Long-term Morphine Administration Research Articles

Navigation system for pedicle screw insertion

The clinical pharmacology of morphine is complicated by its active metabolite, morphine-6-β-glucuronide (M6G). M6G is a potent μ-opioid agonist that has been recognized to play an important role in the clinical effects of morphine. However, M6G probably crosses the blood brain barrier with difficulties, and is of importance for the effects of morphine only during long-term morphine administration because only then M6G may reach high enough CNS concentrations. Since M6G is eliminated from the body via the kidney, it may cause severe opioid side effects with insidious onset and long persistence when renal function is impaired. This time dependent participation of M6G at the clinical effects of morphine makes it difficult to predict the effect of morphine in an individual patient. The problem may be solved using a PK/PD modeling approach to the clinical pharmacology of morphine that takes the delayed action of M6G into consideration.

Removing MRT-caused artifacts from electrooculographic signal by subtraction of the average artifact pattern

The clinical pharmacology of morphine is complicated by its active metabolite, morphine-6-β-glucuronide (M6G). M6G is a potent μ-opioid agonist that has been recognized to play an important role in the clinical effects of morphine. However, M6G probably crosses the blood brain barrier with difficulties, and is of importance for the effects of morphine only during long-term morphine administration because only then M6G may reach high enough CNS concentrations. Since M6G is eliminated from the body via the kidney, it may cause severe opioid side effects with insidious onset and long persistence when renal function is impaired. This time dependent participation of M6G at the clinical effects of morphine makes it difficult to predict the effect of morphine in an individual patient. The problem may be solved using a PK/PD modeling approach to the clinical pharmacology of morphine that takes the delayed action of M6G into consideration.

A training system for endoscopic sinus surgery with skill evaluation

The clinical pharmacology of morphine is complicated by its active metabolite, morphine-6-β-glucuronide (M6G). M6G is a potent μ-opioid agonist that has been recognized to play an important role in the clinical effects of morphine. However, M6G probably crosses the blood brain barrier with difficulties, and is of importance for the effects of morphine only during long-term morphine administration because only then M6G may reach high enough CNS concentrations. Since M6G is eliminated from the body via the kidney, it may cause severe opioid side effects with insidious onset and long persistence when renal function is impaired. This time dependent participation of M6G at the clinical effects of morphine makes it difficult to predict the effect of morphine in an individual patient. The problem may be solved using a PK/PD modeling approach to the clinical pharmacology of morphine that takes the delayed action of M6G into consideration.

INPRES—INtraoperative PRESentation of surgical planning and simulation results

The clinical pharmacology of morphine is complicated by its active metabolite, morphine-6-β-glucuronide (M6G). M6G is a potent μ-opioid agonist that has been recognized to play an important role in the clinical effects of morphine. However, M6G probably crosses the blood brain barrier with difficulties, and is of importance for the effects of morphine only during long-term morphine administration because only then M6G may reach high enough CNS concentrations. Since M6G is eliminated from the body via the kidney, it may cause severe opioid side effects with insidious onset and long persistence when renal function is impaired. This time dependent participation of M6G at the clinical effects of morphine makes it difficult to predict the effect of morphine in an individual patient. The problem may be solved using a PK/PD modeling approach to the clinical pharmacology of morphine that takes the delayed action of M6G into consideration.

Pharmacokinetic modeling of M6G formation after oral administration of morphine in healthy volunteers.

Morphine is metabolized to two major metabolites, morphine-3-glucuronide and morphine-6-glucuronide (M6G). Under the conditions of long-term oral morphine administration, the accumulation of M6G may contribute to the analgesic effects, but it may also cause respiratory depression. Five healthy male volunteers (ages 25-34 yr) received 90 mg MST (morphine sulfate 5H2O sustained-released tablet, equivalent to 67.8 mg oral morphine). Multiple plasma and urine samples were taken for as long as 14 and 36 h, respectively. Individual pharmacokinetics after intravenous administration of morphine and M6G were available from a previous investigation. A new model that considers the M6G-plasma profile as a sum of the input from the first-pass metabolism of morphine and the input from systemically available morphine was applied to the plasma concentration versus time curves of M6G. The concentrations of M6G at the effect site after long-term morphine administration were simulated. The fraction of morphine absorbed from the gut was 82+/-14%. Of this, 42+/-8% passed through the liver, resulting in an oral bioavailability of morphine of 34+/-9%. Of the total amount of M6G, 71+/-7% was formed during the first-pass metabolism, and 29+/-7% was formed by metabolism of systemic morphine. After 36 h, the amounts of M6G and morphine excreted in the urine were 92+/-17% and 9+/-3%, respectively. Simulation of effect-site concentrations of M6G indicated that after multiple oral dosing of morphine in patients with normal liver and renal function, M6G might reach concentrations two times greater than that of morphine. M6G may contribute to the analgesic and side effects seen with long-term morphine treatment. The current model of morphine and M6G pharmacokinetics after oral administration of morphine may serve as a pharmacokinetic basis for experiments evaluating the analgesic contribution of M6G with long-term oral dosing of morphine.

Role of prolactin in the modulation of NK and lak cell activity after short- or long-term morphine administration in neoplastic patients

In a previous work we demonstrated that chronic in vivo antalgic therapy of cancer patients with morphine reduced the endogenous cytotoxic activity of natural killer (NK) cells, while increasing the development of lymphokine activated killer (LAK) cell cytotoxicity. In order to investigate the mechanisms by which morphine affects NK and LAK cell function further, we evaluated the modulation exerted by short- or long-term morphine administration on either NK/LAK cell cytotoxicities or plasma levels of prolactin (PRL) and other immunomodulating neurohormones. An intravenous morphine injection (10mg) significantly increased the plasma levels of PRL, reduced the cytotoxic activity of NK cells, and increased the development of LAK cell activity 30 min after drug injection in neoplastic patients. The administration of bromocriptine before the injection of morphine prevented both PRL augmentation and the increase in LAK cell activation, although it did not prevent the inhibition of NK cytotoxicity. The chronic oral administration of morphine (90±30mg/day for 1 month) also resulted in higher PRL levels; the NK and LAK cell activities were, respectively, lower than or higher than those found in neoplastic patients untreated with morphine. The plasma levels of thyrotropin (TSH), adrenocorticotropic hormone (ACTH) and cortisol were not significantly modified in either short- or long-term experiments. The absolute number and the percentages of lymphocyte populations, as well as the percentage of IL-2 receptors, were not modified after short-term morphine administration whereas little changes of T lymphocyte populations and NK cell number were observed after oral treatment with morphine. In vitro morphine did not affect the development of LAK cell activity. In conclusion, our findings indicate that morphine reduces NK cytotoxicity and increases the development of LAK cell cytotoxicity after short- and long-term administration. The effect of morphine on LAK cell activation but not on NK cell reduction is related to the modulation of PRL levels determined by the opioid drug.

Oral papaverine prevents morphine-induced constipation without interfering with analgesia achieved with oral morphine

Long-term administration of morphine for the treatment of chronic pain produces constipation; this requires the use of laxatives, which impair water absorption and upset the electrolyte balance. Morphine-induced constipation is mainly due to inhibition of the propulsive movement of the gastrointestinal tract combined with spastic contraction of smooth circular muscles as a result of drug binding to opioid receptors in the tract. Since papaverine lacks affinity for opioid receptors but relaxes smooth muscle, it seemed possible that oral papaverine might be capable of diminishing constipation without impairing the analgesia achieved with morphine. For this purpose, experiments were carried out on rats: constipation was checked for by measuring the intestinal transit time, and analgesia was assessed by measuring the latency of the tail-flick response to radiant heat or nociceptive activity in single neurons of the thalamus evoked by supramaximal electrical stimulation of afferent C fibres in the sural nerve. Morphine and papaverine were administered by the oral route. Control animals received saline. To measure the intestinal transit time, India ink solution was given orally. Morphine (2.5 and 5 mg/kg orally) prolonged the transit time from approx. 420 min in the controls to more than 600 min, a dose of 2.5 mg/kg producing the maximum effect. Papaverine (0.5, 1, and 2 mg/kg) administered orally together with morphine significantly reduced morphine-induced constipation (Tables 1, 2). Papaverine given alone at a dose of 2 mg/kg caused no change in transit time, while 5 mg/kg significantly increased it (Table 2). The latency of the tail-flick response was increased by oral morphine (2.5 and 5 mg/kg) at 1, 2, and 3 h after administration. Papaverine (0.5, 1 and 2 mg/kg) given in combination with morphine left the antinociceptive effect of morphine unchanged (Figs. 1-3). A study of the nociceptive activity evoked in thalamus neurons of rats under urethane anaesthesia indicated that intestinal absorption of morphine was blocked. Therefore, metoclopramide (0.15 mg/kg) was injected i. v. 10 min before oral administration of morphine or the combination of morphine plus papaverine. Subsequently, morphine produced a dose-dependent depression of evoked nociceptive activity (Fig. 4), the mean effect amounting to 60 % of the control activity and being produced by 2.5 mg/kg (Fig. 5). Since in former experiments on nociceptive activity evoked in thalamus neurones it has been found that the ED(50) of i. v. morphine is 0.05 mg/kg, it is very likely that the presystemic elimination of orally administered morphine is very high and, in addition, that the efficiency of its active metabolite, morphine-6-glucuronide, is rather poor. When morphine 2.5 mg/kg was given together with papaverine 0.5 mg/kg, and morphine 5 mg/kg was administered in combination with papaverine 2 mg/kg, there was no significant reduction in the depressant effect of morphine on nociceptive activity evoked in thalamus neurons (Figs. 6, 7). The results suggest that papaverine given by the oral route may reduce morphine-induced constipation without impairment of the analgesic action of morphine in patients suffering from pain.

Spleen and thymus cell subsets modified by long-term morphine administration in protein-undernourished mice — I

Severe infections in intravenous drug abusers could be the consequence of morphine-induced damage on the immune system. To evaluate the long-term effect of in vivo morphine administration on the immune system we developed an experimental model where we studied the combined effects of morphine treatment and protein malnutrition. We treated protein-undernourished mice daily for 11 weeks with increasing doses of morphine. Morphine treatment produced a decrease in body weight and spleen cell number. The changes observed were partially independent of the nutritional status of the host. Saline-injected mice showed a decrease in the percentage of Thy 1 + cells in the spleen. Morphine treatment induced a decrease in the total number of cells and therefore in the absolute number of T-(Thy 1, CD4, CD8), B- and Mac 1 + (macrophages) cells in protein-undernourished mice. Saline-injected mice showed a decrease in the percentage of Thy 1 + cells and an increase in the percentage of B- and Ia +-cells in the spleen. We conclude that morphine altered the immune system by down-regulating splenocyte proliferation. We also studied the effects of i.p. administered morphine on expression of thymocyte phenotype in well-nourished and protein-undernourished mice. In well-nourished mice, morphine treatment reduced the number of Thy 1 +, CD4 + and CD8 + cells per thymus to 30% of that found in untreated mice and to 40% of the cells in those saline-treated controls. In protein-undernourished mice the absolute number of Thy 1 +, CD4 + and CD8 + cells per thymus in morphine-treated mice was reduced to 4% of that in untreated controls, and 8–10% of that in saline-injected mice. The results suggest that morphine has a striking effect on T-cell proliferation that is even more marked when protein-undernutrition is associated.

Spleen and thymus cell subsets modified by long-term morphine administration and murine aids — II

Intravenous heroin abusers suffer a great variety of infections, including AIDS (acquired immune deficiency syndrome). We developed an experimental mouse model to evaluate the long-term effect of in vivo morphine administration during retrovirus-induced immune dysfunction. Mice were treated daily for 11 weeks with increasing doses of morphine. Morphine treatment produced a decrease in body weight and spleen cell number. Murine retrovirus infection provoked an increase in body weight due to enlargement of lymphoid organs, and an increase in the percentage and absolute number of CD4 + and Mac 1 + cells. Interestingly, retrovirus-infected mice that were also morphine-treated did not show the increase in the relative proportion of Mac 1 + cells. Moreover, under the experimental conditions of protein-malnutrition and morphine treatment potentiation of immune dysfunction by murine retrovirus infection was investigated. Retrovirus infection-induced splenocyte proliferation was partially regulated by morphine treatment. Splenocytes from retrovirus-infected mice presented at higher percentage of IL-2R + cells and, lower levels of sIL-2R in splenocyte supernatants. Mitogen-stimulated splenocytes had a lower production of interferon-gamma as well as an increase in the secretion of tumor necrosis factor-alpha. Thus morphine altered the immune system by down-regulating splenocyte proliferation, because retrovirus infection-induced splenocyte proliferation was partially regulated by morphine treatment. We also evaluated the effects of joint murine retrovirus infection and protein undernutrition on the thymus cell subsets. Retrovirus infection was associated with a decrease in the absolute number of Thy 1 +, CD4 + and CD8 + cells per thymus with the CD8 + cell subset being the most affected. Moreover, retrovirus-infected mice presented a dramatic decrease in the percentage of double-positive (CD4 + CD8 +) cells in the thymus as well as changes in its immunoarchitecture. While protein undernutrition alone did not produce further differences between infected versus non-infected, protein-undernourished, morphine treatment induced a greater decrease in thymocyte number than that seen in retrovirus- or morphine-treated animals alone.

Changes in α-adrenoceptor number and function in brains of morphine-dependent rats

The effects of long-term treatment of rats with morphine sulfate were assessed upon the specific binding of [ 3H]clonidine to α 2-adrenoceptors on neural membranes isolated from various brain areas and upon the function of presynaptic α 2-adrenoceptors during field stimulation of hippocampal slices. Rats were injected with morphine every 8 h for 14 days with doses which started at 10 mg/kg per injection i.p., and which increased every 3 days to a final dose of 100 mg/kg per injection on the last 2 days. At 8 and 32 h after the last injection the B max for [ 3H]clonidine binding to neural membranes from various brain areas was significantly decreased. At the same times, the fractional release of [ 3H]noradrenaline during field stimulation of hippocampal slices was increased and the sensitivity of the hippocampal slice to clonidine was reduced which indicated the development of a functional subsensitivity of the presynaptic α 2-adrenoceptor. These changes in receptor function persisted at 72 h after the last morphine injection although at this time there were marked increases over control values in [ 3H]clonidine binding to membranes from all rat brain areas except the caudate nucleus. These findings suggest that changes in α 2-adrenoceptor number and function which develop during long-term morphine administration might play an important role in opiate dependence.

A simplified approach to the subcutaneous placement of epidural catheters for long-term administration of morphine.

Abstract The use of intraspinal narcotics to relieve pain of malignant origin represents a great advance in cancer pain management. For patients with a relatively short life expectancy, the delivery of intraspinal narcotics may be carried out using an as needed single-shot approach or via a simple percutaneous catheter. For patients with a longer life expectancy, implantation of subcutaneous delivery systems has been advocated to avoid complications including infection and catheter breakage. A simplified approach to placement of subcutaneous epidural catheters utilizing the Groshong silastic catheter and tunneling device is described.

β-Endorphin-like immunoreactivity in plasma, pituitaries and hypothalamus of rats following treatment with opiates

β-Endorphin was measured using a radioimmunoassay (RIA) in plasma, pituitary lobes and hypothalamus of rats following treatment with the opiate agonist morphine and the antagonist naloxone. β-Endorphine-like immunoreactivity (β-ELI) in plasma was found to be increased after high doses of morphine (50 mg/kg i.p.). A high increase of β-ELI in plasma was further observed in morphine tolerant/dependent rats after precipitated withdrawal by naloxone. This release of β-ELI into plasma was accompanied by a significant reduction of β-ELI content in the anterior lobe of the pituitary and the hypothalamus but not in the intermediate/posterior lobe of pituitary. Chronic treatment of the rats by the s.c. implantation of morphine pellets (each containing 75 mg morphine; 6 within 10 days) did not alter β-ELI levels in plasma and in the pituitary lobes. A long term administration of morphine (21 pellets within 1 month), however, causes a significant reduction of the β-ELI content of anterior lobe and intermediate/posterior lobe of pituitary without changing the β-ELI levels in plasma.

Narcotic drugs: effects on the serotonin biosynthetic systems of the brain.

The effects of short- and long-term administration of morphine on the activity of two measurable forms of rat brain tryptophan hydroxylase were studied. Morphine administration produced an immediate decrease and a longterm increase in the nerve ending (particulate) enzyme activity but did not change the cell body (soluble) enzyme activity. Cocaine administration demnonstrated a short-term decrcease in measurable nerve eniding enzyme activity that was due to the inhibition of the high affinity uptake (the Michaelis constant, K(m) is 10-(5) molar) of trytophan, the serotonin precursor. Cocaine did not aflect the low affinity uptake K(m) = 10-(5) molar) of tryptophan. Both the uptake of the precursor and the enizymiie activity appeared to be drug-sensitive regullatory processes in the biosynthlesis of serotonin.