Healthcare utilization of back pain patients: results of a claims data analysis.

OBJECTIVES: The high life-time prevalence of chronic back pain (25-30% according to surveys in small samples) suggests that it may be a major source of healthcare cost and that prevention of chronic back pain may be both ethically and economically recommendable. To obtain valid economic data on the cost of back pain in Germany, a retrospective claims data analysis was performed. METHODS: Using data from 2006 of 5.2 million beneficiaries of a German statutory health insurance fund (DAK Unternehmen Leben) covering ~7% of the German population, mean value analyses report on key healthcare utilization figures from a sickness funds? perspective. In contrast to other studies, cost data are primary data and not extrapolated, but clinical characteristics include surrogate markers as no clinical case descriptions were available. RESULTS: Based on previously investigated diagnosis patterns three types of back pain could be identified: (other) specific back pain (n=211,216), pain due to spinal disk disease (n=195,712), and non-specific back pain (n=534,272). Of all back pain patients, 25.8% were identified as at risk to develop chronic pain, where only 2.6% were detected as patients with chronic back pain. Mean resource utilization and related healthcare costs were significantly higher for beneficiaries with indicators for chronic back pain than for beneficiaries with only risk factors for developing chronic back pain. This especially holds for outpatient analgesic prescriptions (p<0.05), for in-hospital multimodal pain therapy (p<0.05), for in-hospital care in general (p<0.05), as well as for direct cost of care (p<0.05). CONCLUSION: The results show the potential that could be made accessible by an early detection of back pain patients who bear a risk of pain becoming chronic, both in terms of quality-of-life as well as in financial terms.

[Opioid therapy in patients with back pain. Claims data analysis for patient group characterization, influence on opioid therapy and work disability]. / Opioidtherapie bei Versicherten mit Rückenschmerzen. Sekundärdatenanalyse zur Charakterisierung von Patientengruppen, Einfluss auf Opioidtherapie und Arbeitsunfähigkeit.

This study features an analysis of the analgesic therapy of patients with back pain focusing on opioid administration. Using claims data of a German statutory health insurance fund the analysis focuses on prescription patterns, the association between opioids and antiemetics as well as between opioid therapy and work disability. Based on typical diagnosis patterns three types of back pain could be identified: (other) specific back pain (46.0%), pain due to spinal disc diseases (23.5%) and non-specific back pain. The proportion of patients receiving continuous opioid therapy ranged between 24.3% and 48.8%. The prescription of antiemetics was associated with a higher chance of continuous opioid therapy (odds ratio [OR] 1.93; 95% confidence interval [CI] 1.79-2.08). The chance of continuous opioid therapy was higher in pain patients with spinal disc diseases and patients with (other) specific back pain (OR 1.62 and 1.76, respectively; 95% CI 1.56-1.69 and 1.69-1.83, respectively). Continuous opioid therapy appears to increase the probability of a lower number of days off work due to disability (incidence rate ratio [IRR] 0.76; 95% CI 0.70-0.84). Adequate prospective studies should test if the associations found can be confirmed.

[Pain-specific diagnosis patterns in claims data - Identification by means of classification and regression trees (CART)]. / Schmerztypische Diagnosemuster in Routinedaten - Identifikation mittels Classification and Regression Trees (CART).

The identification of beneficiaries with persistent, recurrent or chronic pain in claims data by means of individual diagnoses or analgesic prescription is not sufficient and reliable. By using CLASSIFICATION AND REGRESSION TREES (CART) it was possible to identify specific diagnosis patterns for patients suffering from pain. Diagnosis patterns are considered as specific if they occur more frequently among beneficiaries with at least two opioid prescriptions within one year compared with beneficiaries who did not receive any analgesic therapy. Diagnosis and prescription data of 2006 were provided by the German sickness fund DAK. As a result, 65 diagnosis patterns occurred more frequently among beneficiaries treated with opioids than among the control group. These 65 patterns can be classified as follows: cancer-related pain (4), specific back pain/osteoporosis (8), spine-related pain (6), arthritis-related pain/rheumatoid arthritis (22), pain after traumatic fractures (5), pain in multimorbid, dependent patients (3), neuropathic pain (7), headache (5), non-specific back pain (5). The derived diagnosis patterns showed high predictive values (sensitivity: 78%, specificity: 66%) and are suitable for the identification of beneficiaries suffering from pain - the first step towards health services research in pain-based on claims data.

[Identification and grouping of pain patients according to claims data]. / Identifikation und Gruppierung von Schmerzpatienten anhand von Routinedaten einer Krankenkasse.

The ICD classification does not provide the opportunity to adequately identify pain patients. Therefore we developed an alternative method for the identification and classification of pain patients which is based on prescription and diagnoses data from the year 2006 of one nationwide sickness fund (DAK) and which is led by two main assumptions: 1. Beneficiaries without prescription of an analgetic drug but with a diagnosis pattern that is characteristic of patients who are treated with opioids are also likely to be pain patients. 2. Each combination of diagnosis groups can be traced back to one primary diagnosis out of a diagnosis group according to the patient classification system CCS (Clinical Classifications Software). The selection of this diagnosis group (CCS) allows for the allocation of the beneficiary to only one pain type. As a result we identified 65 combinations of CCS diagnosis groups--aggregated to nine "CCS pain types"--to which 77.1% of all patients with at least two opioid prescriptions can be allocated: 26.3% to pain due to arthrosis, 18.0% to pain due to intervertebral disc illnesses, 13.1% to other specific back pain, 6.7% to neuropathic pain, 4.5% to unspecific back pain, 4.2% to headache, 2.4% to pain after traumatic fractures, 1.3% to pain of multimorbid, high-maintenance patients, and 0.6% to cancer pain. Based on our method beneficiaries who have a high probability of suffering from moderate to strong pain can be identified and included in further claims data analyses of health care delivery and utilization pattern of pain-related disorders in Germany.

[Transdermal and oral opioids for outpatient pain therapy. Comparing patients' characteristics by a claims data analysis]. / Transdermale und orale Opioide in der ambulanten Schmerztherapie. Vergleich von Patientencharakteristika anhand einer GKV-Datenanalyse.

Opioid prescriptions have increased in Germany in recent years. The usage of transdermal therapeutic systems has substantially driven this growth. The analysis was based on claims data of a German statutory health insurance (2001-2003). Statistical analysis applied univariate comparisons (exploratively only) as well as a multivariate logistic regression models. Patients in the transdermal group were older and the percentage of women was higher than in the oral group. Patients in the transdermal group received their opioids significantly more often from a GP. They had significantly less prescriptions for laxatives and antidepressants. The patients in both groups differed significantly with regard to a number of characteristics. The results indicate that GPs prefer transdermal opioids if prescribing strong-acting opioids.

Influence of phosphatidylinositol 4,5-bisphosphate on human phospholipase D1 wild-type and deletion mutants: is there evidence for an interaction of phosphatidylinositol 4,5-bisphosphate with the putative pleckstrin homology domain?

Phosphatidylinositol 4,5-bisphosphate (PIP(2)) is an essential cofactor of phospholipase D (PLD) enzymes. In order to further characterize its role in PLD activation, we have constructed N-terminal deletion mutants of the human PLD1 (hPLD1) and a mutant lacking the putative pleckstrin homology domain (delta PH), which has been proposed to be involved in PIP(2) binding. For the N-terminal deletion mutants (up to 303 amino acids) and the delta PH mutant we found no significant differences compared to the hPLD1 wild-type, except changes in the specific activities: the K(m) values were about 20 microM for the substrate phosphatidylcholine, and PIP(2) activated the PLD enzymes maximally between 5 and 10 microM. In contrast, preincubation of the PLD proteins with 5-10 microM PIP(2) or PIP(2)-containing lipid vesicles inhibited the PLD activity. This inhibition was neither abolished by n-octyl-beta-D-glucopyranoside or neomycin nor by the ADP-ribosylation factor, another activator of PLD enzymes. All tested PLD proteins were active without PIP(2) in the presence of 1 M ammonium sulfate. The 303 N-terminal amino acids of hPLD1 are not involved in substrate binding or the interaction with PIP(2). Our data indicate further that the putative PH domain of hPLD1 is not responsible for the essential effects of PIP(2) on PLD activity.

Enhancement of phospholipase D activity following baculovirus and adenovirus infection in Sf9 and COS-7 cells.

In order to purify the human phospholipase D1 (hPLD1) for analysis of its functional properties, we applied a baculovirus-based high-expression system. As expected, Sf9 cells infected with a baculovirus encoding for the hPLD1 displayed a 7.5-fold increase in PLD activity compared to uninfected cells. Sf9 cells infected with the wild-type (WT) and other recombinant baculoviruses were used as an expression control. Surprisingly, all baculoviruses tested led to a 3-5 fold increase in basal PLD activity when compared to uninfected cells. To further characterize the nature of the increased PLD activity, the influence of ADP-ribosylation factor (ARF) and phorbol 12-myristate 13-acetate (PMA) was studied. In contrast to membranes containing the hPLD1, the PLD activity in membranes from uninfected and WT-infected Sf9 cells was not stimulated by ARF. PMA did not affect the increase in PLD activity in any case. To further study whether the virus-mediated increase in PLD activity is a more general phenomenon, we infected COS-7 cells with recombinant and WT adenoviruses. Only the infection with the WT adenovirus resulted in an approx. 2-fold increase in PLD activity. Our results demonstrate for the first time that a viral infection elevates the PLD activity in insect and mammalian cells.

Role of antigen-induced cytokine release in atopic pruritus.

In order to further evaluate the role of cytokines in the induction of atopic pruritus, leukocytes from 10 atopic eczema patients or 10 nonallergic controls were stimulated in vitro with mite or birch pollen antigen for 1 and 4 days. Subjects were prick-tested with the supernatants, and whealing and itching were evaluated 20 and 60 min later. The supernatants were also examined for the contents of GM-CSF, IL-2, IL-6 and IL-8 by ELISA and TNFalpha. Two hours prior to testing, the antihistamine cetirizine (20 mg) or a placebo tablet were given to the patients according to a randomized, double-blind study protocol. After pricking with antigen-stimulated leukocyte supernatants, 6 of 10 patients but no controls reacted mostly at 20 min with whealing and/or pruritus. In the cetirizine-treated group, no decrease in these skin reactions was seen compared to placebo. Analysis for cytokines showed increased levels of IL-8 in allergen-stimulated samples, with no correlation to the induction of itching or whealing by these supernatants. IL-6 levels were low and variable, and GM-CSF, IL-2 and TNFalpha levels were always below standard values. These data show that leukocytes selectively release IL-8 in response to in vitro antigen stimulation. They furthermore provide additional support for the concept that as yet to be identified products play a role in atopic pruritus.

Expression and regulation of phospholipase D in the human keratinocyte cell line HaCaT.

The generation of lipid second messengers via phosphatidylcholine (PC)-specific phospholipase D (PLD) has emerged as an important step leading to transduction of extracellular signals. In the present investigation the expression of human cytosolic PLD isoenzymes in the immortalized human keratinocyte cell line HaCat was determined. At the mRNA level we found the expression of hPLD1b and for the first time in human cells also the expression of hPLD2. For further analysis of enzyme expression at the protein level, hPLD1 peptide fragments were synthesized and specific antibodies were generated (rabbit) to be used for detection of hPLD1 in Western blot experiments. Furthermore, small G-proteins were found to be involved in the regulation of PLD activity in HaCaT cells using the guanine nucleotide analogue GTPgammaS.

Signaling effects of alpha-thrombin and SFLLRN in rat glioma C6 cells.

Effects of thrombin on brain cells, including change of neurite outgrowth and astrocyte shape, are described, but the molecular mechanisms are unclear. We investigated the effects of human alpha-thrombin and a six amino acid thrombin receptor activating peptide (TRAP-6, SFLLRN) on [Ca2+]i, phosphoinositide hydrolysis, and protein kinase C in rat glioma C6 cells. Stimulation of C6 cells with both alpha-thrombin and TRAP-6 resulted in [Ca2+]i mobilization, [3H]Inositol phosphate response, and enhanced immunoreactivity of the protein kinase C (PKC) isoenzymes alpha, beta, gamma, delta, and epsilon. Results suggest that alpha-thrombin and TRAP-6 activate at least partially the same intracellular signaling pathways in rat glioma C6 cells, which is evidence for involvement of "tethered ligand" receptor in thrombin induced signaling in glioma C6 cells.

Characterization of a phosphatidic acid phosphatase from rat brain cell membranes.

We have characterized a phosphatidic acid phosphatase (PAP, EC 3.1.3.4) that is associated with cell membranes from rat brain using [32P]phosphatidic acid as substrate in a simple assay. The enzyme could be activated by Triton X-100, cholic acid and Chaps and inhibited by Lubrol PX and sodium dodecyl sulfate. The optimal pH was between 6.0 and 7.0 Mg2+ was not essential for enzyme activity. The enzyme activity was decreased by about 50% by Ca2+ at concentrations of 0.1 to 1 mmol/l. Zn2+ inhibited the enzyme by 50% at concentrations of about 10 mumol/l in the absence of, and 100 nmol/l in the presence (3 mmol/l) of, Triton X-100. NaF decreased the activity by about 50% at concentrations between 0.3 and 1 mmol/l when Triton X-100 was added, but did not inhibit the enzyme if the detergent was not present. N-Ethylmaleimide (NEM) did not affect the enzyme. In the absence of Triton X-100, propranolol and metoprolol enhanced the PAP activity. In the presence of 3 mmol/l Triton X-100, the enzyme was inhibited by about 50% by propranolol at a concentration of 10 mmol/l, whereas metoprolol caused only a slight inhibition of PAP. The Km for phosphatidic acid was 150 mumol/l and was changed to 20 mumol/l by 3 mmol/l Triton X-100 without the Vmax being changed. Enzyme activity could be solubilized by 1-5% (w/v) Triton X-100. Gel filtration chromatography showed a M(r) of 320,000. This membrane-associated PAP from neuronal tissue probably belongs among the NEM-insensitive forms of PAP enzymes which have been proposed to play a role in transmembrane signal transduction via phospholipase D.

The H1 receptor agonist 2-(3-chlorophenyl)histamine activates Gi proteins in HL-60 cells through a mechanism that is independent of known histamine receptor subtypes.

In dibutyryl-cAMP-differentiated HL-60 cells, histamine H1 and formyl peptide receptors mediate increases in the cytosolic Ca2+ concentration ([Ca2+]i) via pertussis toxin-sensitive G proteins of the Gi family. We compared the effects of 2-(3-chlorophenyl)-histamine (CPH) [2-[2-(3-chlorophenyl)-1H-imidazol-4-yl] ethanamine], one of the most potent and selective H1 receptor agonists presently available, with those of histamine and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) in these cells. CPH increased [Ca2+]i through Ca2+ mobilization and Ca2+ influx. Unlike histamine-induced rises in [Ca2+]i, those induced by CPH were not desensitized in a homologous manner, and there was no cross-desensitization between CPH and histamine. Like fMLP, CPH activated phospholipases C and D, tyrosine phosphorylation, superoxide anion formation, and azurophilic granule release. The effects of CPH on [Ca2+]i, phospholipase D, and superoxide anion formation were inhibited by pertussis toxin. CPH and fMLP stimulated high affinity GTP hydrolysis by Gi proteins in HL-60 membranes. They also enhanced binding of guanosine-5'-O-(3-thio)triphosphate and GTP azidoanilide to, and cholera toxin-catalyzed ADP-ribosylation of, Gi protein alpha subunits. Histamine receptor antagonists did not inhibit the stimulatory effects of CPH, and CPH did not reduce fMLP binding in HL-60 membranes. Our data suggest that CPH activates Gi proteins in HL-60 cells through a receptor agonist-like mechanism that is, however, independent of known histamine receptor subtypes and formyl peptide receptors. CPH may be an agonist at an as yet unknown histamine receptor subtype or, by analogy with other cationic-amphiphilic substances, may activate G proteins directly. Future studies will have to take into consideration the fact that CPH, in addition to activating H1 receptors, may show other, most unexpected, stimulatory effects on G protein-mediated signal transduction processes.

Lipopeptides activate Gi-proteins in dibutyryl cyclic AMP-differentiated HL-60 cells.

Synthetic lipopeptides activate superoxide-anion (O2-) formation in human neutrophils in a pertussis-toxin (PTX)-sensitive manner, suggesting the involvement of G-proteins of the Gi family in the signal-transduction pathway. We compared G-protein activation by lipopeptides and the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) in dibutyryl-cyclic-AMP-differentiated HL-60 cells. The lipopeptide (2S)-2-palmitoylamino-6-palmitoyloxymethyl-7-palmitoyloxy heptanoyl-SK4 (Pam3AhhSK4) and fMLP activated high-affinity GTPase, i.e. the enzymic activity of G-protein alpha-subunits, in HL-60 membranes in a time- and protein-dependent manner, but they had no effect on Mg(2+)-ATPase and Na+/K(+)-ATPase. Pam3AhhSK4 and fMLP increased Vmax. of GTP hydrolysis. Pam3AhhSK4 activated GTP hydrolysis with half-maximal and maximal effects at about 2 microM and 10 microM respectively. Other lipopeptides activated GTP hydrolysis as well. Lipopeptides were less effective than fMLP to activate GTPase. In membranes from PTX-treated cells, the stimulatory effects of lipopeptides and fMLP on GTPase were abolished. In N-ethylmaleimide-treated membranes, the relative stimulatory effect of Pam3AhhSK4 on GTP hydrolysis was enhanced, whereas that of fMLP was diminished. fMLP and Pam3AhhSK4 activated GTPase in an over-additive manner in N-ethylmaleimide-treated membranes. Unlike fMLP, Pam3AhhSK4 did not enhance incorporation of GTP azidoanilide into, and cholera-toxin-catalysed ADP-ribosylation of Gi-protein alpha-subunits in, HL-60 membranes and did not induce rises in cytosolic Ca2+ concentration. Pam3AhhSK4 and fMLP stimulated phosphatidic acid formation in a PTX-sensitive manner. Pam3AhhSK4 itself did not activate O2- formation, but potentiated the stimulatory effects of fMLP. Our data suggest that (i) lipopeptides activate the GTPase of Gi-proteins, (ii) lipopeptides and fMLP activate Gi-proteins differently, (iii) lipopeptides stimulate phospholipase D via Gi-proteins, and (iv) phosphatidic acid formation is not sufficient for activation of O2- formation.

Histamine increases cytosolic Ca2+ in dibutyryl-cAMP-differentiated HL-60 cells via H1 receptors and is an incomplete secretagogue.

Human neutrophils and dibutyryl-cAMP (Bt2cAMP)-differentiated HL-60 cells possess receptors for the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe), which mediate activation of phospholipase C, with subsequent increase in cytosolic Ca2+ concentration ([Ca2+]i) and activation of specific cell functions. In many cell types, histamine, via H1 receptors, activates phospholipase C, but it is unknown whether neutrophilic cells possess functional H1 receptors. We compared the effects of histamine with those of fMet-Leu-Phe on activation of these cells. In Bt2cAMP-differentiated HL-60 cells, substances increased [Ca2+]i in the effectiveness order fMet-Leu-Phe greater than histamine greater than betahistine. Pertussis toxin diminished fMet-Leu-Phe-induced rises in [Ca2+]i to a greater extent than those induced by histamine. H1 but not H2 antagonists inhibited histamine- and betahistine-induced rises in [Ca2+]i. fMet-Leu-Phe and histamine activated phospholipase C and increased [Ca2+]i through release of Ca2+ from intracellular stores and sustained influx of Ca2+ from the extracellular space. The substances also induced Mn2+ influx. Ca2+ and Mn2+ influxes were inhibited by 1-(beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl)-1H-imida zole hydrochloride (SK&F 96365). The stimulatory effects of histamine on [Ca2+]i were more sensitive to inhibition by 4 beta-phorbol 12-myristate 13-acetate than were those of fMet-Leu-Phe. Unlike fMet-Leu-Phe, histamine did not activate superoxide anion formation, release of beta-glucuronidase, and tyrosine phosphorylation. In neutrophils, histamine and betahistine did not induce rises in [Ca2+]i. Our data show that (i) in Bt2cAMP-differentiated HL-60 cells, histamine increases [Ca2+]i via H1 receptors coupled to pertussis toxin-sensitive and possibly, pertussis toxin-insensitive heterotrimeric regulatory guanine nucleotide-binding proteins, (ii) histamine activates nonselective cation channels, and (iii) unlike fMet-Leu-Phe, histamine is an incomplete secretagogue.

Histamine increases cytosolic Ca2+ in HL-60 promyelocytes predominantly via H2 receptors with an unique agonist/antagonist profile and induces functional differentiation.

Histamine H1 receptors mediate activation of phospholipase C, with subsequent increases in cytosolic Ca2+ concentration ([Ca2+]i), and H2 receptors mediate accumulation of cAMP. HL-60 promyelocytes possess H2 receptors, but it is not known whether these cells also possess H1 receptors. We studied the effects of histamine on [Ca2+]i and the functional importance of histamine receptors in HL-60 promyelocytes. In these cells, histamine and dimaprit increased [Ca2+]i with EC50 values of 15 microM and 30 microM, respectively. Diphenhydramine inhibited the effect of histamine (100 microM) on [Ca2+]i up to 40%, with an IC50 of 100 nM. Famotidine and cimetidine diminished the effect of histamine (100 microM) up to 75%, with IC50 values of 85 nM and 300 nM, respectively. Diphenhydramine plus famotidine abolished histamine-induced rises in [Ca2+]i. Impromidine, with an IC50 of 100 nM, abolished the effect of histamine (100 microM) on [Ca2+]i. Diphenhydramine, famotidine, cimetidine, and impromidine showed marked noncompetitive antagonism with histamine. Histamine-induced increases in [Ca2+]i were largely due to influx of Ca2+ from the extracellular space. Ca2+ influx was inhibited by 1-(beta-[3-(4-methoxyphenyl)propoxyl]-4-methoxyphenethyl)-1H-imida zole hydrochloride (SK&F 96365). Histamine activated phospholipase C. Histamine induced expression of formyl peptide receptors, which effect was abolished by famotidine. In U-937 promonocytes and in the human erythroleukemia cell lines HEL and K-562, histamine did not induce rises in [Ca2+]i. Our data suggest the following. (i) In HL-60 promyelocytes, histamine increases [Ca2+]i predominantly via H2 receptors and to a lesser extent via H1 receptors. (ii) The agonist/antagonist profile of the H2 receptor-mediated increases in [Ca2+]i differs markedly from that for cAMP accumulation, suggesting the involvement of different H2 receptor subtypes. (iii) In HL-60 promyelocytes, histamine activates nonselective cation channels and induces functional differentiation via H2 receptors.

Characterization of an inositol 1,3,4,5-tetrakisphosphate 3-phosphatase from porcine brain.

Some of the properties of a high affinity Ins(1,3,4,5)P4 3-phosphatase (Km approximately 400 nM) from the soluble fraction of pig brain are presented. Several inositol polyphosphates reduced the activity of the Ins-(1,3,4,5)P4 3-phosphatase. The most effective inhibitors were Ins(1,3,4, 5,6)P5 and InsP6 with Ki-values of about 60 nM and 3 nM, respectively. We could show that at least InsP6 is a likely substrate of the Ins(1,3,4,5)P4 3-phosphatase, which degraded InsP6 with a very low reaction velocity. This 3-phosphatase may be important for the metabolism of higher phos-phorylated inositol polyphosphates.