The Pharmacogenetics of Cannabis in the Treatment of Chronic Pain.

BACKGROUND: The increase in the medical use of cannabis has revealed a number of beneficial effects, a variety of adverse side effects and great inter-individual variability. Association studies connecting consumption, addiction and side effects related to recreational cannabis use have led to the identification of several polymorphic genes that may play a role in the pharmacodynamics and pharmacokinetics of cannabis. METHOD: In total, 600 patients treated with cannabis were genotyped for several candidate polymorphic genes (single-nucleotide polymorphism; SNP), encoding receptors CNR1 and TRPV1; for the ABCB1 transporter; for biotransformation, bioactivation and biosynthesis; and CYP3A4, COMT and UGT2B7 conjugation. RESULTS: Three polymorphic genes (ABCB1, TRPV1 and UGT2B7) were identified as being significantly associated with decline in pain after treatment with cannabis. Patients simultaneously carrying the most favourable allele combinations showed a greater reduction (polygenic effect) in pain compared to those with a less favourable combination. Considering genotype combinations, we could group patients into good responders, intermediate responders and poor or non-responders. Results suggest that genetic makeup is, at the moment, a significant predictive factor of the variability in response to cannabis. CONCLUSIONS: This study proves, for the first time, that certain polymorphic candidate genes may be associated with cannabis effects, both in terms of pain management and side effects, including therapy dropout. SIGNIFICANCE: Our attention to pharmacogenetics began in 2008, with the publication of a first study on the association between genetic polymorphisms and morphine action in pain relief. The study we are presenting is the first observational study conducted on a large number of patients involving several polymorphic candidate genes. The data obtained suggest that genetic makeup can be a predictive factor in the response to cannabis therapy and that more extensive and planned studies are needed for the opening of new scenarios for the personalization of cannabis therapy.

The Pharmacokinetics of Morphine and Codeine in Human Plasma and Urine after Oral Administration of Qiangli Pipa Syrup.

Papaveris pericarpium, a natural source of morphine and codeine, is the principal active component in many antitussive traditional Chinese medicines. We herein report the first PK study of papaveris pericarpium in human plasma and urine following oral administration of single (15, 30, 60 mL) and multiple dose (15 mL) of Qiangli Pipa Syrup (MOR 0.1 mg/mL, COD 0.028 mg/mL) by monitoring morphine and codeine using a HPLC-MS/MS method. Their Tmax and t1/2 values are independent of dosages, while the AUC0-t linearly increased with higher dosages, indicating linear PK characteristics. AUC0-t increased obviously after multiple doses, indicating possible risk of accumulative toxicity. Urine studies suggested risks of positive opiate drug tests with a cutoff of 300 ng/mL, which lasted 6-14 h at different doses. These results provide important information for clinical safety, efficacy and rational drug use of Qiangli Pipa Syrup and also guide the related judicial expertise of its administration.

The feasibility of physiologically based pharmacokinetic modeling in forensic medicine illustrated by the example of morphine.

In forensic medicine, expert opinion is often required concerning dose and time of intake of a substance, especially in the context of fatal intoxications. In the present case, a 98-year-old man died 4 days after admission to a hospital due to a femur neck fracture following a domestic fall in his retirement home. As he had obtained high morphine doses in the context of palliative therapy and a confusion of his supplemental magnesium tablets with a diuretic by the care retirement home was suspected by the relatives, a comprehensive postmortem examination was performed. Forensic toxicological GC- and LC-MS analyses revealed, besides propofol, ketamine, and a metamizole metabolite in blood and urine, toxic blood morphine concentrations of approximately 3 mg/l in femoral and 5 mg/l in heart blood as well as 2, 7, and 10 mg/kg morphine in brain, liver, and lung, respectively. A physiologically based pharmacokinetic (PBPK) model was developed and applied to examine whether the morphine concentrations were (i) in agreement with the morphine doses documented in the clinical records or (ii) due to an excessive morphine administration. PBPK model simulations argue against an overdosing of morphine. The immediate cause of death was respiratory and cardiovascular failure due to pneumonia following a fall, femur neck fracture, and immobilization accompanied by a high and probably toxic concentration of morphine, attributable to the administration under palliative care conditions. The presented case indicates that PBPK modeling can be a useful tool in forensic medicine, especially in question of a possible drug overdosing.

Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain.

Despite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacological interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of morphine and gabapentin in range of different dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7mg/kg), gabapentin (10, 30 and 100mg/kg) or their combination (9 combinations in total) were evaluated in the rat plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58% for the synergistic doses. The finding of dose-dependent synergistic effects highlights that choosing the right dose-dose combination is of importance in postoperative pain therapy. Our results indicate benefit of high doses of gabapentin as adjuvant to morphine. If these findings translate to humans, they might have important implications for the treatment of pain in postoperative patients.

Mechanistic Population Pharmacokinetics of Morphine in Neonates With Abstinence Syndrome After Oral Administration of Diluted Tincture of Opium.

Conducting and analyzing clinical trials in vulnerable neonates are extremely challenging. The aim of this analysis is to develop a morphine population pharmacokinetics (PK) model using data collected during a randomized control trial in neonates with abstinence syndrome (NAS). A 3-compartment morphine structural PK model after intravenous (IV) administration from previously published work was utilized as prior, whereas an allometric scaling method with physiological consideration was used to extrapolate a PK profile from adults to pediatrics. The absorption rate constant and bioavailability were estimated in NAS after oral administration of diluted tincture of opium (DTO). Goodness-of-fit plots along with normalized prediction distribution error and bootstrap method were performed for model evaluation. We successfully extrapolated the PK profile from adults to pediatrics after IV administration. The estimated first-order absorption rate constant and bioavailability were 0.751 hour(-1) and 48.5%, respectively. Model evaluations showed that the model can accurately and precisely describe the observed data. The population pharmacokinetic model we derived for morphine after oral administration of DTO is reasonable and acceptable; therefore, it can be used to describe the PK and guide future studies. The integration of the previous population PK knowledge as prior information successfully overcomes the logistic and practical issue in vulnerable neonate population.

Loss of antinociceptive effectiveness of morphine and oxycodone following titration of levothyroxine: case reports and a brief review of published literature.

Chronic pain management is a complex process involving numerous facets of care. Although pharmacotherapy is a part of the treatment plan for these patients, it often represents the most complex of the modalities to manage. Two chronic pain patients with loss of pain control following dosage increase in levothyroxine supplementation are presented. The authors sought to identify relationships among thyroid status, opioid pharmacokinetics, and nociceptive processing. In conclusion, well-designed human studies using pain models and controlling for thyroid status are warranted to better understand the impact this system has on pain control.

Cannabinoid-opioid interaction in chronic pain.

Cannabinoids and opioids share several pharmacologic properties and may act synergistically. The potential pharmacokinetics and the safety of the combination in humans are unknown. We therefore undertook a study to answer these questions. Twenty-one individuals with chronic pain, on a regimen of twice-daily doses of sustained-release morphine or oxycodone were enrolled in the study and admitted for a 5-day inpatient stay. Participants were asked to inhale vaporized cannabis in the evening of day 1, three times a day on days 2-4, and in the morning of day 5. Blood sampling was performed at 12-h intervals on days 1 and 5. The extent of chronic pain was also assessed daily. Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration-time curves for either morphine or oxycodone after exposure to cannabis. Pain was significantly decreased (average 27%, 95% confidence interval (CI) 9, 46) after the addition of vaporized cannabis. We therefore concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels. The combination may allow for opioid treatment at lower doses with fewer side effects.

Radiolabeling of morphine with (131)i and its biodistribution in rats.

This study was conducted to determine the possible radiopharmaceutical potential of morphin labeled with (131)I. Morphine was extracted from dry capsules of the opium poppy (Papaver somniferum L.), purified by high-performance liquid chromatography, and characterized with nuclear magnetic resonance and infrared spectroscopy. The purified compound was labeled with (131)I. Male Albino Wistar rats (18) were used for receptor blockage and unblockage biodistribution studies. Tissue distribution studies showed that radiolabeled morphine had higher uptake in lung, liver, small intestines, large intestines, and stomach than the other tissues. The highest uptake of radiolabeled compounds in rats' brain was found to be in the midbrain and hypothalamus. After receptor blockage with morphine, uptake of (131)I-morphine decreased in the lungs, liver, kidney, testis, prostate, spinal cord, cerebellum, hippocampus, striatum, and temporal cortex with respect to receptor unblockage studies of rats. This study concludes that the labeling yield of (131)I-morphine was high, high amount of (131)I-morphine was found in the hypothalamus, and (131)I-morphine has enough stability for diagnostic scanning.

Withania somnifera prevents morphine withdrawal-induced decrease in spine density in nucleus accumbens shell of rats: a confocal laser scanning microscopy study.

Opiate withdrawal is associated with morphological changes of dopamine neurons in the ventral tegmental area and with reduction of spine density of second-order dendrites of medium size spiny neurons in the nucleus accumbens shell but not core. Withania somnifera has long been used in the Middle East, Africa, and India as a remedy for different conditions and diseases and a growing body of evidence points to its beneficial effects on a number of experimental models of neurological disorders. Recently, many studies focused on the potential neuritic regeneration and synaptic reconstruction properties of its methanolic extract and its constituents (withanolides). This study investigates whether morphine withdrawal-induced spine reduction in the nucleus accumbens is affected by the administration of a Withania somnifera extract. To this end, rats were chronically treated with Withania somnifera extract along with morphine or saline and, upon spontaneous (1 and 3 days) or pharmacologically precipitated withdrawal, their brains were fixed in Golgi-Cox stain for confocal microscopic examination. In a separate group of animals, Withania somnifera extract was administered during three days of spontaneous withdrawal. Withania somnifera extract treatment reduced the severity of the withdrawal syndrome when given during chronic morphine but not during withdrawal. In addition, treatment with Withania somnifera extract during chronic morphine, but not during withdrawal, fully prevented the reduction of spine density in the nucleus accumbens shell in spontaneous and pharmacologically precipitated morphine withdrawal. These results indicate that pretreatment with Withania somnifera extract protects from the structural changes induced by morphine withdrawal potentially providing beneficial effects on the consequences related to this condition.

Mecanismos de tolerancia a los opioides en el control del dolor / No disponible

Durante la última década hemos asistido al descubrimiento de una serie de proteínas de señalización de expresión exclusiva o mayoritaria en el sistema nervioso que se han revelado esenciales en el procesamiento delas señales iniciadas en los receptores opioides. Estos estudios nos han permitido avanzar de modo definitivo en el conocimiento de los mecanismos que a nivel neuronal son responsables de la aparición de tolerancia/desensibilización a los analgésicos opioides. Este tipo de investigación no es posible abordarlo en estudios clínicos por lo que cobran relevancia los modelos de experimentación animal, celular o molecular. Así, gracias a los avances de la investigación básica empezamos a comprender el porqué en la clínica del dolor la rotación de opioides o su combinación con analgésicos no opioides es beneficiosa para prolongar la eficacia anticonceptiva durante el mayor tiempo posible. Asimismo, podemos afirmar que hay razones objetivas para según que tipo de dolor necesitemos tratar elegir uno u otro opioide. En estas líneas hemos tratado de aproximar ambos aspectos, investigación básica y experiencia clínica, a fin de aportar información válida al profesional del tratamiento del dolor (AU)

During the last few years nervous system research has unveiled the crucial role of a series of regulatory proteins in opioid receptor signaling. Therefore, our understanding of the molecular mechanisms responsible for the development of tolerance to opioid-induced analgesia has greatly expanded. Obviously, research of this kind is not carried out in clinical studies, and has to be performed in animal models, cultured cells, and in vitro systems. Clinical approaches such as opioid rotation or the combination of opioids with other analgesic drugs bring about the benefit of pain control during extended periods of time. Thus, the advances achieved by the basic research help us understand the efficacy of these treatments in the control of human pain. Moreover, this knowledge also provides objective reasons for selecting opioids depending on the type of pain to be treated. In the present article we have tried to approximate the outcome of basic research to clinical experience. We believe that the information provided herein will be useful to those involved in treating pain suffering in humans (AU)

Antinociceptive effects of St. John's wort, Harpagophytum procumbens extract and Grape seed proanthocyanidins extract in mice.

Hypericum perforatum extract (St. John's wort, SJW), Harpagophytum procumbens extract (HPE) and Grape seed proanthocyanidin extract (GSPE) have a broad spectrum of biological activities including antidepressant, anti-inflammatory or anti-oxidant effects. The aim of this study was to clarify antinociceptive properties of SJW, HPE and GSPE in mice with mechanisms that might potentially underlie these activities. Also, the effects of these herbal extracts on the antinociception and plasma and brain concentrations of morphine were examined. Oral pretreatment with SJW (100-1000 mg/kg) and HPE (30-300 mg/kg) attenuated significantly times of licking/biting both first and second phases of formalin injection in mice in the dose-dependent manner, and GSPE (10-300 mg/kg) suppressed second phase. Naloxone (5 mg/kg, s.c.) significantly attenuated antinociceptive effect of HPE but not SJW and GSPE. Formalin injection resulted in significant increase in the content of nitrites/nitrates (NO(x)) in mouse spinal cord. The rise of spinal NO(x) content by formalin was significantly attenuated by HPE and SJW. The pretreatment with SJW significantly potentiated an antinociceptive effect of morphine (0.3 mg/kg, s.c.), although concentrations of morphine in plasma and brain were not significantly changed by these herbal extracts. In conclusion, the present study has shown that SJW, HPE and GSPE exert significant antinociceptive effects in the formalin test of mice. In addition, opioidergic system seems to be involved in the antinociceptive effect of HPE but not SJW and GSPE. Furthermore, SJW potentiates morphine-induced antinociception possibly by pharmacodynamic interaction.

¿Sigue siendo la morfina el analgésico de elección en el infarto agudo de miocardio? / Is morphine still the analgesic of choice in acute myocardial infarction?

El dolor torácico es el síntoma más frecuente de presentación en pacientes con cardiopatía isquémica. Tradicionalmente la morfina ha sido el fármaco de elección para el control del dolor torácico en el síndrome coronario agudo (SCA) ya que su potencia analgésica es muy elevada, sin embargo sus efectos fisiológicos no están del todo claros. Su uso como terapéutica para el control del dolor torácico es de rutina, e incluso está incluida como recomendación en las guías de la ACC/AHA (American College of Cardiology/American Heart Association) delaño 2002, aunque esta recomendación no está basada enestudios científicos sólidos, sino en la opinión de expertos de la práctica clínica. La presencia de estudios a favor y en contra del uso de la morfina en el SCA, hacen ver que tal vez su beneficio no esté del todo claro. El objetivo de este trabajo es revisar los efectos fisiopatológicos de la morfina y sus implicaciones a nivel cardiaco, alertando de un posible efecto deletéreo en el SCA. Revisamos artículos desde el año 1982 al 2006 incluidos en la base de datos MEDLINE

Chest pain is the most common symptom of patientswho present with ischemic heart disease. Morphine hastraditionally been the drug of choice for managing chestpain in acute coronary syndrome (ACS) due to its highanalgesic potency, though its physiological effects arepoorly understood. Routinely used for managing chestpain, morphine is recommended in the 2002 guidelinesof the American College of Cardiology/American HeartAssociation. This recommendation, however, is not basedon a high level of scientific evidence but on expertopinion. Studies have found both for and against the useof morphine in ACS, suggesting that its benefits are perhaps not altogether clear. This review examines the pathophysiological effects of morphine and their cardiacimplications, with special attention to a possible negative effect on ACS. We reviewed articles in the MEDLINE database from 1982 to 2006

Mechanisms of nociception evoked by intrathecal high-dose morphine.

Morphine is recommended by WHO as the analgesic of choice for effective treatment of moderate to severe cancer pain . Indeed spinally administered morphine at small doses injected intrathecally (i.t.) or intracerebroventricularly into animals produces a profound antinociception at both spinal and supraspinal sites. Conversely, high doses of spinally administered morphine elicit a series of scratching, biting and licking in mice, and vocalization and agitation in rats, indicative of a spontaneous nociceptive behavioural response. Hyperalgesia and allodynia are also induced by such morphine treatment in humans as well as animals. These behaviours are not an opioid receptor-mediated event. This article will review the potential mechanisms of spinally mediated nociceptive behaviour evoked by i.t. morphine at high concentrations. We will discuss a possible presynaptic release of nociceptive neurotransmitters/neuromodulators (e.g., substance P, glutamate and dynorphin) in the primary afferent fibers following i.t. high-dose morphine. There must be an intimate interaction of i.t. high-dose morphine with tachykinin neurokinin 1 (NK1) receptors and multiple sites on the N-methyl-D-aspartate (NMDA) receptor complex in the dorsal spinal cord. Since the effect of NMDA receptor activation and the associated Ca2+ influx results in production of nitric oxide (NO) by activation of NO synthase, it seems that spinal NO also plays an important role in nociception evoked by i.t. high-dose morphine. Morphine-3-glucuronide, one of the major metabolites of morphine, has been found to evoke nociceptive behaviour similar to that of i.t. high-dose morphine. It is plausible that morphine-3-glucuronide may be responsible for nociception seen after i.t. high-dose morphine treatment. The demonstration of neural mechanism underlying morphine-induced nociception provides a pharmacological basis for improved pain management with morphine at high doses.

Farmacología de los opioides / Pharmacology of opioid drugs

En los últimos años se ha avanzado en el conocimiento de la farmacología de los opioides. Los opioides endógenos y exógenos se unen a receptores específicos. Existen cuatro tipos de receptores opioides; mu, kappa, delta y nociceptina. Todos ellos pertenecen a la familia de receptores de membrana acoplados a proteína G. Los opioides se clasifican según su afinidad y eficacia en agonistas puros, agonistas-antagonistas, agonistas parciales y antagonistas. Los principales efectos farmacológicos tras la administración de un agonista son sedación, euforia, analgesia, náusea y vómito, miosis, supresión de la tos, depresión respiratoria, rigidez, estreñimiento, enrojecimiento facial y prurito, retención urinaria y la posibilidad de dependencia (tolerancia y abstinencia). La tolerancia y dependencia física parecen deberse a una regulación por incremento de la adenilciclasa y aumento del AMPc. Los opioides además producen efectos duraderos que parecen relacionados con un aumento de la concentración de factores de transcripción como el CREB y ΔFosB y que son relevantes para las recaídas. Se revisan la farmacocinética de los principales opioides, las interacciones farmacológicas y su utilización en terapéutica (AU)

Endogenous and exogenous opioid bind to specific receptors. There are four different types of opioid receptors: mu, kappa, delta and nociceptin. All of them are membrane receptors coupled to protein G. Opioid drugs are classified, taking into account its affinity and efficacy for receptors, in four classes: pure agonists, agonist-antagonists, partial agonists and antagonists. The main pharmacological effects induced by agonists are sedation, euphoria, analgesia, nausea and vomiting, miosis, cough suppression, respiratory depression, truncal rigidity, constipation, face flushing and pruritus, urinary retention, and dependence (tolerance, withdrawal). The upregulation of the AMPc pathway seem responsible for tolerance and withdrawal symptoms. Opioide agonist induce long-lasting neural adaptations that are related to the synthesis of some transcription factors as CREB and ΔFosB, that seem relevant in relapse. Pharmacokinetic, drug interactions and therapeutic indications are reviewed (AU)

Antinociceptive effect of trans-resveratrol in rats: Involvement of an opioidergic mechanism.

trans-Resveratrol, a polyphenolic compound with potent antioxidant activity has recently been shown to be effective against carrageenan-induced hyperalgesia. In the present study, the effect of graded doses of trans-resveratrol was studied using a hot plate analgesiometer in rats. trans-Resveratrol at graded doses of 5, 10, 20 and 40 mg/kg i.p. produced dose-dependent analgesia. Pretreatment (20 min) with naloxone (1 mg/kg i.p.) blocked the analgesic effect. When the submaximal dose of trans-resveratrol (5 mg/kg i.p.) was combined with a submaximal dose of morphine (2 mg/kg i.p.), a potentiation effect was observed. The effect of trans-resveratrol (20 mg/kg i.p.) was also studied on morphine tolerance. Rats were divided into different groups: Group 1: morphine (10 mg/kg i.p.); Group 2: trans-resveratrol (5 mg/kg i.p.) administered 10 min before morphine (2 mg/kg i.p.); Group 3: trans-resveratrol (20 mg/kg i.p.) per se. Vehicle treated groups were run parallel. The treatment continued for 7 days. The occurrence of tolerance was estimated by comparing the antinociceptive effect of morphine with trans-resveratrol on day 1 and day 8. Both morphine and trans-resveratrol produced tolerance. However, in the group that received the combination of submaximal doses of trans-resveratrol and morphine, there was insignificant tolerance. These findings suggest that trans-resveratrol analgesia is mediated via an opioidergic mechanism and produces tolerance to its analgesic effect similar to morphine.

Colostrum morphine concentrations during postcesarean intravenous patient-controlled analgesia.

UNLABELLED: Patient-controlled analgesia (PCA) with morphine is a convenient method for providing postoperative analgesia. Despite the fact that it is used after cesarean delivery, data on transfer of morphine and of its active metabolite morphine-6 glucuronide (M6G) into maternal milk are scarce. It is not known whether breast-feeding during PCA with morphine has neonatal implications. We sought to measure morphine and M6G concentrations in colostrum during postpartum IV PCA and evaluate the potential for drug intake by neonates being breast-fed by these mothers. Seven informed and consenting mothers, given IV PCA with morphine, were investigated. Plasma and milk samples were obtained at titration, and at 12, 24, 36, and 48 h. Morphine and M6G were measured by high-performance liquid chromatography. In plasma, morphine concentrations ranged from <1 to 274 ng/mL, M6G ranged from <5 to 974 ng/mL. In milk, opioids were found in only 3 patients in whom morphine concentrations ranged from <1 to 48 ng/mL and M6G from <5 to 1084 ng/mL. The milk-to-plasma ratio was always <1 for morphine. In conclusion, we observed very small morphine and M6G concentrations in colostrum during PCA with morphine. Under these conditions, the amounts of drug likely to be transferred to the breast-fed neonate are negligible. IMPLICATIONS: Colostrum concentrations of morphine and its active metabolite morphine-6 glucuronide were measured in mothers receiving patient-controlled analgesia with morphine after cesarean delivery. The concentrations were found to be very small, thus supporting the safety of breast-feeding in mothers receiving IV patient-controlled analgesia with morphine.

Effects of Shilajit on the development of tolerance to morphine in mice.

Effects of concomitant administration of Processed Shilajit (PS, 0.1 and 1 mg/kg, i.p.), in Swiss mice were evaluated on the development of tolerance to morphine induced analgesia in the hot plate test. Chronic administration of morphine (10 mg/kg, i.p., b.i.d.) to mice over a duration of 10 days resulted in the development of tolerance to the analgesic effect of morphine. Concomitant administration of PS with morphine, from day 6 to day 10, resulted in a significant inhibition of the development of tolerance to morphine (10 mg/kg, i.p.) induced analgesia. Processed Shilajit per se, in the doses used, did not elicit any significant analgesia in mice; nor did the chronic concomitant administration of Processed Shilajit alter the morphine-induced analgesia. These findings with Processed Shilajit indicate its potential as a prospective modifier of analgesic tolerance to morphine.

Analgesia opiácea potenciada por nimodipino en enfermos de cáncer que necesitan escalada de la dosis de morfina: estudio doble ciego controlado con placebo / Nimodipine-enhanced opiate analgesia in cancer patients requiring morphine dose escalaion: a double-blind, placebo-controlled study

Se estudió la capacidad del nimodipino, un antagonista del calcio derivado de la dihidropiridina, de reducir la dosis diaria de morfina oral en enfermos de cáncer que necesitan escalada de la dosis. Se realizó un estudio aleatorio, doble ciego y controlado con placebo en el que participaron 54 pacientes. Los pacientes seleccionados habían necesitado al menos dos incrementos sucesivos de la dosis de m o rfina para mantener el alivio del dolor. Se estudió también la posible interacción farmacocinética entre el nimodipino y la morfina en 14 pacientes, determinando las concentraciones plasmáticas en estado estable de la morfina y sus derivados 3- y 6-glucurónidos. En total, 30 pacientes fin a l i z a ron el estudio, 14 y 16 en los grupos de nimodipino y placebo, respectivamente. El nimodipino controló la escalada de la dosis de morfina en 9 pacientes (65 por ciento) y el placebo en 4 (28 por ciento), siendo la diferencia estadísticamente significativa (p = 0,03). La dosis de morfina se redujo de 313 ñ 52 a 174 ñ 33 mg.día- 1 (p <0,001) en el grupo del nimodipino, y de 254 ñ 26 a 218 ñ 19 mg.día- 1 (no significativo) en el grupo del placebo. Los porcentajes de re d u cción de la dosis diaria de morfina mostraron también d i f e rencias significativas entre ambos grupos (p = 0,02). Una semana después de iniciarse la administración de nimodipino o placebo, la dosis de morfina se mantuvo igual que en la semana previa al estudio y las concentraciones plasmáticas de morfina y sus derivados glucurónidos no se modificaron significativamente. Nuestra conclusión ha sido que la administración de nimodipino a pacientes tratados crónicamente con morfina puede ser una alternativa segura para reducir los requisitos diarios del opiáceo. Sugerimos que la interferencia con los procesos relacionados con el Ca2 + podría atenuar la aparición y/o manifestación de tolerancia a la morfina de una manera clínicamente relevante (AU)

Nimodipine-enhanced opiate analgesia in cancer patients requiring morphine dose escalation: a double-blind, placebo-controlled study.

The ability of nimodipine, a dihydropyridine calcium antagonist, to reduce the daily dose of oral morphine in cancer patients who had developed dose escalation, was tested in 54 patients under randomized, double-blind, placebo-controlled conditions. We selected patients that required at least two successive increments of morphine to maintain pain relief. A possible pharmacokinetic interaction between nimodipine and morphine was also studied in 14 patients by assaying steady-state serum levels of morphine and its 3- and 6-glucuronides. A total of 30 patients completed the study, 14 and 16 in the nimodipine and placebo groups, respectively. Nimodipine controlled the escalation of the morphine dose in 9 patients (65%), and placebo in 4 (28%), the difference being statistically significant (P=0.03). The dose of morphine was reduced from 313+/-52 to 174+/-33 mg/day (P < 0.001) in the nimodipine group, and from 254+/-26 to 218+/-19 mg/day (not significant) in the placebo group. The percentages of reduction in the daily dose of morphine also showed significant differences between both groups (P=0.02). One week after introducing nimodipine or placebo, while the dose of morphine remained similar to that of the pre-test week, the serum levels of morphine and its glucuronides were not modified significantly. We conclude that the introduction of nimodipine in patients chronically treated with morphine may be a safe alternative to reduce the daily requirements of the opioid. It is suggested that interference with Ca2+-related events may attenuate the development and/or expression of tolerance to morphine in a clinically relevant way.

Poppy seeds: differences in morphine and codeine content and variation in inter- and intra-individual excretion.

Poppy seeds from seven different origins (Dutch, Australian, Hungarian, Spanish, Czech, and two Turkish) were analyzed for the amount of opiates present. Four grams of each kind of seeds, equivalent to the amount of seeds on two bagels, were ingested by volunteers. One volunteer also ingested four times the same amount of poppy seeds from the same origin (Spanish). During 24 hours urine samples were obtained and screened for the presence of morphine and codeine using the FPIA technique (cut-off = 200 ng/mL) and a GC/MS confirmation with a limit of detection (LOD) of 25 ng/mL for codeine and morphine. Poppy seeds from different origins contain a wide variation of morphine (2-251 micro g/g) and codeine (0.4-57.1 micro g/g) content. No other opiate could be detected. After ingestion a large interindividual variation of excretion of opiates exists. The testing results from the same kind of seeds ingested four times with a one week interval by the same volunteer also show a poor reproduceability. Several kinds of poppy seeds can give positive testing results (Australian, Hungarian, Spanish and one kind of Turkish seeds). Within 24 hours all testing results became negative.