensitive anti-analgesic effect that is activated along with, and summates with, the analgesic effect of these agents, resulting in decreased analgesia or increased pain. For example, nalbuphine (5 mg) produces profound anti-analgesia (i.e. enhanced pain) in men, but addition of a low dose of the opioid receptor antagonist naloxone (0.4 mg, opioid antagonist) induces significant analgesia in men and enhances nalbuphine analgesia in women. To further delineate the dose-dependent relationship of nalbuphine and naloxone, we recently evaluated the effect of a lower dose of nalbuphine (2.5 mg) with and without naloxone (0.4 mg) on dental postoperative pain. In women, nalbuphine alone induced modest short duration analgesia, which was antagonized by the addition of naloxone. In men, this dose of nalbuphine alone did not produce analgesia or anti-analgesia, and naloxone did not alter the response to nalbuphine. Thus, it appeared that the 2.5 mg dose of nalbuphine was not sufficient to induce anti-analgesia while the 0.4 mg dose of naloxone was able to antagonize the analgesic effect of nalbuphine, at least in women. In the current study, we tested the hypothesis that an important determinant of naloxone enhancement of nalbuphine analgesia is the dose ratio of nalbuphine to naloxone. Since a dose ratio of 12.5:1 (i.e. 5 mg nalbuphine:0.4 mg naloxone) resulted in analgesic enhancement, but a dose ratio of 6.25:1 (2.5 mg:0.4 mg) did not, we tested the same, lower, dose of nalbuphine (2.5 mg) in combination with a lower dose of naloxone (0.2 mg) to maintain the 12.5:1 dose ratio. This lower dose of naloxone significantly prolonged the analgesic effect of nalbuphine in both men and women, suggesting that the anti-analgesic effect of nalbuphine is present in both sexes at the 2.5 mg dose and that the dose ratio of nalbuphine to naloxone is an important determinant of the analgesic efficacy of this combination.

Interaction between the spinal melanocortin and opioid systems in a rat model of neuropathic pain.

The authors recently demonstrated that administration of the melanocortin-4 receptor antagonist SHU9119 decreased neuropathic pain symptoms in rats with a sciatic chronic constriction injury. The authors hypothesised that there is a balance between tonic pronociceptive effects of the spinal melanocortin system and tonic antinociceptive effects of the spinal opioid system. Therefore, they investigated a possible interaction between these two systems and tested whether opioid effectiveness could be increased through modulation of the spinal melanocortin system activity. In chronic constriction injury rats, melanocortin and opioid receptor ligands were administered through a lumbar spinal catheter, and their effects on mechanical allodynia were assessed by von Frey probing. Naloxone (10-100 microg) dose-dependently increased allodynia (percent of maximum possible effect of -67 +/- 9%), which is in agreement with a tonic antinociceptive effect of the opioid system. SHU9119 decreased allodynia (percent of maximum possible effect of 60 +/- 13%), and this effect could be blocked by a low dose of naloxone (0.1 microg), which by itself had no effect on withdrawal thresholds. Morphine (1-10 microg) dose-dependently decreased allodynia (percent of maximum possible effect of 73 +/- 14% with the highest dose tested). When 0.5 microg SHU9119 (percent of maximum possible effect of 47 +/- 14%) was given 15 min before morphine, there was an additive antiallodynic effect of both compounds. Together, these data confirm that there is an interaction between the spinal melanocortin and opioid systems and that combined treatment with melanocortin-4 receptor antagonists and opioids might possibly contribute to the treatment of neuropathic pain.

Absence of nalbuphine anti-analgesia in the rat

In humans, kappa agonist-antagonist opioids such as nalbuphine have been proposed to produce both analgesia and anti-analgesia by acting at distinct receptors. The anti-analgesia appears to be greater in men, which may contribute to the greater nalbuphine analgesia observed in women. Kappa agonist-antagonists are also known to produce sexually dimorphic antinociception in nonhuman species but are generally more potent in males; anti-analgesia has not been reported in animals. The aim of the present study was to determine if nalbuphine anti-analgesia can be detected in the rat. Since nalbuphine anti-analgesia is more sensitive to naloxone antagonism than its analgesic effect, low doses of naloxone were combined with nalbuphine. Using the Randall–Selitto paw-withdrawal test, nalbuphine (0.5–10 mg/kg) induced dose-dependent antinociception in the rat. The antinociceptive effect of nalbuphine (0.5 or 1 mg/kg) was not enhanced by lower doses of naloxone but was antagonized by higher doses. These data do not support the hypothesis that the naloxone-sensitive anti-analgesic effect of nalbuphine observed in humans is present in the rat and could explain, at least in part, the opposite direction of the sex differences for kappa agonist-antagonist opioid analgesia observed in these two species.