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.

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.

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.

Symptoms and side effects in chronic non-cancer pain patients: clinical implications and development of new assessment tools.

OBJECTIVE: To improve a 41-item screening tool evaluated in our previous study by making it more simple and convenient to patients and at the same time maintain the level of information and the sensitivity. METHODS: In a prospective, two-period questionnaire study, patients suffering from chronic pain of non-cancer origin for more than 6 months, were asked to fill in two questionnaires: QSSE-41 or QSSE-33 and SF-36. The first part of the study (QSSE-41) included an age- and sex-matched control group. RESULTS: A total of 67 patients were included in QSSE-41 and 60 patients in QSSE-33. In QSSE-41, the mean number of symptoms reported by the patient group (12.3) was significantly higher than those reported by the controls (6.8) (P < 0.001). Out of the total number of symptoms, 40.3% were reported to be side effects caused by analgesics, and out of those 61.3% were reported as acceptable and 38.7% as unacceptable side effects. In the QSSE-33, the mean number of symptoms reported by the patient group was 13.6. Out of the total number of symptoms, 46.3% were reported to be side effects caused by analgesics, and out of those 56.4% were reported as acceptable and 43.6% as unacceptable side effects. CONCLUSIONS: This new and shorter screening tool QSSE-33 may substitute the original QSSE-41 and in clinical use, contribute substantially to a more comprehensive and detailed understanding of symptoms/side effects and may consequently lead to improved therapies.

Renal function and symptoms/adverse effects in opioid-treated patients with cancer.

BACKGROUND: Renal impairment and the risk of toxicity caused by accumulation of opioids and/or active metabolites is an under-investigated issue. This study aimed at analysing if symptoms/adverse effects in opioid-treated patients with cancer were associated with renal function. METHODS: Cross-sectional multicentre study (European Pharmacogenetic Opioid Study, 2005-2008), in which 1147 adult patients treated exclusively with only one of the most frequently reported opioids (morphine/oxycodone/fentanyl) for at least 3 days were analysed. Fatigue, nausea/vomiting, pain, loss of appetite, constipation and cognitive dysfunction were assessed (EORTC QLQ-C30). Glomerular filtration rate (GFR) was estimated using Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations. RESULTS: Mild to severe low GFR was observed among 40-54% of patients. CG equation showed that patients with mild and moderate/severe low GFR on morphine treatment had higher odds of having severe constipation (P < 0.01) than patients with normal GFR. In addition, patients with moderate/severe low GFR on morphine treatment were more likely to have loss of appetite (P = 0.04). No other significant associations were found. CONCLUSION: Only severe constipation and loss of appetite were associated with low GFR in patients treated with morphine. Oxycodone and fentanyl, in relation to the symptoms studied, seem to be safe as used and titrated in routine cancer pain care.

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.

Pain characteristics and management of inpatients admitted to a comprehensive cancer centre: a cross-sectional study.

AIMS: This prospective, cross-sectional study aimed to assess cancer pain and its management in an inpatient setting at a comprehensive cancer centre in Denmark. METHODS: One hundred and eighty-eight inpatients with cancer were invited to participate (May/June 2011). Demographics, diagnoses, World Health Organization performance status, health-related quality of life, pain and data regarding analgesic treatment were registered. RESULTS: One hundred and thirty-four (71.3%) patients agreed to participate in the study. Most frequent diagnoses were leukaemia (27.6%) and lung cancer (14.2%). A high prevalence of pain was observed, 65.7%. Thirty-two per cent reported moderate to severe pain when it was at its worst, 96% reported no or mild pain when it was at its least. Nearly 22% reported moderate to severe pain when the pain was categorised as average. Breakthrough pain episodes were reported by 30.5%. Adjuvant medication was sparsely used and not always correctly indicated. Out of 88 patients with pain, 62.5% were left untreated according to the Electronic Medication System. Higher health-related quality of life was associated with lower pain intensity. The use of opioids with or without adjuvants was associated with higher pain intensity and higher number of breakthrough pain episodes. CONCLUSIONS: Approximately two thirds of inpatients reported pain and one third had breakthrough pain. A substantial number of patients with pain were left untreated. Opioid-treated patients reported highest pain intensity and number of breakthrough episodes; however, analgesic medication seemed to be underused. Measures to improve pain assessment and management are highly required.

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.

The Danish version of the questionnaire on pain communication: preliminary validation in cancer patients.

BACKGROUND: The modified version of the patients' Perceived Involvement in Care Scale (M-PICS) is a tool designed to assess cancer patients' perceptions of patient-health care provider pain communication process. The objective of this study was to examine the psychometric properties of the shortened Danish version of the M-PICS (SDM-PICS). METHODS: The validated English version of the M-PICS was translated into Danish following the repeated back-translation procedure. Cancer patients were recruited for the study from specialized pain management facilities. RESULTS: Thirty-three patients responded to the SDM-PICS, Danish Barriers Questionnaire II, Hospital Anxiety and Depression Scale, and Brief Pain Inventory Pain Severity Scale. A factor analysis of the SDM-PICS resulted in two factors: Factor one, patient information, consisted of four items assessing the extent to which the patient shared information with his/her health care provider, and Factor two, health care provider information, consisted of four items measuring the degree to which a health care provider was perceived as the one who shares information. Two separate items addressed the perceived level of information exchange between the patient and the health care provider. The SDM-PICS total had an internal consistency of 0.88. The SDM-PICS scores were positively related to pain relief and inversely related to the measures of cognitive pain management barriers, anxiety, and reported pain levels. CONCLUSION: The SDM-PICS seems to be a reliable and valid measure of perceived patient-health care provider communication in the context of cancer pain.

Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone.

OBJECTIVE: To investigate the influence of CYP2D6 genotype on the oral clearance of (R)-, (S)- and rac-methadone. METHODS: In this retrospective study, CYP2D6 genotypes were identified in 56 methadone maintained subjects. Plasma concentrations of (R)-, (S)- and rac-methadone were determined by stereoselective HPLC and sufficient data were available to estimate the apparent oral clearances of (R)-, (S)- and rac-methadone using a population kinetic model in 37 of the genotyped subjects. RESULTS: The CYP2D6 allele frequencies were similar to those previously reported in Caucasians, the most common being: CYP2D6*1 (35.2%), CYP2D6*2 (12.0%) and CYP2D6*4 (22.2%). Three unknown SNPs were found in four subjects: 1811G > A (n = 1), 1834C > T (n = 1) and 2720G > C (n = 2). The oral clearances of (R)-, (S)- and rac-methadone varied 5.4-, 6.8- and 6.1-fold, respectively. No significant differences in methadone oral clearance were found between CYP2D6 genotypic PM, IM and EM (p = 0.57, 0.40 and 0.43 for (R)-, (S)- and rac-methadone, respectively). Only 1 subject had duplication of functional CYP2D6 alleles and the oral clearance of the three analytes was not markedly altered. CONCLUSIONS: CYP2D6 poor, intermediate and extensive metabolizer genotypes did not appear to impact on the oral clearance of (R)-, (S)- or rac-methadone. In addition, methadone dosage requirements were not influenced by CYP2D6 genotypes in these subjects. However, the impact of duplication of functional CYP2D6 alleles on oral clearance and dosage requirements requires further investigation.

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.

Pain, sedation and morphine metabolism in cancer patients during long-term treatment with sustained-release morphine.

BACKGROUND: Morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) are the two most important metabolites of morphine. Both are pharmacologically active, however, with different effects. M-6-G has been demonstrated capable of inducing anti-nociception and sedation, and M-3-G may induce behavioural excitation and possibly antagonise anti-nociception. Their impact on pharmacodynamics in patients in long-term treatment with oral morphine remains to be settled. METHODS: Forty-two cancer patients treated with oral sustained-release (SR) morphine were assessed for pain, sedation and other side effects related to morphine treatment. Blood samples were analysed for morphine, M-3-G and M-6-G by high-performance liquid chromatography (HPLC). RESULTS: Significant correlations were found between the daily dose of SR morphine and plasma morphine (M) (r = 0.535, P < 0.001), plasma M-6-G (r = 0.868, P < 0.001) and plasma M-3-G (r = 0.865, P < 0.001). There was no relationship between plasma morphine, M-6-G, M-6-G/M and pain and sedation scores. Seventy-nine percent of the patients suffered from dryness of the mouth, which was the most frequent side effect observed. Patients in this group had higher plasma morphine and M-6-G concentrations than patients who did not suffer from this side effect. CONCLUSION: The plasma concentrations of morphine and its metabolites, M-3-G and M-6-G, are significantly correlated to the daily dose of SR morphine. Although M-6-G has analgesic properties, no associations were found between pain and plasma morphine and morphine metabolites. This may be due to the multitudinous factors affecting the dose-effect relationship. Patients with dryness of the mouth had higher concentrations of morphine and M-6-G than patients without this side effect.

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.

Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration? Six case histories.

BACKGROUND: Recently, clinical reports have suggested a relationship between the occurrence of hyperalgesia, allodynia and/or myoclonus and treatment with high doses of morphine in humans. Although few clinical descriptions of these phenomena are available, experimental work supports the notion that high doses of morphine may play a pathogenetic role in the observed behavioural syndrome. METHODS: Six patients, four with malignant and two with chronic, non-malignant pain conditions, treated with moderate to high doses of oral, continuous intravenous infusion or intrathecal morphine developed hyperalgesia, allodynia and/or myoclonus. When the side-effects occurred, blood or CSF samples were taken and analyzed for contents of morphine, morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G). RESULTS: When comparing the plasma and CSF concentrations from these patients with data from available literature obtained from patients not suffering from these side-effects, it was demonstrated that the values deviated in five patients. In all six patients, the side-effects disappeared after substituting morphine with other opioid agonists or after lowering the daily dose of morphine. CONCLUSION: These results may indicate that elevated concentrations of M-3-G in plasma as well as the plasma and CSF M-3-G/M-6-G ratios may play a pathogenetic role in the development of hyperalgesia, allodynia and myoclonus.

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.