Pain management in hemophilia: expert recommendations.

INTRODUCTION: As a typical consequence of bleeding into muscles and joints, patients with severe hemophilia suffer from acute and chronic pain. In spite of its high prevalence, pain in this patient group is not always sufficiently considered or treated in an effective manner. AIM: The recommendations presented in this paper address possible improvements in pain management in hemophilia patients and particularities that have to be taken into account in this patient group. METHOD: The manifold aspects of pain management in hemophilia patients were discussed within the framework of an expert meeting. Based on the available literature and the experts' clinical experience, the participants developed a set of recommendations presented in this paper. RESULTS: Pain management in patients with hemophilia is often insufficient, a fact that not only influences the patients' quality of life but also implies the risk of difficult to manage chronic pain. Both the prevalent polypharmacy (due to comorbidities) as well as the underlying disease itself present special challenges to pain therapy in this patient group. The present review and recommendations are intended to support medical professionals in recognising the risks of pain chronicity, applying basic principles of multimodal pain therapy, including the options of psychological intervention and modalities of physical medicine in therapy concepts, and reaching a comprehensive understanding of the range of analgesic options available.

[Pain treatment in old age: special features and recommendations]. / Schmerztherapie im Alter: Besonderheiten und Empfehlungen.

BACKGROUND: For geriatric patients with chronic pain, a comprehensive well-coordinated pain management is pivotal to ensure the best possible pain relief and to minimize as far as possible preventable negative side effects of treatment. OBJECTIVE: Description of the difficulties in pain management of geriatric patients with respect to general basic rules that are worth paying attention to and presentation of pharmacological and non-pharmacological treatment options. METHODS: This article describes the special features of pain management in older patients and gives recommendations on the use of analgesics and potential drug interactions in geriatric patients with organ dysfunction. Furthermore, individual substance groups are described with respect to their use in geriatric patients based on the recent literature. CONCLUSION: The aim of an individualized pain treatment in older and multimorbid patients is the relief of pain to an appropriate level, preservation of mobility, self-reliance and autonomy of each individual. The ability to participate in social activities as well as improvement in the quality of life need to be the focus of pharmacological and non-pharmacological treatment.

[Pain and pain management in old age: special features and recommendations]. / Schmerzen und Schmerzerfassung im Alter: Besonderheiten und Empfehlungen.

INTRODUCTION: Pain is highly prevalent in older persons and has a variety of causes. In geriatric patients, especially in patients with dementia, pain is often not sufficiently recognized and therefore frequently remains untreated. For the affected patient group this can have far-reaching consequences for their functional and cognitive abilities and may consequently lead to loss of autonomy. OBJECTIVE: Existing deficits of pain assessment for geriatric patients are described, with a primary focus on those patients suffering from cognitive impairments and pain. In addition, the influence of multimorbidity on pain management in old age is considered in detail. METHODS: The diagnostics and measurement of pain in older individuals are described based on recent literature and corresponding instruments used in the assessment of pain are outloned. The authors pay special attention to the possibilities of pain measurement in patients with higher grade cognitive impairments and non-communicative patients. CONCLUSION: A standardized pain assessment should be an integral component in the care and treatment of geriatric patients and individuals suffering from dementia. Validated instruments for pain measurement exist for both groups and should be integrated into daily clinical practice.

Effect of CB1 Ligands on Neurogenic and Myogenic Contractile Responses in the Guinea-Pig Ileum.

This study aimed at investigating whether the synthetic cannabinoid receptor agonist (+)-WIN 55212-2 has neurogenic and myogenic relaxant effects on the longitudinal muscle-myenteric plexus (LMMP) strip of the guinea-pig ileum. (+)-WIN 55212-2, 1-1,000 nmol/L, concentration-dependently inhibited both the electrical stimulation-induced cholinergic twitch responses as well as the myogenic smooth muscle contractions in the LMMP preparation. SR-141716A (rimonabant) 1-1,000 nmol/L, the cannabinoid CB1 receptor antagonist, being without effect on its own, antagonized the (+)-WIN 55212-2-induced effects. The allyl isothiocyanate (mustard oil, 100 µmol/L) induced a relaxant effect in the guinea-pig ileum, which can be regarded as neurogenic and myogenic, was augmented by (+)-WIN 55212-2, and inhibited by SR-141716A. (+)-WIN 55212-2 only moderately modified the 60 mmol/L KCl-evoked contractions. These results provide functional evidence that the CB1 agonist (+)-WIN 55212-2-induced inhibitory effects in the guinea-pig ileum are exerted both at the neuronal as well as at the intestinal smooth muscle cell level.

Upregulation of BDNF and Interleukin-1ß in rat spinal cord following noxious hind paw stimulation.

The aim of the present study was to investigate the protein levels of BDNF and IL-1ß in the lumbar dorsal horn of the rat by Western blot analysis following a noxious thermal hind paw stimulation. Ten min, 1h and 3h after the combined chemical and thermal stimulation an up to 2-fold increase in BDNF and Il-1ß protein expression was observed in the lumbar dorsal spinal cord. A pretreatment with the opioid analgesic morphine or the glial cell activation inhibitor minocycline partly attenuated protein expression. The present findings indicate that the BDNF and IL-1ß induction within the dorsal horn may be linked to the development of hyperalgesia, and that opioid analgesics and probably inhibitors of glial cell activation can prevent sensitization in the pain pathway at spinal level.

Effects of Allyl Isothiocyanate, Acetaminophen, and Dipyrone in the Guinea-Pig Ileum.

Allyl isothiocyanate (AITC, mustard oil, 50-200 µmol/l), depending on specific dosages, inhibited the cholinergic twitch response in the longitudinal muscle-myenteric plexus (LMMP) strip of the guinea-pig ileum. AITC also induced short-lasting contractile responses, and decreases of the basal tone of the LMMP strip at low concentrations and increases at high concentrations. Hexamethonium, a blocker of nicotinic ganglionic transmission, was able to prevent the AITC-evoked inhibitory effect, an effect that was also observed with the opioid antagonist naloxone. The P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2'-4'-disulphonic acid and guanethidine had no significant influence on the inhibitory effect of AITC. Since AITC also reduced the electrical stimulation-induced myogenic smooth muscle contractions in the LMMP preparation, its contractile and relaxant actions can be regarded as neurogenic and myogenic in nature. The analgesics, acetaminophen (paracetamol, 100-500 µmol/l) and dipyrone (metamizole, 100-500 µmol/l), reduced both the cholinergic twitch and the myogenic contractions in the LMMP strip to the same extent; therefore, their action in the intestinal smooth muscle can be regarded as myogenic spasmolytic in nature.

Interaction of αß-Methylene ATP with the Cholinergic Twitch Response in the Guinea-Pig Ileum.

In this study, direct effects of the P2X purinoceptor agonist αß-methylene ATP (αß-meATP) and effects on the cholinergic twitch response of the electrically stimulated longitudinal muscle-myenteric plexus (LMMP) strip of the guinea-pig ileum, were investigated. αß-meATP (1, 3, and 10 µmol/l) induced short-lasting contractions on its own, followed by an inhibition of the twitch response during its presence in the organ bath. The inhibitor of small conductance Ca2+-activated K+ (SK) channels, apamin (100 nmol/l), prevented the inhibitory effect of αß-meATP on the twitch response, whereas tetraethylammonium (300 µmol/l), a blocker of voltage-gated K+ channels and an inhibitor at nicotinic acetylcholine receptors, augmented the inhibitory effect of αß-meATP on the twitch response. It is concluded, that there is a functional interaction between P2X receptors and nicotinic receptors in the LMMP strip, and that a major part of the excitatory input to the cholinergic motor neuron evoking the twitch response is purinergic and not nicotinergic.

ERK1/2 Phosphorylation in the Rat Supraoptic Nucleus, Dorsal Raphe Nucleus, and Locus Coeruleus Neurons Following Noxious Stimulation to the Hind Paw.

Phospho-ERK1/2 (pERK1/2) fluorescence-immunohistochemistry is specifically well suited to mirror neuronal activity in the pain pathway at the cellular level. This study employed this method to visualize neuronal activity in 3 rat CNS nuclei following an acute noxious stimulation. The rat hind paw was stimulated either by heat or by a sequence of mustard oil and heat. Two min after the thermal stimulation or after the combined mustard oil and thermal stimulation, there was a significant increase in cells showing pERK1/2 immunoreactivity in the supraoptic nucleus (SON), in the dorsal raphe nucleus (DRN), and in the locus coeruleus (LC). Pretreatment with the opioid analgesic morphine or the N-methyl-D-aspartate antagonist MK-801 markedly attenuated ERK1/2 phosphorylation. These findings support the concept that the SON, the DRN, and the LC are integrated into pain processing at the hypothalamic and brain stem level.

Nicotine-Induced Modulation of the Cholinergic Twitch Response in the Ileum of Guinea Pig.

In the present study, the direct drug effects of nicotine and its effects on the cholinergic twitch responses of the electrically stimulated longitudinal muscle-myenteric plexus strip from the ileum of guinea pig were investigated. Nicotine dose-dependently (0.3-10 µmol/l) evoked the well-known contractile responses on its own. Whereas the interposed twitch responses remained present without a change in height at 1 µmol/l nicotine, a nicotine concentration of 3 µmol/l slightly and a concentration of 10 µmol/l markedly diminished the twitch during their presence. After the washout of 1-10 µmol/l nicotine, the height of the twitch response was also temporarily and significantly reduced by 30-77%. The P2X purinoceptor agonist αß-methylene ATP (1-10 µmol/l) dose-dependently induced contractions on its own and reduced the twitch response during its presence in the organ bath; however, it did not diminish the twitch responses after washout of the drug as nicotine did. The P2X antagonist pyridoxalphosphate-6-azophenyl-2'-4'-disulphonic acid, the NMDA channel blocker MK-801 and the inhibitor of small conductance Ca(2+)-activated K(+) (SK) channels apamin reduced the contractile effect of 1 µmol/l nicotine. Apamin also significantly prevented the 'post-nicotine inhibition of the twitch' following the washout of 1-3 µmol/l nicotine. As a conclusion, we provide evidence for a functional interaction between nicotinic receptors and the P2X receptors in the ileum of the guinea pig. The 'post-nicotine inhibition of the twitch' is not due to nicotinic acetylcholine receptor desensitization or transmitter depletion, but most probably the secondary effects of nicotine on SK channels determine the reduced cholinergic motor neuron excitability.

Drug fever due to a single dose of pantoprazole.

Although proton pump inhibitors (PPI) are generally well tolerated, with most adverse effects being minor and self-limiting, there are singular reports on hypersensitivity immune reactions triggered by a PPI or its metabolites. Here we report a case of acute drug-induced fever with leukocytosis and a transient increase in CRP due to pantoprazole. This was apparently an idiosyncratic reaction (inflammatory fever), showing no cross-sensitivity towards esomeprazole.

Amphotericin B transfer to CSF following intravenous administration of liposomal amphotericin B.

OBJECTIVES: Although amphotericin B (AmB) and its lipid formulations are used for the treatment of fungal infections of the CNS, the kinetics of AmB in the CSF after intravenous administration of liposomal amphotericin B (LAmB) are not well characterized. PATIENTS AND METHODS: From 14 paediatric haemato-oncological patients (aged 0.4-19.5 years, median 7.6 years), we obtained 30 CSF samples by means of routine punctures (performed for intrathecal treatment of the underlying diseases) at different timepoints after the prophylactic intravenous infusion of LAmB (AmBisome, 3 mg/kg/day). Concurrent serum samples were obtained to calculate the transfer rates. An HPLC method was used for AmB detection. RESULTS: CSF levels of AmB 1-100 h after the intravenous infusion of LAmB were between 10 and 120 ng/mL, except in one case with a level of 529 ng/mL. Concurrent serum levels were about 1000-fold higher, ranging between 3 and 75 µg/mL. CSF levels did not show a clear time-dependent concentration profile, but remained at a steady-state for longer than 48 h after infusion. The transfer rate ranged from 0.02% to 0.92% (median 0.13%) and correlated significantly (r=0.801, P<0.001) with increasing time after infusion. CONCLUSIONS: After the intravenous administration of LAmB, AmB CSF levels were low, confirming published animal data. CSF levels remained at a steady-state level for longer than 48 h. As indicated by published post mortem data, higher levels in brain tissue, which would be necessary for the successful treatment of CNS infections, might be possible.

Hexamethonium-induced augmentation of the electrical twitch response in the guinea-pig ileum longitudinal muscle-myenteric plexus strip.

Longitudinal muscle-myenteric plexus strips of the guinea-pig ileum were used to investigate the nature of the hexamethonium-induced augmentation of the twitch response. All preparations were set up in Tyrode solution and intermittent longitudinal twitch contractions were evoked by single pulse electrical field stimulation. Hexamethonium, a blocker of nicotinic ganglionic transmission, at 300 µmol/l and 1 mmol/l augmented the twitch contractions by 21% and 35%, respectively. First we tested for a possible nicotinic drive onto an inhibitory neuronal component to the longitudinal smooth muscle cells. However, guanethidine (5 µmol/l), naloxone (1 µmol/l), or l-NAME (300 µmol/l) were without effect on the hexamethonium-induced augmentation. The P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2'-4'-disulphonic acid (PPADS), 25-100 µmol/l, without altering the control twitch responses, dose-dependently reduced the hexamethonium-induced augmentation; at 100 µmol/l a statistically significantly inhibition was observed. Based on these functional experiments we found no evidence that blocking nicotinic transmission removed a tonic adrenergic, opioidergic or nitrergic inhibitory input to the longitudinal muscle. However, we provide evidence for a hexamethonium-induced augmentation of the P2 purinergic input to cholinergic motoneurons of the guinea-pig ileum longitudinal muscle. The P2-nicotinic receptor interaction presents a novel modulatory mechanism to cholinergic myenteric motor neurons.

The pain pathway in the rat following noxious thermal stimulation: effect of morphine on pERK1/2 and TRPV1 at the dorsal horn level, and on hyperalgesia.

The aim of the present study was to investigate the phosphorylation of ERK1/2 in the lumbar dorsal horn of the rat by fluorescence immunohistochemistry following a noxious thermal stimulation of the hind paw. The protein level of TRPV1 in the dorsal spinal cord and the development of a heat hyperalgesia after the acute noxious thermal stimulation were also measured. The protein content of TRPV1 was determined by Western blot and heat hyperalgesia by the plantar test. At 2 and 10 min after the thermal stimulation a 4-fold increase in pERK1/2 immunoreactivity was observed in cells of lamina I/II of the L3-L5 dorsal horn. A pretreatment with the opioid analgesic morphine markedly attenuated ERK1/2 phosphorylation. The protein content of TRPV1 in the lumbar dorsal spinal cord was not significantly altered at 1 and 4 h after the thermal hind paw stimulation and by the morphine pretreatment. Heat hyperalgesia in the plantar test was observed at 8 h, but not at 24 h after the noxious stimulation. This temporary hyperalgesia was prevented by the morphine pretreatment. The present findings indicate that ERK1/2 activation in dorsal horn nociceptive neurons may be linked to the development of hyperalgesia, and that opioid analgesics are effective agents to prevent sensitization in the pain pathway at spinal level.

Thermal stimulation of primary sensory neurons in the rat hind paw: effect of morphine on ERK1/2 phosphorylation, TRPV1 and TRPA1 channel expression.

Temperature-sensitive transient receptor potential (TRP) channels or 'thermo-TRP' were stimulated on rat sensory afferents, and the effects on the phosphorylation of ERK1/2, on the regulation of TRPV1 and TRPA1, as well as the pharmacological modulation by the opioid analgesic morphine were investigated. The thermal stimuli were applied to the rat hind paw by immersion into either hot or cold water. Phospho-ERK1/2 (p-ERK1/2) was measured by fluorescence-immunohistochemistry in the lumbar dorsal root ganglion (DRG) neurons. TRP channel mRNA expression was measured by RT-PCR in the innervating DRGs, and the protein content of TRPV1 and TRPA1 was determined by Western blot in the DRGs and in the sciatic nerve. The thermal stimuli led to a time-dependent increase in the number of DRG cells displaying cytoplasmic and nuclear staining for p-ERK1/2. Morphine partly prevented this increase in ERK1/2 phosphorylation, exerting its effect mainly on the nuclear staining. The mRNA expression for TRPV1 and TRPA1 in the DRG did not change within 24 h following the thermal stimuli. However, the protein content of both TRPV1 and TRPA1 was regulated by the thermal stimulation and by morphine. In the DRGs and in the sciatic nerve, heat or cold stimuli per se tended to decrease TRP protein levels, whereas with morphine pretreatment protein levels were raised. The present findings shed new light on the time-dependent reactions of primary sensory neurons towards irritant thermal stimuli to the skin and on their opioid modulation.

Phosphorylation of ERK1/2 in dorsal root ganglia following sequential mustard oil and thermal stimulation of the rat hind paw.

The effect of a sequential stimulation by mustard oil and noxious heat or cold on the phosphorylation of ERK1/2 in sensory afferents was investigated. The stimuli were applied to the rat hind paw and phospho-ERK1/2 (p-ERK1/2) was measured by fluorescence-immunohistochemistry in the lumbar dorsal root ganglia (DRGs) neurons. All stimuli lead to a significant increase in the number of small size DRG cells displaying cytoplasmic staining for p-ERK1/2. The combination of mustard oil with cold significantly increased the number of cells with cytoplasmic staining above the level obtained with cold stimulus alone, however this was not observed with the combination of mustard oil and heat. Nuclear staining was weak and was found increased by mustard oil combined with cold stimulation. Mustard oil is known to activate TRPA1 and TRPV1 channels, heat TRPV1, and cold TRPA1 and TRPM8. The present findings shed new light on the DRG cell populations reacting with cytoplasmic and nuclear staining for p-ERK1/2 following sequential irritant chemical and thermal stimuli to the skin.

A fluorescence-immunohistochemical study on phosphorylation of ERK1/2, p38, and STAT3 in rat dorsal root ganglia following noxious stimulation of hind paw sensory neurons.

A fluorescence-immunohistochemical investigation was performed in lumbar dorsal root ganglia (DRGs) neurons of the rat with regard to ERK1/2-, p38- and STAT3-phosphorylation in response to nociceptor activation in the rat. The stimuli applied were perineural capsaicin treatment of the sciatic nerve, mustard oil application to the hind paw and heat or cold stimulation of the hind paw. The time points of investigations were 15 min/30 min after perineural capsaicin, 30 min/2 h/4 h for mustard oil, 10 min/4 h for cold and 30 min/2 h/8 h for the heat stimulus. All four stimuli lead to a time-dependent, significant 2-3 fold increase in the number of small and medium size DRG cells displaying cytoplasmic staining for p-ERK1/2, but to no activation of satellite cells. Phosphorylated p38 immunoreactivity was increased in the cytoplasma of DRG cells at 2 h after the mustard oil treatment of the hind paw and 30 min after the perineural capsaicin application to the sciatic nerve axons, but not following heat or cold stimuli to the hind paws. Phospho-STAT3 staining was characteristically observed as nuclear and cytoplasmic staining. It was found increased after the perineural capsaicin application to the sciatic nerve axons, however, no marked increase was found with the other 3 noxious stimuli. The present results show that sensory neurons respond with a selective long-lasting increase in p-ERK1/2 in small and medium-size DRG cells, when their axons or axon terminals are stimulated by capsaicin, mustard oil, noxious heat or noxious cold.

Antidepressants: clinically relevant drug interactions to be considered.

Drug interactions in clinical practice are common and have developed into an increasing challenge for the medical profession. Specifically antidepressant drugs (ADs), which are among the 5 most frequently prescribed drugs, are predestined for adverse drug interactions because of their multiple mechanisms of action and/or their influence on drug-metabolizing cytochrome P450 (CYP) enzymes. Although selective serotonin reuptake inhibitors (SSRIs) and other new-generation ADs have an overall improved safety profile, their potential for drug interactions is to be considered. A review of the current literature has been performed, and selected examples of clinically relevant interactions with ADs have been chosen. With regard to pharmacodynamic interactions, the serotonin syndrome, the risk of bleeding under SSRI therapy, and the corrected Q-T interval prolongation are discussed in this review. The inhibitory effects of new-generation ADs on CYP enzymes show great variability and might be relevant for prescription recommendations in elderly patients and in patients with polypharmacy. The CYP-enzyme-inducing effect of St. John's wort, a popular over-the-counter herbal drug, may lead to decreased plasma levels of CYP substrates. When comparing prescription data and observed adverse drug events, there is fortunately a safety gap between the number of potential drug-drug interactions and the number of clinically observed side effects due to drug-drug interactions.

Seminal fluid ribavirin level and functional semen parameters in patients with chronic hepatitis C on antiviral combination therapy.

BACKGROUND & AIMS: Due to the possible teratogenic effect of ribavirin, effective contraception is mandatory during antiviral therapy in patients with chronic hepatitis C (CHC). The aim of this study was to evaluate seminal parameters and ribavirin and HCV-RNA concentrations in seminal fluid and serum prior to and during antiviral treatment. PATIENTS AND METHODS: Fifteen male patients (age: 42+/-9 (years+/-SD)) with CHC treated with pegylated interferon-alpha-2a and ribavirin were investigated. Seminal fluid (sperm concentration, motility, and morphology) was analysed morphologically. HCV-RNA and ribavirin concentration were determined by quantitative PCR and HPLC, respectively. Examinations were carried out at baseline, week 4, and week 12. RESULTS: Ribavirin concentration was higher in seminal fluid than in serum (week 4: 5.2+/-2.5 vs. 2.1+/-0.3; week 12: 4.4+/-1.8 vs. 2.0+/-0.3 (microg/ml, mean+/-SD; p<0.001)). Semen abnormalities were common at baseline (asthenoteratozoospermia: n=6; asthenozoospermia: n=3; teratozoospermia: n=3). Sperm density (BL: 67+/-33x10(6)/ml; week 4: 42+/-25 (p<0.05); week 12: 49+/-33 (n.s.)), percentage of sperm with progressive motility (BL: 40+/-26%; week 4: 27+/-25; week 12: 31+/-20 (n.s.)), and percentage of sperm with normal morphology (BL: 25+/-15; week 4: 20+/-11; week 12: 16+/-9; p<0.05 for both) further decreased during antiviral therapy. HCV-RNA was detectable in the seminal fluid of only two patients prior to antiviral therapy and was undetectable in all patients during combination therapy. CONCLUSION: Semen abnormalities were common in CHC patients, with further impairment during antiviral therapy. Ribavirin concentration was elevated twofold in seminal fluid compared to serum levels, which reinforces the need for contraception during antiviral combination therapy.