Birgit Kraft

Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers.

Background:Cannabinoid-induced analgesia was shown in animal studies of acute inflammatory and neuropathic pain. In humans, controlled clinical trials with &Dgr;9-tetrahydrocannabinol or other cannabinoids demonstrated analgesic efficacy in chronic pain syndromes, whereas the data in acute pain were less conclusive. Therefore, the aim of this study was to investigate the effects of oral cannabis extract in two different human models of acute inflammatory pain and hyperalgesia. Methods:The authors conducted a double-blind, crossover study in 18 healthy female volunteers. Capsules containing &Dgr;9-tetrahydrocannabinol–standardized cannabis extract or active placebo were orally administered. A circular sunburn spot was induced at one upper leg. Heat and electrical pain thresholds were determined at the erythema, the area of secondary hyperalgesia, and the contralateral leg. Intradermal capsaicin-evoked pain and areas of flare and secondary hyperalgesia were measured. Primary outcome parameters were heat pain thresholds in the sunburn erythema and the capsaicin-evoked area of secondary hyperalgesia. Secondary measures were electrical pain thresholds, sunburn-induced secondary hyperalgesia, and capsaicin-induced pain. Results:Cannabis extract did not affect heat pain thresholds in the sunburn model. Electrical thresholds (250 Hz) were significantly lower compared with baseline and placebo. In the capsaicin model, the area of secondary hyperalgesia, flare, and spontaneous pain were not altered. Conclusion:To conclude, no analgesic or antihyperalgesic activity of cannabis extract was found in the experiments. Moreover, the results even point to the development of a hyperalgesic state under cannabinoids. Together with previous data, the current results suggest that cannabinoids are not effective analgesics for the treatment of acute nociceptive pain in humans.

Opioid medication and driving ability.

In many European countries the use of opioids for long‐term treatment of nonmalignant pain has dramatically increased during the last decade in order to improve the patients quality of life, to allow an active social life and the return to work. In modern society, driving is regarded as an essential activity of daily living. Since opioids are centrally acting drugs that may interfere with the ability of safely driving a motor vehicle, the question arises of whether or not and on which conditions patients under continuous opioid medication may be considered fit to drive. In this article the evidence from recent studies of opioid effects on driving ability of patients is reviewed. Based on these data, the prerequisites and restrictions for driving under chronic opioid medication are outlined and practical guidelines are proposed.

The procoagulatory effects of delta-9-tetrahydrocannabinol in human platelets.

Delta-9-tetrahydrocannabinol (THC) is increasingly used for the long-term treatment of nausea, vomiting, cachexia, and chronic pain. Recent reports, however, have indicated an increased risk of myocardial infarction and thromboangiitis obliterans after THC intake. Blood platelets have an essential role in the pathogenesis of these two diseases, but it is unclear whether platelets are potential target cells for cannabinoids. We investigated the effects of THC on human platelets and the expression of cannabinoid receptors on their cell membranes in this in vitro study. The effects of THC (final concentrations 10−7 to 10−5 M) on the expression of activated platelet fibrinogen receptor (glycoprotein IIb-IIIa) and P selectin were characterized by flow cytometry. Western blotting was performed with platelet membrane preparations to determine the surface expression of cannabinoid receptors on human platelets. THC increased the expression of glycoprotein IIb-IIIa and P selectin on human platelets in a concentration-dependent manner. The two known cannabinoid receptors (CB1 and CB2) were both detected on the cell membrane of human platelets. Our functional results may suggest a receptor-dependent pathway of THC-induced platelet activation. However, further in vivo studies are warranted to evaluate the role of cannabinoid receptors in mediating the demonstrated procoagulatory effect of THC.

Is There Any Clinically Relevant Cannabinoid-Induced Analgesia?

Cannabis sativa is one of the oldest crops cultivated for the production of fibers and for medical and recreational purposes. Since the detection of specific cannabinoid receptors and their physiological ligands, the understanding of the cannabinoid signalling system has increased, leading to a recent resurgence of interest in its medicinal properties. In animal studies, cannabinoids exerted significant analgesic and antihyperalgesic effects, suggesting the usefulness of cannabinoids in pain conditions. However, in human experimental or clinical trials, no convincing reduction of acute pain was observed. In contrast, in chronic pain and (painful) spasticity, an increasing number of randomized, double-blind, placebo-controlled studies have shown some efficacy of cannabinoids. Besides pain, cannabinoids consistently improved mood, sleep and coping. Although cannabinoids are not first-line analgesics, they may be useful adjuvants for some special groups of patients.

No evidence for direct modulatory effects of Δ9-Tetrahydrocannabinol on human polymorphonuclear leukocytes

The effects of cannabinoids (CB) that have been reported in various leukocyte populations were mainly immunosuppressive or immunomodulatory. Almost nothing is known, however, about direct interactions of cannabinoids with human polymorphonuclear cells (PMN), although m-RNA for the cannabinoid receptor-2 (CB(2)) was found in human PMN. In order to investigate a potential influence of cannabinoids on human PMN, the migration and phagocytosis of PMN were studied in the presence of Delta(9)-Tetrahydrocannabinol (Delta(9)-THC) at final concentrations between 10(-10) and 10(-5) M. No effect was detectable on these essential PMN functions; and besides, no CB(2)-receptor expression could be detected using the Western blotting technique. Thus, circulating human PMN from healthy individuals remain unaffected by Delta(9)-THC due to the absence of functional CB(2)-receptor expression.

No carnitine palmitoyltransferase deficiency in skeletal muscle in 18 malignant hyperthermia susceptible individuals

Malignant hyperthermia is a rare, potentially life threatening pharmacogenetic disorder triggered by volatile anaesthetics and depolarizing muscle relaxants. The clinical picture comprises rhabdomyolysis, metabolic and respiratory acidosis, and hyperthermia. Carnitine palmitoyltransferase II deficiency is a metabolic myopathy affecting the transport of fatty acids into the mitochondria, leading to impaired energy supply under stressful conditions resulting in muscle weakness and rhabdomyolysis. It was postulated in a previous study that some patients with the MH phenotype have a carnitine palmitoyltransferase deficiency. To investigate a potential association, we tested 18 individuals with proven MH susceptibility for impairment of carnitine palmitoyltransferase enzyme activity in muscle. Enzyme activity was normal in all individuals tested indicating no impairment of the CPT system in this sample of malignant hyperthermia susceptible individuals. Thus our data do not support the hypothesis that susceptibility to malignant hyperthermia has an effect on the carnitine palmitoyltransferase enzyme system.

Novel double and single ryanodine receptor 1 variants in two Austrian malignant hyperthermia families.

BACKGROUND: Malignant hyperthermia (MH) is a potentially lethal genetic disorder in response to volatile anesthetics and depolarizing muscle relaxants. To support the claim that a novel genetic variant causes MH, it is necessary to demonstrate that it has significant effects on the sensitivity of the ryanodine receptor (RYR1) calcium channel. In this study we focused on 2 Austrian families with strong MH disposition and new RYR1 variants. METHODS: We sequenced the entire coding region of the RYR1 from 2 Austrian MH individuals. Genotype–phenotype segregation and evolutionary conservation of the variants were considered. On a functional level, Ca2+ release experiments with fura-2-acetoxymethyl ester were performed in cultured skeletal muscle cells derived from individuals carrying the new variants and compared with control cells from nonsusceptible individuals. Caffeine, 4-chloro-m-cresole (4-CmC), and halothane were used as specific Ca2+ releasing agents. RESULTS: The variant p.A612P in family A segregated with an MH-susceptible phenotype and cells showed an increased sensitivity for all Ca2+-releasing substances tested. In family B, 2 variants (p.R2458H/p.R3348C) were identified. While p.R2458H and p.R2458H/p.R3348C segregated with an MH-susceptible diagnosis, p.R3348C alone showed an MH equivocal diagnosis. Ca2+-release experiments showed that exchanges of these highly conserved amino acids increased the sensitivities for the substances tested (except 4-CmC with p.R2458H and p.R3348C) when compared with the MH-negative control group. CONCLUSIONS: Our results suggest that these variants are new causative MH variants.

3,5-Di-t-butyl catechol is a potent human ryanodine receptor 1 activator, not suitable for the diagnosis of malignant hyperthermia susceptibility

3,5-Di-t-butyl catechol (DTCAT) releases Ca(2+) from rat skeletal muscle sarcoplasmic reticulum (SR) vesicles. Hence, it is a candidate for use as a substitute for halothane or caffeine in the in vitro contracture test for the diagnosis of susceptibility to malignant hyperthermia (MH). To characterize the effect of DTCAT at cell level, Ca(2+) release experiments were performed on cultured, human skeletal muscle myotubes using the fluorescent Ca(2+) indicator fura2-AM. DTCAT was also assayed in the in vitro contracture test on human skeletal muscle bundles obtained from individuals diagnosed susceptible (MHS), normal (MHN) or equivocal for halothane (MHEH) and compared to the standard test substances caffeine and halothane. DTCAT increased, in a concentration-dependent manner and with a higher efficacy as compared to caffeine, the free, intracellular Ca(2+) levels of cultured MHN and MHS skeletal muscle myotubes. This effect was similar in both types of myotubes and involved the release of Ca(2+) from SR stores as well as Ca(2+)-influx from the extracellular space. Inhibition of ryanodine receptors either with ryanodine or with ruthenium red markedly reduced DTCAT-induced increase in intracellular Ca(2+) concentration while abolishing that induced by caffeine. In MHN skeletal muscle bundles, DTCAT induced contractures with an EC(50) value of 160 ± 91 μM. However, the sensitivity of MHS or MHEH muscles to DTCAT was similar to that of MHN muscles. In conclusion, DTCAT is not suitable for the diagnosis of MH susceptibility due to its failure to discriminate between MHN and MHS muscles.

Systemische und rückenmarknahe Therapie mittels Schmerzpumpen und Ports

Bei schwer behandelbaren Krebsschmerzen, die auch unter Ausschopfung aller enteralen und/oder transdermalen Optionen des WHO-Stufenschema nicht oder nur mit inakzeptablen Nebenwirkungen beherrschbar sind, stellen intravenose, subkutane und vor allem ruckenmarknahe Applikationswege guteunderfolgversprechende Alternativen dar [4, 6, 8, 12, 9, 20].Hierzu stehen neben externen, druckbetriebenen Einmalreservoirpumpen, vor allem externe, mikroprozessorgesteuerte, programmierbare Patienten-kontrollierte Pumpen (PCA-Pumpen), implantierbare Portsysteme fur intravenosen, epiduralen oder intrathekalen Zugang sowie vollstandig implantierbare gas- oder batteriebetriebene Pumpen (ausschlieslich zur Intrathekalgabe) verschiedener Hersteller zurVerfugung. Insgesamt bleiben diese invasivenVerfahren wenigen Patienten vorbehalten und werden — abhangig von der Spezialisierung der jeweiligen Einrichtung — nur bei ca. 5%bis 10%der Tumorschmerzbehandlungen notwendig.

3,5-Di-t-butyl catechol (DTCAT) as an activator of the human skeletal muscle ryanodine receptor Ca2+ channel and its evaluation as a test substance for the assessment of susceptibility to malignant hyperthermia

3,5-Di-t-butyl catechol (DTCAT) has been shown to release Ca2+ from rat skeletal muscle sarcoplasmic reticulum (SR) vesicles, which makes it a possible candidate for use as a substitute for halothane or caffeine in the in vitro contracture test (IVCT) for the assessment of susceptibility to malignant hyperthermia (MHS).