Effects Of Intravenous Morphine Research Articles

Comparing the efficacy of nebulized morphine with intravenous morphine in traumatic musculoskeletal pain management

Introduction: This study was designed to compare the effectiveness of intravenous morphine with nebulized morphine in pain relief of patients referring to the emergency setting with traumatic musculoskeletal pain. Methods: This randomized, placebo-controlled and double-blind clinical study evaluated 160 patients 18 to 65 years of age with acute traumatic pain, who attended the emergency department during 2019. Subjects were assessed with Numerical Rating Scale based on inclusion and exclusion criteria and randomly divided into two groups. In one group, 80 patients received IV morphine (0.1 mg/kg+5 mL normal saline) plus an equivalent volume of IV placebo. In the second group, 80 patients received nebulized morphine (0.2 mg/kg+5 mL normal saline) plus nebulized placebo. Pain score was monitored in all patients with Numerical Rating Scale before and after intervention at baseline, 15, 30, 45, and 60-minute intervals. Patients’ vital signs and possible adverse events were evaluated in each observation time points. Finally, all participants were assessed for their satisfaction with pain management. Data were analyzed using repeated measure analysis for continuous variables and Binomial test for categorical variables Results: There was no significant difference between the demographic characteristics of patients in study groups. Pain relief between the two groups was similar during the observation (0, 15, 30, 45, 60 min) (P>0.05). There were no changes in vital signs between two groups, although the nebulized group had lower systolic blood pressure at the time-point of 15 minutes after the treatment initiation (P=0.03). Conclusion: Although Nebulized morphine has similar efficacy in comparison with IV route, nebulization might be considered as the clinically efficacious route of morphine administration with minimal side effects, providing optimal pain relief in patients.

Effect of Intravenous Morphine and Ketorolac on Pain Control in Long Bones Fractures

Background:According to the lack of adequate studies on comparing the analgesic effect and complications of ketorolac with morphine in long bone fractures, this study aimed to compare the efficacy of ketorolac with morphine in patients referring to the Emergency Department with long bones damage and fracture.Materials and Methods:In this clinical trial study, 88 patients with long bone fracture were selected randomly and divided into two groups. To scale the intensity of pain, visual analog scale (VAS) were used. Intravenous ketorolac and morphine with the loading dose of 10 mg and 5 mg, respectively was administered to a group, followed by 5 mg and 2.5 mg every 5–20 min, if necessary (VAS ≥4). The pain scores before injection and at 5 min, half an hour and 1-h after the injection were measured and recorded for all patients.Results:The mean age of the ketorolac and morphine groups was 29.1 ± 12.5 and 33.2 ± 11.4, respectively. In the groups, there was 63.6% and 70.5% of male patients respectively. The mean ± SD of pain score before the injection was 7.59 ± 1 and 7.93 ± 1.09 (P = 0.13). One hour after the injection, the mean ± SD of pain in the both groups was 1.41 ± 0.9 and 1.61 ± 1.17 and the mean pain score has no significant difference in the two groups before the injection. Repeated measures ANOVA test also showed that the trend of changes in pain score had no significant difference in both groups (P = 0.08).Conclusion:According to the fewer side effects of ketorolac and effective pain release versus morphine, ketorolac could be suggested to use.

Differential effects of systemic morphine on responses elicited by tooth pulp stimulation of nociceptive neurons in lateral and medial thalamic nuclei.

The effects of intravenous morphine on responses of feline thalamic nociceptive neurons receiving afferent input from the tooth pulp (TP) were investigated. Morphine suppressed responses to TP stimulation in both tooth pulp specific (TPS) and wide dynamic range (WDR) neurons with TP input recorded from the nucleus ventralis posteromedialis (VPM). However, there was scant morphine effect on responses to stimulation of trigeminothalamic tract (TTT) fibers in the trigeminal medial lemniscus. Furthermore, in nociceptive neurons with TP input recorded from nucleus centralis lateralis (CL) and parafascicularis (Pf) of the intralaminar nuclei, intravenous morphine suppressed responses both to stimulation of the mesencephalic reticular formation (MRF) as well as TP stimulation. The suppressive action of morphine on responses elicited by TP stimulation of VPM, CL and Pf neurons was antagonized by intravenous naloxone (1 mg/kg). Results suggest that intravenous morphine suppresses synaptic transmission of nociceptive impulses in the intralaminar nuclei as well as in the lower brain stem but not in the VPM.

The onset of analgesic effect of intravenous morphine when used for the treatment of moderate-to-severe postoperative pain

The onset of analgesic effect of intravenous morphine when used for the treatment of moderate-to-severe postoperative pain

Differential behavioral effects of peripheral and systemic morphine and naloxone in a rat model of repeated acute inflammation. (Unité de Physiopharmacologie du Système Nerveux, Paris, France) Anesthesiology. 2001;94:870–875.

This study compared the behavioral effects of intraplantar and intravenous morphine and naloxone in a rat model of repeated acute carrageenan‐induced inflammation in which enhanced response to noxious stimuli result from sensitization in peripheral tissues or central sensitization. After the first carrageenan injection, intraplantar and intravenous morphine produced significant increase of vocalization thresholds to paw pressure in inflamed, but not in noninflamed paws. After the second carrageenan injection, the antinociceptive effects of intraplantar morphine were significantly reduced compared with those obtained after the first carrageenan injection, whereas effects of intravenous morphine were significantly enhanced and present in both hind paws. Intravenous naloxone demonstrated similar pronociceptive patterns after the first and second carrageenan injection. Intraplantar naloxone methiodide produced pronociceptive effects in inflamed hind paw that were significantly enhanced after the second carrageenan injection. Conclude that when the inflammation is enhanced by recurrent stimulations, the antinociceptive effects of systemic morphine are enhanced. This increase is more likely related to central than peripheral sites of action, beyond endogenous opioid system activation.Comment by Octavio Calvillo, M.D., Ph.D. There is evidence that opioid antinociception is enhanced in the presence of inflammation. In fact, there is evidence that opioids produce analgesia through peripheral opioid receptors within inflamed tissue. Primary afferent neurons are known to contain opioid receptors. It remains unclear whether the antinociceptive effects of opioids are related predominantly to central, peripheral sites of action or both. The authors compared the effects of intraplantar and intravenous morphine and naloxone in a rat model of carrageenan‐induced inflammation. In this model, hyperalgesia is due probably to both peripheral and central sensitization. The antinociceptive effects of intraplantar morphine, intravenous morphine, intraplantar naloxone, and intravenous naloxone were assessed on the vocalization thresholds to noxious pressure 3 hours after carrageenan plantar injections. Intraplantar and intravenous morphine increased the vocalization thresholds after carrageenan injection in inflamed but not on noninflamed paws. The antinociceptive effects of intraplantar morphine were reduced compared to the first response whereas the effects of intravenous morphine were significantly enhanced and present on both inflamed and noninflamed paws. Intravenous naloxone demonstrated similar pronociceptive patterns after the first and second carrageenan injection. Intraplantar naloxone produced pronociceptive effects in inflamed hind paws that were significantly enhanced after the second carrageenan injection. The authors concluded that when inflammation is enhanced by recurrent stimulation the antinociceptive effects of systemic morphine are enhanced. This is more probably related to central than to peripheral sites of action.

Systemic morphine reduces the wind-up of trigeminal nociceptive neurons

We assessed the effects of intravenous morphine on the wind-up of nociceptive neurons of the spinal trigeminal nucleus oralis (Sp5O). Extracellular recordings of Sp5O nociceptive convergent neurons were performed in intact halothane-anesthetized rats. Wind-up of C-fiber-evoked responses was elicited by repetitive electrical stimulation (train of 16 shocks, 0.66 Hz) of their receptive field at C-fiber intensity (3 times the threshold). Wind-up was tested for its sensitivity to morphine (6 mg/kg,i.v.), and the specificity of the effects was verified with naloxone (0.4 mg/kg, i.v.). Nineteen convergent neurons displaying wind-up were recorded. Morphine reduced the wind-up of all but one. In five cases, notwithstanding a reduced wind-up, the neuronal response evoked by the first stimulus in the train (initial input) was unexpectedly increased. Naloxone always antagonized morphine inhibitory effects on the wind-up. When administered systemically, morphine reduced the wind-up of trigeminal nociceptive neurons. This inhibitory effect occurred independently of morphine's ability to affect the initial C-fiber-evoked input. Our findings support the idea that systemic morphine probably blocks wind-up by acting at opioid receptors located postsynaptically to nociceptive primary afferents.

Differential behavioral effects of peripheral and systemic morphine and naloxone in a rat model of repeated acute inflammation.

It has been reported that opioid antinociceptive effects are enhanced in animal models of inflammation, but it remains unclear whether this sensitization to morphine is related to predominant central or peripheral increased effects. The authors compared the behavioral effects of intraplantar and intravenous morphine and naloxone in a rat model of repeated acute carrageenan-induced inflammation in which enhanced responses to noxious stimuli result from sensitization in peripheral tissues or central sensitization. The antinociceptive effects of intraplantar morphine (50, 75, 100, 150, and 200 microg), intravenous morphine (0.3, 0.6, and 1 mg/kg), and the pronociceptive effects of intraplantar naloxone methiodide (150 microg) and intravenous naloxone (1 mg/kg) against noxious pressure (vocalization thresholds to paw pressure) in rats were assessed 3 h after one or two carrageenan plantar injections performed 7 days apart. After the first carrageenan injection, intraplantar and intravenous morphine produced significant increase of vocalization thresholds to paw pressure in inflamed but not in noninflamed paws. After the second carrageenan injection, the antinociceptive effects of intraplantar morphine were significantly reduced compared with those obtained after the first carrageenan injection, whereas effects of intravenous morphine were significantly enhanced and present in both hind paws. Intravenous naloxone demonstrated similar pronociceptive patterns after the first and second carrageenan injection. Intraplantar naloxone methiodide produced pronociceptive effects in inflamed hind paw that were significantly enhanced after the second carrageenan injection. When inflammation is enhanced by recurrent stimulations, the antinociceptive effects of systemic morphine are enhanced. This increase is more likely related to central than peripheral sites of action, beyond endogenous opioid system activation.

A comparison of sympathetic adrenal nerve responses to intravenous high-dose morphine and fentanyl administration in rats

We compared the effects of intravenous morphine (5 mg·kg(-1)) and fentanyl, (50μg·kg(-1)) on systolic blood pressure (SBP), heart rate (HR), and efferent sympathetic adrenal nerve action potentials (SANA) in rats. We also determined the extent of the reflex responses of these parameters of 9% carbon dioxide (CO2) challenge during the above narcotic anesthesia. In the morphine group, SBP was elevated and the elevated levels were maintained, while changes in SBP in the fentanyl group were not significant. In the morphine group, SANA showed initial stimulation and subsequent depression, while in the fentanyl group, SANA showed sustained depression. CO2 challenge induced only very small changes in SBP and HR, suggesting that during high-dose narcotic anesthesia the hypercapnic stimulus may not be reflected in circulatory parameters. In both groups, hypercapnia increased SANA to 30% of the baseline values from the pre-challenge level. However, these values were only 91% and 56% of the baseline value in the morphine and the fentanyl, groups, respectively.

Differential inhibitory mechanisms in VPL versus intralaminar nociceptive neurons of the cat: II. Effects of systemic morphine and CCK.

In urethane-chloralose anesthetized cats, the effects of intravenous morphine on responses of thalamic nociceptive units were studied. In both nociceptive specific (NS) and wide dynamic range (WDR) units recorded from the nucleus ventralis posterolateralis (VPL), intravenous morphine suppressed unit responses to the greater splanchnic nerve (SPL) stimulation, but had little effect on responses to stimulation of spinothalamic tract fibers in the ventrolateral funiculus. In nociceptive units recorded from nuclei centralis lateralis (CL) and parafascicularis (Pf) of the intralaminar nuclei, intravenous morphine suppressed responses to stimulation of the mesencephalic reticular formation as well as to SPL stimulation. Intravenous cholecystokinin (CCK) antagonized the suppressive action of morphine on responses of VPL units, but did not antagonize the suppressive action of morphine on responses of intralaminar units. The results suggest that intravenous morphine inhibits synaptic transmission of nociceptive impulses in the intralaminar nuclei as well as in the spinal cord, but not in the VPL, and that CCK antagonizes the antinociceptive action of morphine in the spinal cord, but not in the intralaminar nuclei.

Gamma-aminobutyric acid type A receptor blockade at the intermediate area of the ventral surface of the medulla counteracts the cardiorespiratory depression produced by intravenous midazolam.

Intravenous administration of midazolam (2 mg/kg) to 8 pentobarbital-anesthetized cats produced a significant decrease in minute ventilation, tidal volume, blood pressure and heart rate. Treatment with the gamma-aminobutyric acid (GABA) type A receptor antagonist bicuculline (10 micrograms/side) at the intermediate area of the ventral surface of the medulla (VSM) oblongata completely reversed the cardiorespiratory depressant effects of intravenous midazolam. In contrast, treatment with bicuculline at the same area failed to counteract the respiratory depressant effects of intravenous morphine (1 mg/kg). We conclude that the cardiorespiratory depressant effects of intravenously administered midazolam are due to enhancement of GABAergic transmission at the intermediate area of the VSM.

Effect of morphine on cortisol and prolactin secretion in anorexia nervosa

Opioidergic regulation has been implicated in the pathophysiology of eating disorders. To investigate this hypothesis further, we conducted a placebo controlled study of the effect of intravenous morphine (0.08 mg/kg) on cortisol and prolactin secretion in six patients with anorexia nervosa and six age-matched healthy volunteers, and compared the results with those obtained in nine depressed patients. Blood samples were drawn immediately before and at 30 minute intervals for three hours. Basal cortisol but not basal prolactin levels were elevated in patients with anorexia nervosa and patients with depression. Following the administration of morphine, plasma concentrations of cortisol levels declined progressively and at a similar rate in all three groups. The prolactin response to morphine was attenuated significantly in patients with depression. Neither the cortisol and prolactin response to morphine in the anorectic patients nor the cortisol response in the depressed patients we observed in this study suggest altered opiate receptor sensitivity. However, the decreased prolactin response to morphine in depressed patients remains compatible with this hypothesis.

Effect of Intravenous Morphine on Capsaicin Induced Airway Responses

Effect of Intravenous Morphine on Capsaicin Induced Airway Responses

Morphine inhibits cortisol and stimulates prolactin secretion in man

The role of opioids in endocrine regulation has been the subject of numerous studies. Surprisingly, however, the acute endocrine effects of morphine on basal hormonal levels in man have not been adequately documented. We report here the effects of intravenous morphine (5 mg) on plasma cortisol and prolactin. Fourteen healthy volunteers (nine male, five female) received morphine at 0930 hr. Blood samples were collected immediately before and 30, 60, 90, 120 and 180 min after the injection. In six of the male subjects the procedure was repeated with a placebo (normal saline) injection. Morphine stimulated prolactin release. There was a trend for a greater response in females compared to male subjects. Cortisol secretion was markedly suppressed by morphine. In sharp contrast to the results obtained with placebo, cortisol levels following morphine declined progressively at a rate consistent with the half-life of cortisol. This downward trend of cortisol values continued uninterrupted for the duration of the experiment in all 14 subjects. These results are consistent with the presence of an inhibitory opioid mechanism in the human hypothalamopituitary-adrenal axis.

Ventilatory response to morphine in young and old subjects

The effects of intravenous morphine (10 mg/70 kg body weight) on ventilation in two groups of subjects, young (age 28-37 years) and old (age 65-82 years) were studied prior to elective surgery. There was no significant difference between the two groups in minute ventilation, ventilatory frequency and end-tidal carbon dioxide before morphine administration. In both groups there was a significant depression of ventilation and elevation of end tidal carbon dioxide tension 20 minutes after intravenous morphine. There was no significant difference between the two groups in the response of these variables to morphine. However, in the older group seven out of thirteen subjects showed frequent periods of apnoea or periodic breathing whereas three of the young subjects had these phenomena at much less frequent intervals. Respiratory depression after morphine is similar in old and young patients but old patients have more change in ventilatory control.

Naloxone enhancement of spinal reflexes in the rabbit.

The effects of intravenous morphine, (-)-naloxone and (+)-naloxone have been studied on three ipsilateral cutaneo-muscular reflexes in spinal rabbits. Morphine, 3 mg/kg caused a slow-onset depression of all three reflexes. This effect was naloxone reversible. The ipsilateral extensor reflexes, sural to gastrocnemius medialis and saphenous to vastus lateralis were both enhanced to more than double control size following a 5 micrograms/kg dose of naloxone given in the absence of morphine. For the sural-gastrocnemius reflex, naloxone potentiated the reflex drive from all groups of myelinated afferent fibres. The ipsilateral flexion reflex, sural to semitendinosus, was only weakly enhanced by naloxone, the 5 micrograms dose leading to an increase in the size of the reflex to 130% of control. All observed actions of naloxone were stereospecific as the enantiomer (+)-naloxone failed to affect any of the reflexes even in a dose of 50 micrograms/kg. We conclude from these findings that opioid peptides are tonically released in rabbit spinal cord, and that they have differential effects in control of flexion and extension reflexes. It is suggested that the ipsilateral extension reflexes are held under a more powerful opioid-mediated depression than that operating upon the flexion reflexes, and that this difference may be related to the greater inhibitory inflow to extensor motoneurones from ipsilateral skin areas.

Pharmacokinetics of intravenous morphine in balanced anesthesia: studies in children.

Intravenous morphine in combination with muscle relaxants, nitrous oxide, and oxygen in so-called balanced anesthesia is commonly used in children between the ages of 0 and 5 yr during surgery. We define dosing rules for a loading dose followed by a continuous intravenous infusion of morphine sulfate to achieve a serum morphine concentration of 75 micrograms/L. This concentration is well above the minimum serum morphine concentration of 50 micrograms/L for moderate analgesic effects in adults. It also exceeds the concentration of 65 micrograms/L claimed to provide adequate analgesia in children during surgery. The clearance of morphine in 8 children between 0 and 5 yr of age was 20.5 +/- 2.8 mL/kg/min (means +/- SD). This result is threefold larger than the clearance value obtained after a single intravenous dose and 1.5 times greater than clearance values found after multiple intravenous doses of morphine, previously reported by others in children between the ages of 1 and 15 yr. Having established a dosing regimen that achieves a steady-state serum morphine concentration of approximately 75 micrograms/L, we plan to investigate the relationship between morphine serum concentration and pharmacologic effect. Intraoperatively the action of morphine at its receptor site will be assessed according to a scoring system including EEG changes, heart rate, blood pressure, response to sensory stimuli, and maintenance of vital functions. The effect of intravenous morphine will further be estimated according to the postanesthetic scoring system described in this report. Using intraoperative and postanesthetic scores to evaluate the pharmacodynamics of morphine for anesthesia in relation to morphine serum concentration will lead to a better understanding and improvement in use of intravenous morphine in young children.

Selective effects of morphine on the nociceptive responses of thalamic neurones in the rat.

1. The effects of intravenous morphine on the firing of single sensory neurones in the thalamus of the anaesthetized rat are described. 2. Low doses (0.38 to 2.00 mg/kg) of morphine depressed the excitation of nucleus lateralis neurones produced by natural noxious stimuli but were without effect on spontaneous activity. The excitation of some of these neurones by iontophoretically applied acetylcholine or glutamate was also depressed by morphine. These effects were reversed by intravenous (0.25 to 1.17 mg/kg) but not iontophoretically applied (50 to 200 nA) naloxone. 3. Similar or higher doses of morphine (0.58 to 5.07 mg/kg) did not prevent the excitation of ventrobasal thalamic neurones by non-noxious stimuli. 4. The possibility of a direct action of intravenous morphine in the thalamus is discussed.