Highly efficient base excision repair (BER) in human and rat male germ cells.

The quality of germ cell DNA is critical for the fate of the offspring, yet there is limited knowledge of the DNA repair capabilities of such cells. One of the main DNA repair pathways is base excision repair (BER) which is initiated by DNA glycosylases that excise damaged bases, followed by incision of the generated abasic (AP) sites. We have studied human and rat methylpurine-DNA glycosylase (MPG), uracil-DNA glycosylase (UNG), and the major AP endonuclease (HAP1/APEX) in male germ cells. Enzymatic activities and western analyses indicate that these enzymes are present in human and rat male germ cells in amounts that are at least as high as in somatic cells. Minor differences were observed between different cellular stages of rat spermatogenesis and spermiogenesis. Repair of methylated DNA was also studied at the cellular level using the Comet assay. The repair was highly efficient in both human and rat male germ cells, in primary spermatocytes as well as round spermatids, compared to rat mononuclear blood cells or hepatocytes. This efficient BER removes frequently occurring DNA lesions that arise spontaneously or via environmental agents, thereby minimising the number of potential mutations transferred to the next generation.

Nucleotide excision repair in rat male germ cells: low level of repair in intact cells contrasts with high dual incision activity in vitro.

The acquisition of genotoxin-induced mutations in the mammalian germline is detrimental to the stable transfer of genomic information. In somatic cells, nucleotide excision repair (NER) is a major pathway to counteract the mutagenic effects of DNA damage. Two NER subpathways have been identified, global genome repair (GGR) and transcription-coupled repair (TCR). In contrast to somatic cells, little is known regarding the expression of these pathways in germ cells. To address this basic question, we have studied NER in rat spermatogenic cells in crude cell suspension, in enriched cell stages and within seminiferous tubules after exposure to UV or N-acetoxy-2-acetylaminofluorene. Surprisingly, repair in spermatogenic cells was inefficient in the genome overall and in transcriptionally active genes indicating non-functional GGR and TCR. In contrast, extracts from early/mid pachytene cells displayed dual incision activity in vitro as high as extracts from somatic cells, demonstrating that the proteins involved in incision are present and functional in premeiotic cells. However, incision activities of extracts from diplotene cells and round spermatids were low, indicating a stage-dependent expression of incision activity. We hypothesize that sequestering of NER proteins by mispaired regions in DNA involved in synapsis and recombination may underlie the lack of NER activity in premeiotic cells.

Enhanced susceptibility of obese mice to glycidamide-induced sperm chromatin damage without increased oxidative stress.

Diet-induced obesity is known to impair male reproduction and may aggravate the male reproductive toxicity of the food contaminant acrylamide. Exposure of male mice to acrylamide induces paternally mediated pre- and post-implantation losses because of spermatozoal toxicity and these effects are potentiated in mice fed a high-fat diet. Glycidamide - an acrylamide metabolite - is the primary mediator of reproductive effects in males. The mechanisms causing the interaction between diet and acrylamide are not clear. However, diet-induced obesity is associated with oxidative stress in male reproductive tissues which might contribute to increased germ cell susceptibility. In this study, we investigated whether a moderate diet-induced obesity regimen could interfere with glycidamide-induced spermatozoal toxicity and increase oxidative stress. For this purpose, sperm chromatin integrity, oxidised DNA and protein levels, transcript levels of oxidative stress responsive genes and glycidamide-induced DNA and haemoglobin adducts were analysed in samples from male mice exposed to a high-fat diet for 6 weeks in combination with a single glycidamide exposure 7 days prior to sacrifice. We found that glycidamide-induced sperm DNA fragmentation was markedly higher in obese than in lean mice. However, the levels of oxidised DNA and/or protein in blood, liver and testicular tissue was lower in obese than in lean mice. Accompanying the reduced level of oxidised macromolecules, the transcript levels of several oxidative stress-related genes were altered in the liver and testis from obese mice suggesting induction of an antioxidant response in these animals. The haemoglobin-glycidamide adduct levels were higher in obese than in lean animals, whereas obesity did not seem to increase the level of glycidamide-induced DNA adducts. These findings show that a moderate diet-induced obesity regimen may potentiate glycidamide-induced sperm cells toxicity and suggest that the increase in glycidamide-induced sperm toxicity observed in obese mice does not depend on overt oxidative stress.

Early postoperative erythromycin breath test correlates with hepatic cytochrome P4503A activity in liver transplant recipients.

BACKGROUND: Interindividual variation in the pharmacokinetics of the immunosuppressive agents cyclosporine (INN, ciclosporin) and tacrolimus may result from differences in the activity of cytochrome P4503A (CYP3A). The erythromycin breath test is an in vivo assay of hepatic CYP3A activity, but the method has never been directly validated. The aim of the study was to investigate whether an early postoperative erythromycin breath test correlated with the hepatic CYP3A protein level and catalytic activity in liver transplant recipients. METHODS: In 18 liver transplant recipients, the erythromycin breath test was performed within 2 hours after transplantation. A graft biopsy was obtained during surgery and analyzed for the CYP3A protein level by Western blotting and for CYP3A activity with erythromycin demethylation and testosterone 6beta- hydroxylation assays. RESULTS: The erythromycin breath test values ranged from 0.14% to 1.65% of carbon 14 per hour, and the CYP3A protein level ranged from 732 to 7822 as measured by optical density. The in vitro catalytic activity determined by the erythromycin demethylation assay ranged from 94 to 902 disintegrations per minute per 5 minutes per milligram of protein, and the activity determined by testosterone 6beta-hydroxylation ranged from 0.030 to 0.627 nmol per minute per milligram of protein. Significant correlation was demonstrated between the erythromycin breath test and both the erythromycin demethylation (Spearman correlation coefficient: R = 0.76, R (2) = 0.57; P =.0004) and the testosterone 6beta-hydroxylation (Spearman correlation coefficient: R = 0.79, R (2) = 0.63; P =.0001) assays. The erythromycin breath test also correlated with the CYP3A protein level (Spearman correlation coefficient: R = 0.60, R (2) = 0.36; P =.01). CONCLUSION: Our data support the erythromycin breath test as a specific in vivo assay of CYP3A activity in humans. The test is applicable in liver transplant recipients in the early postoperative phase. Future studies should evaluate the clinical usefulness of an early postoperative erythromycin breath test as a predictor of cyclosporine-tacrolimus pharmacokinetics in liver transplantation.

Symptomatology of cancer patients in palliative care: content validation of self-assessment questionnaires against medical records.

To elucidate which symptoms or problems to measure when evaluating palliative care, we assessed the content validity of selected patient self-assessment questionnaires used to evaluate palliative care: the European Organization for Research and Treatment of Cancer-Quality of Life-Core 30 (EORTC QLQ-C30), the Edmonton Symptom Assessment System (ESAS), the Palliative Care Outcome Scale (POS), the McGill Quality of Life Questionnaire (MQOL) and the Memorial Symptom Assessment Scale (MSAS). The content of the questionnaires was compared against the symptoms and problems noted in the medical records of 171 consecutive cancer patients on their first admission to a department of palliative medicine. From the records, 63 different symptoms were listed. Two questionnaires covered almost all of the prevalent symptoms/problems: the EORTC QLQ-C30 covered 10 and the MSAS 11 of the 12 most frequent problems. Researchers selecting instruments for evaluating palliative care may use the present study and other reviews to examine to what degree a given selection of instruments cover the symptoms/problems targeted by palliative care physicians.

Neuropsychological performance in cancer patients: the role of oral opioids, pain and performance status.

The aim of the present study was to evaluate the possible influence of oral opioids, pain and performance status on some aspects of psychomotor function and cognition in cancer patients. One hundred and thirty cancer patients between 40 and 76 years of age were consecutively included in the study. In order to separate the impact of performance status, pain and oral opioids on neuropsychological functioning the patients were allocated in a cross-sectional design to five different groups. Group 1 (N=40), which was considered the control group, was characterized by being in Karnofsky Performance Status (KPS) A ('Able to carry on normal activity and work. No special care is needed'), had no pain and received no oral opioid medication. Group 2 (N=19) was characterized by being in KPS B ('Unable to work. Able to live at home and care for most personal needs. A varying degree of assistance is needed'), had no pain and received no oral opioid medication. Group 3 (N=19) was characterized by being in KPS B, had pain, but received no oral opioid medication. Group 4a (N=31) was characterized by being in KPS B, had pain and received stable doses of oral opioids. Group 4b (N=21) was characterized by being in KPS B, had no pain and received stable doses of opioids. Assessments comprised pain intensity, sedation, opioid doses, time from ingestion of last opioid dose to testing and opioid side effects. The neuropsychological tests used were continuous reaction time (CRT), finger tapping test (FTT) and paced auditory serial addition task (PASAT). Regarding the neuropsychological tests group 1 was compared with each of the other groups and respecting the hierarchy of increasing numbers of stigmatizing factors group 1 was compared with group 2, group 2 with group 3 and so forth. Concerning CRT, group 1 performed statistically significantly faster than groups 2, 4a and 4b. Concerning FTT, group 1 performed statistically significantly faster than groups 3 and 4a. Concerning PASAT, groups 1 and 4b performed statistically significantly better than group 4a. Furthermore, the pain-relieved groups 2 and 4b performed statistically significantly better in PASAT than the pain-suffering groups 3 and 4a. We conclude that in cancer patients the impact of stigmatizing factors (oral opioids, pain and reduced performance status) seems to impair some important aspects of neuropsychological performance, but more specifically our results indicate that (1) the use of long-term oral opioid treatment in cancer patients per se did not affect any of the neuropsychological tests used in the present study, (2) cancer patients being in KPS B had statistically significantly slower CRT than patients being in KPS A and (3) pain itself may deteriorate the performance of PASAT more than oral opioid treatment.

Treatment outcome of chronic non-malignant pain patients managed in a danish multidisciplinary pain centre compared to general practice: a randomised controlled trial.

This randomised controlled study investigated the effect of outpatient multidisciplinary pain centre treatment (MPT) compared with treatment by a general practitioner after initial supervision by a pain specialist (GP-group) and with a group of patients waiting for 6 months before treatment was initiated (WL-group). One-hundred-and-eighty-nine chronic non-malignant pain patients were studied. At referral, and after 3 and 6 months patients filled in questionnaires evaluating pain intensity, health related quality of life (HRQL) and use of analgesics. HRQL was evaluated using the Medical Outcome Study-Short Form (SF-36), the Hospital Anxiety and Depression scale (HAD) and the Psychological General Well-being Scale (PGWB). After 6 months patients allocated to MPT (n=63) reported statistically significant reduction in pain intensity (VAS-score, P<0.001), improvement in psychological well-being (PGWB, P<0.001), quality of sleep (P<0.05) and physical functioning (SF-36-Phycical Functioning, P<0.05). No improvements were seen in the GP-group (n=63). In the WL-group (n=63) a statistically significant deterioration was observed in PGWB-scores, HAD-scores and in 6 of 8 SF-36-subscores (P

PET evaluation of the uptake of N-[11C]methyl CP-643,051, an NK1 receptor antagonist, in the living porcine brain.

Antagonists of neurokinin receptors such as CP-643,051 are presently under investigation as potential antidepressants, but little is known about the brain uptake and distribution of these agents. We developed a method for the efficient N-[11C]methylation of CP-122,721, yielding the NK1 antagonist N-[11C]methyl CP-643,051. The brain uptake and distribution of N-[11C]methyl CP-643,051 were studied by positron emission tomography (PET) in the anaesthetized pig, first in a baseline condition, and again after displacement of specific binding with the NK1 receptor antagonist L-732,138 (0.6 mg/kg, i.v.). In order to validate this displacement procedure, we tested the effects of L-732,138 on cerebral blood flow (CBF) in one pig. We found that N-[11C]methyl CP-643,051 had a distribution volume close to 3 ml g(-1), and a binding potential (pB) of 0.3 in the pig striatum; this binding was displaceable by the L-732,138 pre-treatment, which evoked a small (10-20%) global increase in CBF. We conclude that of N-[11C]methyl CP-643,051 may serve as a lead structure for the development of PET NK-1 ligands of higher specific binding in vivo.

Oral glycopyrrolate alleviates drooling in a patient with tongue cancer.

Although sialorrhea and drooling are uncommon symptoms in cancer patients, they can cause considerable discomfort, inconvenience and social embarrassment. In this article we describe a patient with tongue cancer who was successfully treated with oral glycopyrrolate 0.4 mg 3 times daily. Glycopyrrolate is a quaternary ammonium compound. In contrast to the recommended treatment with scopolamine, glycopyrrolate is virtually without side effects to the central nervous system because it penetrates the blood-brain barrier poorly. Glycopyrrolate has a slow and erratic absorption from the gastrointestinal system, but even low plasma levels are associated with a distinct and long-lasting antisialogic effect.

Impaired neuropsychological performance in chronic nonmalignant pain patients receiving long-term oral opioid therapy.

The study investigated neuropsychological performance in chronic nonmalignant pain patients receiving long-term oral opioid therapy. Forty patients treated solely with regular and stable doses of an oral opioid were compared with 40 healthy volunteers. The patients received daily opioid doses of 15-300 mg of oral morphine (median: 60 mg) or equianalgesic doses of other opioids. The neuropsychological tests consisted of continuous reaction time (CRT), which measured vigilance/attention; finger tapping test (FTT), which measured psychomotor speed; and paced auditory serial addition task (PASAT), which measured working memory. Three months after the study had been carried out, 14 of the controls were retested in order to determine the reliability of the three tests. The patients performed statistically significantly poorer than the controls in all the tests. Significantly positive correlations were found between the PASAT and pain visual analogue scales (VAS). In the retesting of 14 controls, it was found that the tests showed high reliability. Vigilance/attention, psychomotor speed, and working memory were significantly impaired in chronic nonmalignant pain patients. The present study cannot determine which factors influenced the test results, but pain itself seemed to have an arousal effect on working memory.

Does the medical record cover the symptoms experienced by cancer patients receiving palliative care? A comparison of the record and patient self-rating.

The aim of this study was to investigate the extent to which the symptoms experienced by advanced cancer patients were covered by the medical records. Fifty-eight patients participated in the study. On the day of first encounter with our palliative care department, a medical history was taken, and on this or the following day, the patients completed the EORTC Quality of Life Questionnaire (EORTC QLQ-C30), Edmonton Symptom Assessment System (ESAS), and Hospital Anxiety and Depression Scale (HADS). The symptomatology reported in the patient-completed questionnaires was compared with the symptomatology mentioned by the physician in the medical record. The analysis revealed good concordance concerning pain, but most other symptoms or problems were reported much more often by patients than by their doctors. Reasons for these discrepancies are discussed. It is suggested that the doctor's knowledge of the patient's symptomatology might gain from more systematic screening and transfer of information from patient self-assessment questionnaires to the medical records.

Pig hepatocytes as an in vitro model to study the regulation of human CYP3A4: prediction of drug-drug interactions with 17 alpha-ethynylestradiol.

The objective of this study was to provide evidence of the validity of pig hepatocytes as a model to study the regulation of human CYP3A4 with special emphasis on drug-drug interactions. Thirteen different drugs were incubated with primary monolayer cultures of pig hepatocytes (n = 4). The study included both drugs reported to cause drug interactions in the clinic with 17 alpha-ethynylestradiol (EE2), other drugs metabolized by CYP3A4, and drugs not reported to cause any problems. Effect of the drug exposure to pig hepatocytes was determined by immunodetection using a monoclonal human CYP3A4 antibody and measurement of 6 beta-hydroxylation of testosterone and 2-hydroxylation of 17 alpha-ethynylestradiol (EE2), both reactions known to be catalyzed by CYP3A4 in humans. Data were compared to data from human hepatocytes and to reported observations of drug-drug interactions in the clinic. The drugs known to be inducers of CYP3A4 in humans significantly increased a CYP isoform in pigs catalyzing 6 beta-hydroxylation of testosterone and 2-hydroxylation of EE2, whereas drugs not reported to have clinical interactions with EE2 had no or only marginal effect. Induction by the drugs known to be inducers of CYP3A4 increased with drug exposure time and the CYP3A4 activity, represented by testosterone 6 beta-hydroxylation, was highest at 72 h for the investigated induction periods (24, 48 and 72 h), except for dexamethasone where the effect peaked after 24 h. Induction of the 2-hydroxylation of EE2 correlated well with the increase in 6 beta-hydroxylation of testosterone (except for sulphinpyranzone) and the increase in the protein level of CYP3A detected by a monoclonal human CYP3A4 antibody, thus confirming the 2-hydroxylation of EE2 in pigs as being biotransformed by a CYP isoform presumably belonging to the CYP3A subfamily as in humans. In conclusion, these results indicate that pig hepatocytes may be a valuable model to mimic the regulation of human CYP3A4.

A high-fat meal does not activate blood coagulation factor VII in minipigs.

It is a matter of debate whether postprandial activation of blood coagulation factor VII (FVII) is associated with an increased risk of thrombosis. To clarify this question, an animal model in which consequences of dietary FVII activation can be studied in a more detailed way would be an important tool. We studied postprandial FVII activation in seven non-fasting Göttingen minipigs. Intralipid (4 g/kg) was administered through a gastric tube in two fractions at 9.00 a.m. (one-third of total dose) and 10.30 a.m. (two-thirds of total dose). Blood samples were drawn 0.5 h before (baseline) and 2, 3, 3.5, 4, 5, and 6 h after the first fat load. Triglycerides, activated FVII (FVIIa), FVII coagulant activity (FVIIc), FVII amidolytic activity (FVIIam) and prothrombin fragment I + 2 (F1 + 2) were analysed in plasma samples. Median plasma triglycerides were significantly raised from 0.67 mmol/l (baseline) to 2.56 mmol/l 5 h postprandially (P < 0.001). There were no significant changes in FVIIa (9.6 U/l at baseline), FVIIam (142% at baseline) and F1 + 2 (0.13 nmol/l at baseline). FVIIc decreased from 141% at baseline to 114% 6 h postprandially (P < 0.001). As a high-fat meal does not seem to activate blood coagulation FVII in minipigs, the pig is apparently not a relevant model for the study of dietary FVII activation and thrombin generation.

Effect of pre-analytical handling on haematological variables in minipigs.

Pre-analytical handling may be an important determinant of haematological variables, if analysis is delayed. We investigated the effect of anticoagulants, i.e. tripotassium ethylenediamine-tetraacetic acid (EDTA) and citric acid, theophylline, adenosine, dipyridamole (CTAD), storage time (0.5, 1.5, 3.5, 5.5, 7.5, 25.5 and 27.5 h after blood sampling), and storage temperature (5 degrees C and 20 degrees C) on the variation in haemoglobin (HGB), red blood cell count (RBC), haematocrit (HCT), white blood cell count (WBC), and platelet count (PLT) in minipigs. Medians of HGB, RBC, HCT, WBC and PLT were significantly higher in EDTA tubes than in CTAD tubes due to the dilution effect of the anticoagulant. We found a minor significant increase in HCT after 25.5 h in blood stored at 20 degrees C, and at the same time a minor significant increase in WBC in EDTA tubes stored at 20 degrees C. We found a significant decrease in PLT in blood stored at 5 degrees C, especially in EDTA tubes. Minor variations were also observed in HGB and RBC. Our results indicate that PLT should only be measured in tubes placed at room temperature. If HCT or WBC analyses are to be performed on the day after blood sampling, the samples must be stored in a refrigerator until analysis. Our studies underline that time delay before analysis of haematological variables can cause increased variation, and should therefore be limited as far as possible in order to reduce the number of animals needed to make reliable conclusions.

The Göttingen minipig as a model for postprandial hyperlipidaemia in man: experimental observations.

Postprandial hyperlipidaemia is believed to be atherogenic. This study aimed to establish a minipig model to investigate determinants of postprandial lipid metabolism. In a randomized cross-over design seven minipigs were subjected to six different feeding regimens: intragastric fat loads of 1, 2, and 4 g fat (Intralipid, 20%) kg(-1) in two fractions 1.5 h apart (1/3 first, 2/3 second), 2 g fat (Intralipid kg(-1) in one fraction, and 2 g olive oil kg(-1) in two fractions, all after pre-feeding with standard diet, and finally 2 g fat (Intralipid kg(-1) in two fractions without pre-feeding. Blood was sampled before and hourly for 7 h after gavaging, and plasma triglycerides were measured. Triglycerides increased significantly in all the feeding regimens (P < 0.001), except when olive oil was used as the fat source. A borderline significant dose-response effect of the Intralipid dose on the triglyceride response was observed. We found no significant differences in triglyceride response whether 2 g fat (Intralipid kg(-1) was given in one or two fractions, with or without pre-feeding. We conclude that postprandial hyperlipidaemia in minipigs can be induced by gavaging an emulgated lipid solution (1-4 g fat/kg, Intralipid, while olive oil is not applicable. There is no need to administer the fat fractionated or to withhold food prior to administration.

[Therapeutic results in chronic, non-malignant pain in patients treated at a Danish multidisciplinary pain center compared with general practice. A randomized controlled clinical trial]. / Behandlingsresultater ved kroniske, non-maligne smertetilstande hos patienter, behandlet i et dansk, tvaerfagligt smertecenter sammenlignet med almen praksis. En randomiseret kontrolleret undersøgelse.

INTRODUCTION: Multidisciplinary pain treatment (MPT) is generally considered to be the most effective treatment of chronic pain, but its long-term effect has not yet been firmly established. METHODS: This randomised controlled study compared the effect of outpatient MPT with that of treatment by general practitioners after initial supervision by a pain specialist (GP group) and with a six-month waiting list group (WL group). The participants were 189 patients with chronic non-malignant pain. On referral and at three and six months, the patients filled in questionnaires evaluating pain intensity, health-related quality of life (HRQL), and the use of analgesics. RESULTS: At six months, the patients allocated to MPT (N = 63) reported a reduction in pain intensity (p < 0.001), and an improvement in psychological well-being (p < 0.001), quality of sleep (p < 0.05), and physical functioning (p < 0.05). The WL group (N = 63) had a statistically significant deterioration in most of the HRQL measures. The only effect of treatment found in the GP group was a reduction in the use of short-acting opioids. In the MPT group, the use of opioids administered on demand and short-acting opioids was decreased (p < 0.001). No change in the use of analgesics was seen in the WL group. DISCUSSION: The study showed that (i) in the MPT group there was a significant reduction in pain intensity and an improvement in HRQL compared to the WL group, and (ii) the mere establishment of a pain diagnosis and management plan by a specialist was not sufficient to enable the referring GP to manage patients with severe chronic pain.

[Continuous subcutaneous infusion of opioids in cancer patients]. / Kontinuerlig subkutan opioidinfusion til cancerpatienter.

This review article describes pharmacokinetics, pharmaco-dynamics, side effects and the practical use of continuous subcutaneous infusion of opioids in cancer patients with pain. Clinical studies have shown that the analgesic effects of continuous subcutaneous infusion of morphine are comparable to continuous intravenous morphine, and that the treatment modality is associated with a low frequency of side-effects and complications. Continuous subcutaneous infusions of morphine are therefore recommended as the treatment of choice for cancer patients with pain, when oral analgesic treatment is no longer possible.

[Morphine-induced hyperalgesia, allodynia and myoclonus--new side-effects of morphine?]. / Morfininduceret hyperalgesi, allodyni og myoklonus--nye morfinbivirkninger?

During the last ten years hyperalgesia (H), allodynia (A) and myoclonia (M) has been reported at an increased frequency in human beings treated with morphine. The side effects are most common in cancer patients treated with high dose morphine, and has been reported for all routes of administration. The mechanisms are unknown, but human cases and experimental works have resulted in the following theories: 1) Morphine and morphine metabolites change the postsynaptic pain-transmission in dorsal horn neurones via non opioid-receptors (glycine and/or N-methyl-D-aspartate). 2) Morphine and morphine metabolites activate other opioid receptor populations. 3) Supplemental drugs in cancer management. 4) An abnormal metabolism of morphine or morphine metabolites. 5) A combination of one or more of the above-mentioned theories. The first mentioned theory is the most likely. The treatment of morphine induced H, A, and M seems to be to discontinue morphine administration and to initiate therapy with other opioids (fentanyl, sufentanyl, methadone or ketobemidone).

[Inhalation of levopromazine (Nozinan) in the treatment of status asthmaticus]. / Inhalation af levomepromazin (Nozinan) i behandling af status asthmaticus.

Levomepromazine reduces histamine-induced bronchial hyperresponsiveness in asthmatics without significant sedation. We present two patients with acute asthma refractory to conventional therapy, who were treated with inhalation of 2.5 mg levomepromazine. Until controlled studies have been done, we suggest that inhalation of levomepromazine be restricted to patients with asthma refractory to conventional therapy.

[Pain epidemiology and health-related quality of life in patients with chronic non-malignant pain]. / Smerteepidemiologi og helbredsrelateret livskvalitet hos patienter med kroniske ikkemaligne smerter.

This paper presents the results of a detailed study of the pain epidemiology and health related quality of life (HRQL) in 150 chronic non-malignant pain patients referred to a Danish multidisciplinary pain centre. Mean pain intensity was 71.6 (SD 18.5) on the VAS scale. HRQL was evaluated using the questionnaires: SF-36, HAD and PGWB. Compared with the normal population (NP) both physical, psychological and social well-being was severely reduced, and 58% were found to have a depressive or anxiety disorder. Sixty-three percent of the patients had neurogenic pain conditions. Of these, only 25% were treated with antidepressants or anticonvulsants. At referral 73% were treated with opioids. Mean opioid consumption was 64 mg of morphine per day. Patients had used the health care system five times more often than the NP (p < 0.001). The study showed that HRQL of chronic non-malignant pain patients is among the lowest observed for any medical condition.