Serum Levels Of Morphine Research Articles

Gender differences in opioid-mediated analgesia: animal and human studies.

Gender differences in opioid-mediated analgesia: animal and human studies.

A comparison of serum levels of morphine and its metabolites in epidural infusions of bupivacaine plus diamorphine vs. morphine PCA and their effect on bowel function

A comparison of serum levels of morphine and its metabolites in epidural infusions of bupivacaine plus diamorphine vs. morphine PCA and their effect on bowel function

Morphine affects cytostatic activity of macrophages by the modulation of nitric oxide release

The serum levels of morphine and its glucuronide metabolites were quantitated in C57BL/6 mice at various intervals following subcutaneous administration of morphine. Since one of the major mechanisms of killing by macrophages is the production of nitric oxide, pharmacokinetics data were correlated with cytostatic activity and the release of NO 2 −(stable end product of NO metabolism). Morphine and its 3-glucuronide metabolite appear in serum of treated mice, reaching a peak of concentration at 20 min. However, morphine 3′-glucuronide levels were much higher than those of the drug itself, even when the morphine concentration levelled off. Both cytostasis and NO 2 − production of L 1210-activated macrophages were significantly enhanced by opioid treatment immediately after drug injection (peaking after 40 min). In contrast, morphine induced a strong inhibition of both cytostasis and NO 2 − production 24 h after treatment. The modulation of both cytostasis and NO 2 − production induced by morphine was completely antagonized by pretreatment of mice with the opioid antagonist naltrexone. The involvement of an inducible isoform of NO synthase was suggested by the inhibitory effects of dexamethasone on NO 2 − production. These data indicate that in vivo administration of morphine can induce a modulation of the NO biosynthesis of peritoneal macrophages.

Effects of naltrexone on pharmacodynamics and pharmacokinetics of intravenously administered morphine in the rat.

Effects of naltrexone administered intravenously on the pharmacological actions and kinetics of morphine in serum following intravenous administration of morphine were determined in male Sprague-Dawley rats. A 10 mg/kg dose of morphine produced an analgesic response as measured by the tail flick test. Morphine also produced a hyperthermic effect. Naltrexone dose (0.625-2.5 mg/kg)-dependently antagonized the analgesic and hyperthermic effects of morphine. The effect of naltrexone (0.625 and 2.5 mg/kg) on the pharmacokinetic parameters area under the serum morphine concentration time curve (AUC0-->infinity), serum levels of morphine extrapolated to zero time (Cmax), half-life (t1/2), mean residence time (MRT), total body clearance (Clt), and volume of distribution at steady state (Vss) of morphine in serum was determined. Naltrexone (0.625 mg/kg) significantly increased AUC0-->infinity, Cmax, t1/2 MRT, but decreased the Vss, elimination rate constant (k) and Clt. The higher dose of naltrexone (2.5 mg/kg) produced an increase in the Cmax value of morphine in the serum, but the other pharmacokinetic parameters were unaffected. Since increased morphine concentrations in serum produced by naltrexone cannot explain its antagonistic effects on analgesia and hyperthermia, it is concluded that naltrexone produces its effects by blocking opiate receptors at the appropriate sites. The increases in serum morphine levels by naltrexone may be related to displacement of morphine from protein binding sites and inhibition of morphine metabolism by glucuronyl transferase. This study for the first time demonstrates that in the rat, when morphine and naltrexone are given concurrently, although serum levels of morphine increase, pharmacological effects of morphine are antagonized.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphine preference in individual rats after morphine ingestion

Individual differences in drug intake were investigated. Inbred Sprague-Dawley male rats were choice-tested after various periods of morphine ingestion. Nearly 10% of the rats showed more than 50% preference already after 4 days ingestion on 340 mg morphine/kg/day, while a further 10% had a mean preference less than 30% over 6 days of choice, even after as long as 38 days' treatment on this same dose. High morphine preference was stable for long choice periods. It was also found that a high morphine preference level in an individual rat persisted over several choice tests, even if the animals had been without morphine for several months. The alpha 2-agonist clonidine diminished high preference to the same extent as it diminished overall morphine preference. There were no differences in food intake, body weight gain, severity of abstinence reactions, morphine serum levels, taste sensitivity tested with quinine, or learning the choice test behaviour comparing extremely high and low morphine preference rats. Thus, two subgroups of high and low morphine-ingesting rats were identified in the Sprague-Dawley strain.

Regional Analgesic Effect of Epidural Morphine in Volunteers

Limb ischaemia induced by a sub-maximum effort tourniquet technique was used to characterize the analgesic effects of lumbar epidural morphine in volunteers. As an index of pain threshold, we measured the time to perception of pain in and upper an a lower limb before and at intervals up to six hours following epidural injections of morphine 3.5 mg an 7.0 mg, and before and after subcutaneous injections of the same doses. Subcutaneous morphine had no significant effect on the times to perception of pain in either limb. Lumbar epidural morphine did not alter upper limb times, but markedly delayed the onset of pain in the lower limbs. This lower limb analgesic effect was apparent thirty minutes after injection, peaked at about ninety minutes and was still present after six hours. Serum levels of morphine were nearly identical after subcutaneous and epidural injections of the same dose. We conclude that lumbar epidural morphine produces marked analgesia for this type of experimental pain primarily by a effect rather than as a result of systemic absorption. This regional effect develops slowly and is prolonged.

Regional analgesic effect of epidural morphine in volunteers.

Limb ischaemia induced by a sub-maximum effort tourniquet technique was used to characterize the analgesic effects of lumbar epidural morphine in volunteers. As an index of pain threshold, we measured the time to perception of pain in and upper an a lower limb before and at intervals up to six hours following epidural injections of morphine 3.5 mg an 7.0 mg, and before and after subcutaneous injections of the same doses. Subcutaneous morphine had no significant effect on the times to perception of pain in either limb. Lumbar epidural morphine did not alter upper limb times, but markedly delayed the onset of pain in the lower limbs. This lower limb analgesic effect was apparent thirty minutes after injection, peaked at about ninety minutes and was still present after six hours. Serum levels of morphine were nearly identical after subcutaneous and epidural injections of the same dose. We conclude that lumbar epidural morphine produces marked analgesia for this type of experimental pain primarily by a "regional" effect rather than as a result of systemic absorption. This regional effect develops slowly and is prolonged.

Enduring effects of morphine pellets revealed by conditioned taste aversion

Morphine pellets (75 mg) were implanted subcutaneously in albino rats. Three days later, following 24 h without water, these rats (Group MSN) were given access to a saccharin solution for 30 min, then injected with naloxone hydrochloride. The classical abstinence signs, including "wet dog shakes"and weight loss, were noted in these subjects, but not in controls given placebo pellets and /or saline injections. In addition, when given an opportunity to drink either saccharine solution or water 24 h later, Group MSN rats drank significantly less saccharin than any of the control groups. Similar drinking patterns were found even when naloxone injection was delayed as long as 3 weeks after pellet implantation, when none of the classical abstinence signs were seen and serum levels of morphine and its metabolites were 100 times lower according to radioimmunoassay. This simple and objective technique is thus more sensitive as a measure of prior morphine exposure than any of the commonly used indices. The continued utility of a dependent-nondependent dichotomy is also examined in light of these and other findings.

THE DISPOSITION OF MORPHINE IN SURGICAL PATIENTS

Berkowitz, B. A.; Ngai, S. H.; Yang, J. C.; Hempstead, J.; Spector, S. Author Information

The relationship of pharmacokinetics to pharmacological activity: morphine, methadone and naloxone.

This review illustrates current approaches to the study of the disposition in man of the strong analagesics morphine and methadone and the narcotic antagonist naloxone. Morphine administered orally is rapidly absorbed but equally rapidly metabolised to morphine glucuronide. This contributes to the diminished oral efficacy of morphine. Following intramuscular administration morphine is very rapidly absorbed. After intravenous injection, the serum levels of morphine during the first 10 minutes are higher and more variable in older patients. The half-life of morphine between 20 minutes and 6 hours is 2 to 3 hours and this value does not appear to be influenced by the age of the patient. Similar half-lives for morphine have been reported to normal volunteers and in anaethetised patients who received morphine. Thus, surgical anaesthesia may not markedly influence morphine half-life and disposition. Based on urinary excretion data in man, accelerated morphine metabolism and excretion do not contribute to morphine tolerance. Methadone is now widely used in the treatment of narcotic abuse. The half-life of methadone averages 25 hours. The prolonged retention of methadone in the plasma may be related to its extensive binding to plasma proteins. With chronic dosing, studies in both animals and man indicate an increase in the metabolism of methadone. Unlike morphine, the urinary excretion of methadone increases with acidification of the urine. Women may metabolise methadone to a greater extent than do men. With the exception of pupillary effects, the plasma levels of methadone correlate poorly with its pharmacological activity. There is a marked variation in methadone plasma levels between patients and within the same patient. Naloxone rapidly disappears from the serum in man and the initial distribution phase has a half-life of 4 minutes. The half-life of naloxone in serum following distribution is 64 minutes. Based on animal studies, the rapid onset of the narcotic antagonist action of naloxone can be related to its rapid entry into the brain, whereas its potency stems in part from its high lipid solubility which allows a high brain concentration to be achieved. The short duration of action of naloxone may result from its rapid egress from the brain.

The diposi tion of morphine in surgical patients.

The disposition of serum morphine following administration of 10 mg/70 kg was determined by a sensitive and specific radioimmunoassay in 31 anethetized surgical patients ranging in age from 23 to 75 yr. Following iv injection, 93 per cent of the morphine disappeared from the serum within 5 min. The early serum levels of the drug (2 min) correlated directly with the patients' ages (r equal to 0.63, p smaller than 0.01). Patient 23 to 50 yr of age averaged 0.29 mug/ml, whereas patients 51 to 75 ur of age averaged 70 percent higher, 0.49 mug/ml. The serum half-life between 10 and 240 min was independent of age and averaged about 2 hr after either iv or im administration. Following im admininstration, morphine was rapidly absorbed, with peak levels occurring within 10 to 20 min. The decline in morphine serum levels paralleled the decline in morphine analgesia and was coincident with the apperance of morphine glucuronide in the serum. These studies demonstrate the applicability and specificity of the radioimmunoassay for morphine and suggest that serum levels of morphine may be a useful and objective indicator of its pharmacologic activity.