Lack of genetic association between OCT1, ABCB1, and UGT2B7 variants and morphine pharmacokinetics.

AIM: A high inter-individual variation in the pharmacokinetics and pharmacodynamics of morphine has been observed. Genetic polymorphisms in genes encoding the organic cation transporter isoform 1 (OCT1), the efflux transporter p-glycoprotein (ABCB1), and the UDP-glucuronosyltransferase-2B7 (UGT2B7) may influence morphine pharmacokinetics and thus, also pharmacodynamics. The aim of this study was to evaluate the association between OCT1, ABCB1, and UGT2B7 variants, and morphine pharmacokinetics and -dynamics in healthy volunteers. METHODS: Pharmacokinetic and pharmacodynamic data were collected from a double-blinded, randomized, crossover trial in 37 healthy subjects. Pharmacokinetic data were analyzed in NONMEM®, and the time-concentration relationship of morphine, morphine-3-glucuronide, and morphine-6-glucuronide was parameterized as the transit compartment rate constant (ktr), clearance (CL), and volume of distribution (VD). The area under the plasma concentration-time curve (AUC0-150min) and the maximum plasma concentration (Cmax) were also calculated. Pharmacodynamic data were measured as pain tolerance thresholds to mechanical stimulation of the rectum and muscle, as well as tonic cold pain stimulation ("the cold pressor test" where hand was immersed in cold water). Six different single nucleotide polymorphisms in three different genes (OCT1 (n=22), ABCB1 (n=37), and UGT2B (n=22)) were examined. RESULTS: Neither AUC0-150min, ktr, CL, nor VD were associated with genetic variants in OCT1, ABCB1, and UGT2B7 (all P>0.05). Similarly, the antinociceptive effects of morphine on rectal, muscle, and cold pressor tests were not associated with these genetic variants (all P>0.05). CONCLUSIONS: In this experimental study in healthy volunteers, we found no association between different genotypes of OCT1, ABCB1, and UGT2B7, and morphine pharmacokinetics and pharmacodynamics. Nonetheless, due to methodological limitations we cannot exclude that associations exist.

European Pain Federation position paper on appropriate opioid use in chronic pain management.

Poorly controlled pain is a global public health issue. The personal, familial and societal costs are immeasurable. Only a minority of European patients have access to a comprehensive specialist pain clinic. More commonly the responsibility for chronic pain management and initiating opioid therapy rests with the primary care physician and other non-specialist opioid prescribers. There is much confusing and conflicting information available to non-specialist prescribers regarding opioid therapy and a great deal of unjustified fear is generated. Opioid therapy should only be initiated by competent clinicians as part of a multi-faceted treatment programme in circumstances where more simple measures have failed. Throughout, all patients must be kept under close clinical surveillance. As with any other medical therapy, if the treatment fails to yield the desired results and/or the patient is additionally burdened by an unacceptable level of adverse effects, the overall management strategy must be reviewed and revised. No responsible clinician will wish to pursue a failed treatment strategy or persist with an ineffective and burdensome treatment. In a considered attempt to empower and inform non-specialist opioid prescribers, EFIC convened a European group of experts, drawn from a diverse range of basic science and relevant clinical disciplines, to prepare a position paper on appropriate opioid use in chronic pain. The expert panel reviewed the available literature and harnessed the experience of many years of clinical practice to produce these series of recommendations. Its success will be judged on the extent to which it contributes to an improved pain management experience for chronic pain patients across Europe. SIGNIFICANCE: This position paper provides expert recommendations for primary care physicians and other non- specialist healthcare professionals in Europe, particularly those who do not have ready access to specialists in pain medicine, on the safe and appropriate use of opioid medications as part of a multi-faceted approach to pain management, in properly selected and supervised patients.

Cortical and spinal assessment - a comparative study using encephalography and the nociceptive withdrawal reflex.

BACKGROUND: Standardized objective methods to assess the analgesic effects of opioids, enable identification of underlying mechanisms of drug actions in the central nervous system. Opioids may exert their effect on both cortical and spinal levels. In this study actions of morphine at both levels were investigated, followed by analysis of a possible correlation between the cortical processing and spinal transmission. METHODS: The study was conducted after a double-blinded, two-way crossover design in thirty-nine healthy participants. Each participant received 30mg morphine or placebo as oral solution in randomized order. The electroencephalogram (EEG) was recorded during rest and during immersion of the hand into ice-water. Electrical stimulation of the sole of the foot was used to elicit the nociceptive withdrawal reflex and the reflex amplitude was recorded. RESULTS: Data from thirty subjects was included in the data analysis. There was no change in the activity in resting EEG (P>0.05) after morphine administration as compared to placebo. During cold pressor stimulation, morphine significantly lowered the relative activity in the delta (1-4Hz) band (P=0.03) and increased the activity in the alpha (8-12Hz) band (P=0.001) as compared to placebo. The reflex amplitudes significantly decreased after morphine administration (P=0.047) as compared to placebo. There was no correlation between individual EEG changes during cold pressor stimulation and the decrease in the reflex amplitude after morphine administration (P>0.05). CONCLUSIONS: Cold pressor EEG and the nociceptive reflex were more sensitive to morphine analgesia than resting EEG and can be used as standardized objective methods to assess opioid effects. However, no correlation between the analgesic effect of morphine on the spinal and cortical assessments could be demonstrated.

The effects of morphine and methylnaltrexone on gastrointestinal pain in healthy male participants.

BACKGROUND: Opioid antagonists are increasingly used to abolish the gastrointestinal side effects of opioids. However, they can potentially interfere with local analgesia exerted via opioid receptors in the gut. Thus, in the current study we aimed to explore the effect of rectal morphine before and after blocking opioid receptors outside the central nervous system with methylnaltrexone (MNTX). METHODS: In this randomized, placebo controlled, cross-over study 15 healthy male participants received the following drugs at three separate sessions: (i) placebo, (ii) 30 mg morphine administered per rectum, or (iii) 12 mg MNTX given subcutaneously before 30 mg rectal morphine. At baseline and after drug administration peripheral and central effects of the drugs were assessed by experimental pain to the skin, muscle, rectum and pupillometry. KEY RESULTS: Compared to placebo there was no local effect of morphine on mechanical rectal distension. In contrast, an increase in tolerated volume was seen following MNTX/morphine administration (p < 0.001), starting 7 min after dosing. Both morphine and MNTX/morphine had a central effect manifested as an increase in mechanical muscle pressure thresholds (both p < 0.001) and a decrease in pupil diameter (both p < 0.001). These effects occurred 30 min after dosing. CONCLUSIONS & INFERENCES: No peripheral analgesic effect of morphine was found. Methodological shortcomings may have contributed to the lack of peripheral analgesia and thus, a peripheral morphine effect on rectal pain cannot be excluded. On the other hand, the combination of MNTX and morphine exerted a local effect on rectal distensions and seems to improve analgesia.

Symptoms and side effects in chronic non-cancer pain: patient report vs. systematic assessment.

BACKGROUND: relieving distressing symptoms and managing the side effects of analgesics are essential in order to improve quality of life and functional capacity in chronic non-cancer pain patients. A quick, reliable and valid tool for assessing symptoms and side effects is needed in order to optimize treatment. We aimed to investigate the symptoms reported by chronic non-cancer pain patients after open-ended questioning vs. a systematic assessment using a list of symptoms, and to assess whether the patients could distinguish between the symptoms and the side effects induced by analgesics. METHODS: patients treated with either opioids and/or adjuvant analgesics were asked to report their symptoms spontaneously, followed by a 41-item investigator-developed symptom checklist. A control group also filled in the checklist. RESULTS: a total of 62 patients and 64 controls participated in the study. The numbers of symptoms reported by the patients (9.9 ± 5.9) were significantly higher than those reported by the controls (3.2 ± 3.9) (P<0.001). In the patient group, the number of spontaneously reported symptoms (1.3 ± 1.4) was significantly lower than the symptoms reported when using the symptom checklist (9.9 ± 5.9) (P<0.001). The six most frequently symptoms reported by the patients were: (1) Fatigue; (2) Memory deficits; (3) Dry mouth; (4) Concentration deficits; (5) Sweating; and (6) Weight gain. Out of the six most frequently reported symptoms, the share of side effects due to analgesics was: (1) Dry mouth (42%); (2) Sweating (34%); (3) Weight gain (29%); (4) Memory deficits (24%); (5) Fatigue (19%); and (6) Concentration deficits (19%). CONCLUSION: the number of symptoms reported using systematic assessment was eightfold higher than those reported voluntarily. Fatigue, cognitive dysfunction, dry mouth, sweating and weight gain were the most frequently reported. The patients reported the side effects of their analgesics to contribute substantially to the reported symptoms.

Blood-brain distribution of morphine-6-glucuronide in sheep.

BACKGROUND AND PURPOSE: At present there are few data regarding the rate and extent of brain-blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented conscious sheep. EXPERIMENTAL APPROACH: Five sheep received an intravenous infusion of M6G 2.2 mg kg(-1) over a four-minute period. Non-linear mixed-effects analysis, with hybrid physiologically based kinetic models, was used to estimate cerebral kinetics from the arterio-sagittal sinus concentration gradients and cerebral blood flow measurements. KEY RESULTS: A membrane limited model was selected as the final model. The blood-brain equilibration of M6G was relatively slow (time to reach 50% equilibration of the deep compartment 5.8 min), with low membrane permeability (PS, population mean, 2.5 ml min(-1)) from the initial compartment (V1, 13.7 ml) to a small deep distribution volume (V2) of 18.4 ml. There was some between-animal variability (%CV) in the initial distribution volume (29%), but this was not identified for PS or V2. CONCLUSION AND IMPLICATIONS: Pharmacokinetic modelling of M6G showed a delayed equilibration between brain and blood of a nature that is primarily limited by permeability across the blood-brain-barrier, in accordance with its physico-chemical properties.

Patients' evaluation of shape, size and colour of solid dosage forms.

AIM: The aim of the study was to investigate the swallow ability and the patient preferences of tablets and capsules with different sizes, shapes, surfaces and colours. METHOD: Patients were asked to swallow tablets with different surface and size, while tablets with different shape and colour were visually assessed. They were asked to indicate their preferences. RESULTS: Gelatine capsules were found easier to swallow than tablets and coated tablets were found easier than uncoated normal tablets. The preferred colour was white both for tables and capsules, and the most disliked colours were purple tablets and brown capsules. The preferred shape was strongly arched circular for small tablets, oval for medium sized and big tablets. The difficulty to swallow tablets increased with increasing size. CONCLUSION: According to the results of this study, the ideal tablet is small and white, strongly arched circular and coated. If the amount of drug requires a bigger tablet, the preferred fomat is oblong or oval with a coating. In general capsules were preferred over tablets.

Gentamicin dosing in critically ill patients.

Gentamicin is used worldwide in the treatment of serious infections in critically ill patients. The therapeutic efficacy of gentamicin is correlated to the peak serum concentration and the adverse effects to the trough concentrations. Information concerning the pharmacodynamics in critically ill patients is scarce, but pharmacokinetic data are available. A once-daily dosage regimen has replaced multiple dosing of gentamicin in most intensive care units. No studies evaluating the superiority of either of these dosage recommendations in critically ill patients have ever been conducted. Based on 8 meta-analyses performed addressing this issue on a wide range of patients and theoretical considerations, we consider a once-daily dosage regimen feasible in critically ill patients. In septic patients the volume of distribution is significantly increased compared to normal patients, implying that the initial dose should be increased in this patient population. Additionally a general trend towards using higher loading doses (5-7 mg/kg) has been observed in USA, and the appropriateness of this dosing strategy is based on a large descriptive American study. We recommend that the initial dosage of gentamicin in critically ill hyperdynamic septic patients should be 7 mg/kg. Optimal and appropriate monitoring of the treatment with gentamicin in the critically ill patient is still an issue for further investigation. The treatment period with gentamicin should be short (3-5 days), bearing the pharmacological properties of aminoglycosides (small volume of distribution and poor tissue penetration) in mind. In patients with reduced renal function the initial dose of gentamicin should also be increased and maintenance dose reduced preferentially by prolonging the dosing intervals. However, the use of aminoglycosides in a high dose regimen in oliguric or anuric patients or patients who present with a rapidly decreasing renal function needs further consideration.

Steady-state kinetics and dynamics of morphine in cancer patients: is sedation related to the absorption rate of morphine?

Eighteen patients suffering from chronic pain due to cancer completed a balanced, double-blind, double-dummy, two period cross-over trial comparing the pharmacokinetics (PK) and pharmacodynamics (PD) of morphine and its metabolites, morphine-3-glucuronide and morphine-6-glucuronide, after administration of morphine given as controlled-release (CR) tablets (every 12 h) and immediate-release (IR) tablets (every 6 h). The same total daily dose of morphine was given in both study periods. Patients received both test formulations for 4 days and on the final day of each period, peripheral venous blood samples for analysis of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were obtained. Pain intensity, sedation, and continuous reaction time (CRT) were assessed. No significant differences could be demonstrated in AUC/dose, Cmin, Cmax or fluctuation index values between the two treatments (IR and CR tablets) for either morphine or its metabolites. Tmax for morphine and its metabolites occurred significantly later after administration of CR tablets than after administration of IR tablets. There were no significant differences between the IR and the CR formulation with respect to analgesia and side effects, and there was no difference in the patients' overall impression of the two treatments. More important, there was no difference between the Tmax and the time to peak sedation after administration of IR tablets (P = 0.63). However, due to the relatively small number of patients and the variability in the data, the statistical power of the test was only 0.074. The risk of a type II error is 0.926. These data demonstrate the PK and PD similarities and differences between CR and IR morphine. They suggest that there may be a relationship between Tmax (determined by absorption rate) and sedation, but further evaluation of this potential relationship is needed.

Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists.

Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However, in order to obtain complete analgesia, a combination of an NMDA receptor antagonist and an opioid receptor agonist is needed. Recent in vitro data have demonstrated that methadone, ketobemidone, and dextropropoxyphene, in addition to being opioid receptor agonists, also are weak noncompetitive NMDA receptor antagonists. Clinical anecdotes suggest that the NMDA receptor antagonism of these opioids may play a significant role in the pharmacological action of these compounds; however, no clinical studies have been conducted to support this issue. In the present commentary, we discuss evidence for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure-activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak noncompetitive NMDA receptor antagonists in vitro has created much attention among clinicians, no clinical studies have been conducted to evaluate the applicability of these compounds in the treatment of neuropathic pain conditions.

[Morphine metabolism--pharmacokinetics and pharmacodynamics]. / Morfinmetabolisme--farmakokinetik og-dynamik.

With the increasing use of morphine, growing interest for the clinical implications of its metabolites, morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) has emerged in the literature. M-6-G binds to the opioid receptor and has analgesic properties in man. Clinical studies have not delivered strong evidence of significant correlation between the concentration of morphine and its glucuronides in plasma and cerebrospinal fluid and pharmacodynamics such as analgesia. There is no clinical evidence to indicate that M-6-G has a pronounced respiratory depressing effect in man, while the literature contains conflicting reports with regard to other side-effects. M-3-G does not bind to the m-opioid receptor and consequently has no antinociceptive effects. Studies in rodents have shown that morphine, M-6-G and especially M-3-G may induce hyperalgesia, allodynia and myoclonus. It is assumed that these side effects are caused by a spinal antiglycinergic mechanism. The role of M-3-G in morphine antagonism and development of tolerance has not yet been settled. As M-3-G and M-6-G are eliminated by the kidneys, renal insufficiency will lead to accumulation of these. Accordingly dosage should be reduced or other opioids be considered in such cases.

Recommended use of morphine in neonates, infants and children based on a literature review: Part 2--Clinical use.

The indication for morphine use is primarily pain, but also a combined analgesic and sedative effect may be the rationale behind morphine administration. Paediatric morphine regimens have been reported for children with postoperative pain, pain related to cancer, sickle cell crisis pain, burns and AIDS. No dose response curve for morphine in neonates, infants or children has been established, and different levels for the minimum effective plasma concentration have been estimated. The side effects observed in neonates, infants, and children are similar to those observed in adults, and neonates do not seem to be more susceptible to respiratory depression than older children. Despite shortcomings in the knowledge of the pharmacodynamics of morphine, it can be considered safe to administer morphine to neonates, infants or children. Initial regimens has been calculated from the pharmacokinetic parameters of morphine, but treatment must be adjusted according to analgesic effect and incidence of side effects.

Recommended use of morphine in neonates, infants and children based on a literature review: Part 1--Pharmacokinetics.

The English language literature has been reviewed in order to evaluate the present knowledge on morphine's metabolism and pharmacokinetics in children. The majority of preterm neonates are capable of glucuronidating morphine, but birth weight; gestational and postnatal age influence the glucuronidation capability. Term neonates, infants, and children are able to produce morphine glucuronides. For the reported pharmacokinetics parameters a meta-analysis was made; volume of distribution, estimated to be 2.8 +/- 2.6 l.kg-1, seems to be regardless of age, while half-life and clearance were found to be related to age. Half-life was estimated to be 9.0 +/- 3.4 h in pre-term neonates, 6.5 +/- 2.8 h in term neonates aged 0-57 days, and 2.0 +/- 1.8 h for infants and children aged 11 days to 15 years. Clearance was estimated to be 2.2 +/- 0.7 ml.min-1.kg-1 for preterm neonates, 8.1 +/- 3.2 ml.min-1.kg-1 in term neonates aged 0-57 days, and 23.6 +/- 8.5 ml.min-1.kg-1 in infants and children more than 11 days old.

Morphine metabolites.

Morphine is a potent opioid analgesic widely used for the treatment of acute pain and for long-term treatment of severe pain. Morphine is a member of the morphinan-framed alkaloids, which are present in the poppy plant. The drug is soluble in water, but its solubility in lipids is poor. In man, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are the major metabolites of morphine. The metabolism of morphine occurs not only in the liver, but may also take place in the brain and the kidneys. The glucuronides are mainly eliminated via bile and urine. Glucuronides as a rule are considered as highly polar metabolites unable to cross the blood-brain barrier. Although morphine glucuronidation has been demonstrated in human brain tissue, the capacity is very low compared to that of the liver, indicating that the M3G and M6G concentrations observed in the cerebrospinal fluid (CSF) after systemic administration reflect hepatic metabolism of morphine and that the morphine glucuronides, despite their high polarity, can penetrate into the brain. Like morphine, M6G has been shown to be relatively more selective for mu-receptors than for delta- and kappa-receptors while M3G does not appear to compete for opioid receptor binding. The analgesic properties of M6G were recognised in the early 1970s and more recent work suggests that M6G might significantly contribute to the opioid analgesia after administration of morphine. The analgesic potency of M6G after intracerebroventricular (ICV) or intrathecal (IT) administration in rats is from 45-800 timer greater than that of morphine, depending on the animal species and the experimental antinociceptive test used. Furthermore, the development of a sensitive high-performance liquid chromatography (HPLC) assay for the quantitative determination of morphine, M6G and M3G has revealed that M6G and M3G were present in abundance after chronic oral morphine administration and that the area under the plasma concentration-time curve exceeded that of morphine. M3G has been found to antagonise morphine and M6G induced analgesia and ventilatory depression in the rat, which has led to the hypothesis that M3G may influence the development of morphine tolerance. M3G exhibits no analgesic effect after ICV or IT administration. Some studies do, however, indicate that M3G may cause non-opioid mediated hyperalgesia/allodynia and convulsions after IT administration in rats. These observations led to the hypothesis that M3G might be responsible for side-effects, hyperalgesia/allodynia and myoclonus seen after high-dose morphine treatment.

Stereoselective pharmacokinetics of methadone in chronic pain patients.

Ten patients with chronic pain were randomized to an open, balanced, crossover study. Each patients received two different preparations of racemic methadone, i.e., tablets and intravenous infusion. The pharmacokinetic parameters of the R- and S-enantiomers of the racemate are reported. The analgesically active R-methadone has a significantly longer mean elimination half-life than the optical antipode S-methadone (t1/2 = 37.5 and 28.6 h, respectively). The mean total volume of distribution is 496.6 L for R-methadone and 289.1 L for S-methadone. Significant differences in the mean clearance between R- and S-methadone are seen (0.158 and 0.129 L/min, respectively). However, the lagtime after oral administration and the bioavailability did not show differences between the isomers. The data suggest that both enantiomers of methadone should be measured if correlations between pharmacodynamics and kinetics are made due to the stereoselective differences in half-life, total volume of distribution, and clearance.

The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine.

The binding affinities of racemic methadone and its optical isomers R-methadone and S-methadone were evaluated for the opioid receptors mu1, mu2, delta and kappa, in comparison with that of morphine. The analgesic R-methadone had a 10-fold higher affinity for mu1 receptors than S-methadone (IC50 3.0 nM and 26.4 nM, respectively). At the mu2 receptor, the IC50 value of R-methadone was 6.9 nM and 88 nM for S-methadone, respectively. As expected, R-methadone had twice the affinity for mu1 and mu2 receptors than the racemate. All of the compounds tested had low affinity for the delta and kappa receptors. This result suggests that S-methadone does not essentially contribute to opioid effect of racemic methadone. R-methadone has a receptor binding profile which resembles that of morphine.

Single-dose and steady-state pharmacokinetics of diltiazem administered in two different tablet formulations.

Single-dose and steady state pharmacokinetics of diltiazem administered in two different oral formulations were assessed with particular reference to rate and extent of absorption. Following single dose administration a significant difference in tmax was observed (2.9 +/- 1.9 and 6.8 +/- 2.6 hr respectively) whereas differences in AUC, t1/2 and Cmax were not significant. The AUC (mean +/- S.D.) values following single dose administration of Cardil and Cardizem were 678.4 +/- 321.5 and 948.6 +/- 580.6 ng.ml-1.hr respectively. The mean and the 95% confidence limits for the observed ratio AUCCardil/AUCCardizem are 0.89 and 0.44-1.34 respectively. At steady-state a significant difference between Cmax/Cmin and tmax was seen Cmax/Cmin being 4.9 and 3.2 respectively and Tmax being 2.7 +/- 2.0 and 6.0 +/- 2.8 hr respectively, whereas Cmax and AUC did not differ significantly. The AUC (mean +/- S.D.) values in steady state of Cardil and Cardizem were 880.1 +/- 399.8 and 1056.8 +/- 509.8 ng.ml-1.hr respectively. The mean and the 95% confidence limits for the observed ratio AUCCardil/AUCCardizem are 0.96 and 0.66-1.26 respectively. Although the observed ratios AUCCardil/AUCCardizem in both the single-dose and the steady-state study do not differ significantly from 1.0, the confidence limits exceed the acceptable values given by Poulsen & Juul (personal communication 1990) (a 20% decrease or increase of the ratio to 0.8 or 1.2).

Relative bioavailability in man of noscapine administered in lozenges and mixture.

The bioavailability of noscapine base administered in lozenges in a dose of 100 mg to twelve healthy volunteers, in a study using an open balanced cross-over design, was compared with that of 100 mg of noscapine hydrochloride given perorally as a mixture. The bioavailability of noscapine after administration in lozenges was significantly higher than that after administration of the drug as a mixture. It is concluded that the lozenges containing noscapine base may be a valuable alternative to the conventional noscapine hydrochloride mixture.