Biologics in the treatment of chronic pain: a new era of therapy?

Existing analgesics fail to provide adequate pain relief in a significant proportion of patients complaining of chronic pain. Furthermore, their use is limited by tolerability and safety concerns. Thus, there is a huge unmet need for effective and safe innovative painkillers. Considering the major role of nerve growth factor (NGF) in the generation and maintenance of a wide range of pain states, the issue is whether anti-NGF biologics under development might offer such an opportunity.

Measuring the contribution of pharmacological treatment to advice to stay active in patients with subacute low-back pain: a randomised controlled trial.

PURPOSE: In clinical guidelines for acute and subacute low-back pain, pharmacological treatment is recommended for short-term symptomatic relief. The objective was to study the effect of the guidelines' advise to remain active, alone and with the addition of the drug adenosine tri-phosphate (ATP), in patients with subacute low-back pain. METHODS: A drug-guidelines effectiveness trial was undertaken simultaneously to an experimental drug efficacy placebo controlled trial in subacute (4-12 weeks) non-specific low-back pain patients. The 132 participating primary care physicians across France were randomised to participate to either trial. In the drug-guidelines trial, all physicians received a quick consultation card containing the key elements of the clinical guidelines and a brochure that gave their patients practical tips to remain active. Patients were then randomised to receive Atepadene, containing 90 mg of ATP by mouth daily for 30 days (guidelines plus ATP group), or nothing beside the rescue drug that was made available to all patients (guidelines alone group). The principal outcome was functional improvement on the Roland-Morris Disability Questionnaire (RDQ) at 90 days. RESULTS: In the drug-guidelines effectiveness trial, 157 patients were randomised. The rate of improvement in the RDQ over the 90 days of follow-up was superior in the group guidelines plus ATP (8.3 points, 95% confidence interval (CI): 7.3-9.3) than in the group guidelines alone (6.5 points, 95%CI: 5.3-7.7) (p = 0.02). In terms of probability of improving between two to five points on the RDQ at 90 days this difference translated in a 2 to 13 times higher probability compared to the group guidelines alone (odds ratios ranging from 2.1, 95%CI: 0.9-5.0 to 12.9, 95%CI: 1.6-103.4). Patients in the group guidelines plus ATP were also three times less likely to report a condition that had worsened or remained unimproved at 90 days (p = 0.02). CONCLUSION: This drug-guidelines effectiveness trial showed a modest advantage of combined specific pharmacologic and non-pharmacological treatments on absolute improvement on the RDQ. A threefold reduction in the risk of chronicity was observed, an important goal in low-back pain guidelines.

[Adverse drug effects: a prospective study by Apnet performed in seven emergency care units in France: propositions for preventive measures]. / Accidents médicamenteux. (A propos d'une étude prospective de l'Apnet réalisée dans sept services d'accueil et d'urgences français). Propositions pour des mesures préventives.

Various studies have shown that adverse drug effects (ADEs) are a substantial cause of hospital admissions. However, little is known about the incidence and severity of ADEs resulting in hospital visits. To address this issue, we conducted a prospective survey in primary care and emergency departments of French public hospitals. This study was performed over two periods of one week, one in January, February and one in June 2003, in primary care and emergengy departments of four university hospitals and three general hospitals throughout France. Out of a total of 1826 patients consulting, 1663 were taking at least one drug during the previous week and were included for analysis according to the protocol. Altogether, 370 (22.2%; IC 95: 20.2-24.3%) of these patients receiving at least one drug consulted because of an ADE. From these 370 patients, 263 (15.8%) where considered as touched by a probably (12), likely (13) or very likely (14) ADE. The sex ratio was the same in both groups with or without ADE (0.88%; P=0.95). Patients with ADE were older than those without (62.4 vs 53.8 years, P=0.0016). Furthermore, ADE patients were more likely to have a higher severity score than no-ADE group (P=0.0003). The outcome seemed to be worse in patients with an ADE. The percentage of patients treated with 2 or more drugs and the number of drug exposures were significantly higher in patients with ADE than in those without (93.2% vs 84.2%, P<0.0001, and 5.8 vs 4.5 P<0.0001, respectively). The most frequent causes of visits for ADE-patients were digestive (n=38: 14.4%), neurological (n=23: 10.6%), malaise (n=48: 18,2%) events. The most frequently incriminated drug classes were (1) psychotropic agents, (including anxiolytics, hypnotics, antidepressants and antipsychotics), (2) diuretics (3) anticoagulants, (4) other cardiovascular drugs and (5) analgesics, including non steroidal anti-inflammatory agents. In 150 cases (40.8%; IC 95: 33.7% - 45%), the ADE was considered to be preventable because a contra-indication or a warning about drug use had not been respected.

[Bone mineral density and bone metabolism in spondylarthropathies]. / Densité minérale et métabolisme osseux des spondylarthropathies.

AIMS: To study the prevalence of osteoporosis in a group of patients with spondyloarthropathy and to investigate bone turnover markers and correlation between bone mineral density and the age at the beginning of the disease. PATIENTS AND METHOD: Patients with spondyloarthropathy as defined by New York and ESSG criteria. Bone mineral density was measured at the lumbar spine and hip with Hologic QDR 1000. Serum levels of osteocalcin, deoxypyridinoline, 25 vitamin D, creatinine and parathyroid hormone were measured. RESULTS: 50 patients were included in the study: 37 men, mean age 40,2+/-13,8 years. Vertebral osteopenia was observed in 34% while femoral osteopenia occurred in 40% of patients. Serum vitamin D was low in 70% of patients without parathyroid hormone or kidney function modification. Markers of bone turn over were increased in 29% of patients. There was no correlation between these biological markers and the bone mineral density. We observed a significative correlation (P=0,02) between the age at the beginning of the disease and the bone mineral density. CONCLUSION: Osteopenia is present in patients with spondyloarthropathy without any correlation with the bone turnover biological markers. We observed a significative correlation between the age at the beginning of the disease and bone mineral density.

EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).

OBJECTIVE: To develop evidence based recommendations for the management of hip osteoarthritis (OA). METHODS: The multidisciplinary guideline development group comprised 18 rheumatologists, 4 orthopaedic surgeons, and 1 epidemiologist, representing 14 European countries. Each participant contributed up to 10 propositions describing key clinical aspects of hip OA management. Ten final recommendations were agreed using a Delphi consensus approach. Medline, Embase, CINAHL, Cochrane Library, and HTA reports were searched systematically to obtain research evidence for each proposition. Where possible, outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. Effect size, rate ratio, number needed to treat, and incremental cost effectiveness ratio were calculated. The quality of evidence was categorised according to the evidence hierarchy. The strength of recommendation was assessed using the traditional A-D grading scale and a visual analogue scale. RESULTS: Ten key treatment propositions were generated through three Delphi rounds. They included 21 interventions, such as paracetamol, NSAIDs, symptomatic slow acting disease modifying drugs, opioids, intra-articular steroids, non-pharmacological treatment, total hip replacement, osteotomy, and two general propositions. 461 studies were identified from the literature search for the proposed interventions of efficacy, side effects, and cost effectiveness. Research evidence supported 15 interventions in the treatment of hip OA. Evidence specific for the hip was strikingly lacking. Strength of recommendation varied according to category of research evidence and expert opinion. CONCLUSION: Ten key recommendations for the treatment of hip OA were developed based on research evidence and expert consensus. The effectiveness and cost effectiveness of these recommendations were evaluated and the strength of recommendation was scored.

[Prescribing patterns of rofecoxib in the primary care setting: results of a French survey]. / Prescription du rofécoxib en pratique médicale courante: résultats d'une enquête française.

OBJECTIVES: To assess the prescribing patterns of rofecoxib, a selective cyclo-oxygenase-2 inhibitor or coxib relative to those of conventional non steroidal anti-inflammatory drugs (NSAIDs) in the primary care setting in France. METHODS: A representative sample of 1010 French general practitioners participated in the study. They recorded the demographic, medical and pharmaceutical characteristics of all patients for whom they prescribed an NSAID between July 1, 2001 and June 30, 2002. RESULTS: The prescribing patterns of rofecoxib were similar for both available dosages (12.5 and 25 mg). The proportion of patients aged 65 years and older was significantly higher among those receiving rofecoxib (48%) than among those receiving a traditional NSAID (37.3%). A history of peptic ulcer or gastrointestinal bleeding was more frequent in the former (4.8%) than in the latter (2.1%). Low dose aspirin and antihypertensive agents were being taken in 6.1% and 34.8%, respectively, of the patients in the rofecoxib group versus 2.3% and 15.6%, respectively, in the conventional NSAID group. Concurrent use of a proton pump inhibitor (PPI) was marginally less frequent in the rofecoxib group (16.9%) than in the conventional NSAID group (18.6%). However, a significantly higher proportion of patients were given a PPI prior to rofecoxib therapy (10.4%) than prior to conventional NSAID therapy (3.7%). CONCLUSION: Our findings show that French general practitioners are more likely to prescribe rofecoxib for patients who have risk factors of NSAID gastropathy.

Direct injection HPLC micro method for the determination of voriconazole in plasma using an internal surface reversed-phase column.

A direct plasma injection liquid chromatographic method has been developed for the determination of a new triazole antifungal agent, voriconazole, using an internal surface reversed phase column. Therapeutic drug monitoring of voriconazole is relevant for patient management, especially in the case of drug-drug interaction. The method is easy to perform and requires 10 microL of a plasma sample. The chromatographic run time is less than 9 min using a mobile phase of 17:83 v/v acetonitrile-potassium dihydrogen phosphate buffer, 100 mM, pH 6.0 and UV detection at 255 nm. The fl ow rate was 1 microL/min. A linear response was observed over the concentration range 0.5-10 microg/mL (r2 = 0.977). A good accuracy (bias < or = 7.5%) was achieved for all quality controls, with intra-day and inter-day variation coefficients inferior to 6.7%. The lower limit of quantitation was 0.2 microg/mL, without interference of endogenous components. The stability of voriconazole in plasma stored at different temperatures was checked. Finally, the possibility of direct injection of plasma samples into the column permits a reduction in reagent consumption and in analytical steps, and hence in analytical error.

HPLC microdetermination of flurbiprofen enantiomers in plasma with a glycopeptide-type chiral stationary phase column.

A rapid and stereospecific HPLC micromethod to quantify flurbiprofen enantiomers was developed. Both flurbiprofen enantiomers and indomethacin, used as internal standard, were extracted with methylene chloride from 100 microL of acidified plasma. The resolution of the R- and S-forms was performed on a bonded vancomycin chiral stationary phase (Chirobiotic V) with 20% of tetrahydrofuran in ammonium nitrate (100 mM, pH 5) as mobile phase. Calibration curves were linear in the range 0.5-10 microg/mL for both enantiomers. A good accuracy (< or = 5%) was obtained for all quality controls, with intra-day and inter-day variation coefficients equal or less than 7.7%. Recovery of both enantiomers was found in the range 77.4-86.3%. The lower limit of quantitation was 0.25 microg/mL for both enantiomers, without interference of endogenous components. This validated micromethod has been successfully applied for quantifying R- flurbiprofen and S- flurbiprofen in rat plasma.

Management of osteoarthritis (OA) with an unsupervised home based exercise programme and/or patient administered assessment tools. A cluster randomised controlled trial with a 2x2 factorial design.

BACKGROUND: Diary recording of pain and disabling activities in osteoarthritis (OA) is widely recommended, but, to our knowledge, its impact on symptoms has not been investigated. Exercise programmes have been shown to be effective when patients are closely supervised by nurses or physiotherapists; however, data are lacking on the efficacy of an unsupervised home based exercise regimen in patients with OA. OBJECTIVES: To evaluate the clinical efficacy of patient administered assessment tools and an unsupervised home based exercise programme alone or in combination in patients with OA. METHODS: The study was a 24 week, open cluster randomised controlled trial with a factorial design. Rheumatologists (n = 867) were assigned to four groups according to the treatment given: standardised tools (ST; n = 220), exercises (EX; n = 213), both tools and exercises (ST+EX; n = 213), or usual care (n = 221). Each rheumatologist was to enroll four patients who met the American College of Rheumatology criteria for OA (three with knee OA, one with hip OA). "Tools" consisted of weekly recording of pain and disabling activities in a diary. A home based exercise programme was performed daily at least four times per week with the aid of videotape and booklet. In addition to exercise and assessment, all patients received 12.5 mg or 25 mg of the non-steroidal anti-inflammatory drug rofecoxib once daily. Outcome variables were: pain (measured on a visual analogue scale, 0-100); Western Ontario and McMaster Universities Osteoarthritis Index, function subscale (0-100); and patient assessment of the quality of care (0-100). RESULTS: Overall, 2957 patients with OA (2216 knee, 741 hip) were included. After 24 weeks, both pain and function improved in the ST, EX, ST+EX, and usual care groups (mean (SD) -17 (27), -20 (29), -15 (27), -19 (29); and -11 (19), -12 (19), -10 (19), -11 (20), respectively), without significant differences between groups. However, patients in the EX and ST+EX groups were more likely to agree that their rheumatologist had done his best to preserve their functional and physical activities. CONCLUSION: Although patients' assessments favoured the exercise programme, results from this study failed to demonstrate a short term symptomatic effect of the two non-pharmacological treatments (weekly recording of condition and exercise) in patients with OA concurrently receiving nonsteroidal anti-inflammatory drugs.

EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).

OBJECTIVES: To update the EULAR recommendations for management of knee osteoarthritis (OA) by an evidence based medicine and expert opinion approach. METHODS: The literature search and guidelines were restricted to treatments for knee OA pertaining to clinical and/or radiological OA of any compartment of the knee. Papers for combined treatment of knee and other types of OA were excluded. Medline and Embase were searched using a combination of subject headings and key words. Searches for those treatments previously investigated were conducted for January 1999 to February 2002 and for those treatments not previously investigated for 1966 to February 2002. The level of evidence found for each treatment was documented. Quality scores were determined for each paper, an effect size comparing the treatment with placebo was calculated, where possible, and a toxicity profile was determined for each treatment modality. RESULTS: 497 new publications were identified by the search. Of these, 103 were intervention trials and included in the overall analysis, and 33 treatment modalities were identified. Previously identified publications which were not exclusively knee OA in the initial analysis were rejected. In total, 545 publications were included. Based on the results of the literature search and expert opinion, 10 recommendations for the treatment of knee OA were devised using a five stage Delphi technique. Based on expert opinion, a further set of 10 items was identified by a five stage Delphi technique as important for future research. CONCLUSION: The updated recommendations support some of the previous propositions published in 2000 but also include modified statements and new propositions. Although a large number of treatment options for knee OA exist, the evidence based format of the EULAR Recommendations continues to identify key clinical questions that currently are unanswered.

Influence of a polymeric formulation of ketoprofen on its diffusion into cerebrospinal fluid in rats.

Poly(D,L)lactide nanocapsules (NCs) have been proposed as an alternative carrier for many drugs. We investigated the influence of this formulation on the pharmacokinetics of ketoprofen in the plasma and cerebrospinal fluid (CSF). Male Wistar rats were given intraperitoneal dose of ketoprofen (5 mg/kg) in a suspension of NCs or in a carboxymethylcellulose (CMC) solution (reference preparation). Blood and CSF samples were collected at different times up to 24 h after dosing. The unbound fraction of ketoprofen in plasma (f(u)) was determined using ultrafiltration. The total (C(T)) and free (C(F)) concentrations of ketoprofen in plasma and the simultaneous CSF concentrations (C(CSF)) were measured by a HPLC method and the areas under the curve (AUC(T), AUC(F), AUC(CSF)) were calculated. AUC(T) of ketoprofen-loaded NCs in plasma was similar to that of the reference solution, while AUC(F) of the former (5.41 mg/l x h) was higher than that produced by the latter (4.03 mg/l x h). Accordingly, the unbound fraction (f(u)) was higher after administration of NCs than that of the solution (2.5 and 1.8%, respectively). Finally, AUC(CSF) were identical for both formulations. These findings suggest that the binding of ketoprofen to plasma proteins is not the major factor that governs its blood-to-CSF exchanges.

[Comparative safety of traditional non-steroidal anti-inflammatory drugs and COX-2 selective inhibitors]. / Tolérance comparée des anti-inflammatoires non stéroïdiens classiques et des inhibiteurs sélectifs de la cyclo-oxygénase-2.

SIDE EFFECTS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS: Digestive disorders and skin and mucosal reactions, more rarely neurosensorial, renovascular, gyneco-obstetrical and hematological disorders are the main side effects of non-steroidal anti-inflammatory drugs. DIGESTIVE USEFULNESS OF COXIBS: Coxibs reduce the risk of symptomatic complicated or uncomplicated gastroduodenal ulcers by 1 to 1.5 per 100 patient-years compared with conventional NSAID. They do however induce a similar number of dyspeptic disorders and are contraindicated in case of inflammatory bowel disease. Extra-digestive tolerance is comparable with that for classical NSAID. PLATELET AGGREGATION AND THROMBOSIS: If the patient's vascular status requires an anti-platelet agent, aspirin must be combined with the coxib which in itself cannot provide cardiovascular protection.

Placental transfer of SR49059 in the human dually perfused cotyledon in vitro.

SR49059 is an antagonist of vasopressin V(1a)receptors currently developed as a tocolytic drug. We investigated the transplacental transfer of SR49059 in vitro using the single pass dually perfused human cotyledon model. Thirteen placentae were collected from normal term pregnancies immediately after delivery. The placental transfer of SR49059 was tested at steady state at three different concentrations (100 ng/ml, 200 ng/ml and 500 ng/ml) along with that of antipyrine 20 mg/l as a reference substance. Concentrations were assayed by liquid chromatography with UV (antipyrine) or mass spectrometry (SR49059) detection. At steady state, the mean+/-s.d. fetal transfer rate of SR49059 was 10.80+/-4.33 per cent, 9.34+/-4.41 per cent, and 11.78+/-3.26 per cent at 100 ng/ml, 200 ng/ml and 500 ng/ml, respectively. The corresponding clearance indices were 0.29+/-0.14, 0.25+/-0.08, and 0.31+/-0.06, respectively. The absence of saturation kinetics is consistent with a passive mechanism of transfer. Moderate amounts of SR49059 are transferred from the maternal to the fetal circulation. The clearance index of SR49059 appeared to be very similar to that of ritodrine, which is currently used as a tocolytic.

In vitro distribution of ketoprofen enantiomers in articular tissues of osteoarthritic patients.

The distribution of ketoprofen enantiomers in joint tissues was studied as a function of their relative tissular affinities using the multi-chamber distribution dialysis system described by Bickel et al. Selected off-cuts of synovial membrane, joint capsule, cartilage and ligament were obtained from ten patients suffering from osteoarthritis of the knee (n=3) or hip (n=7). Sörensen solution (4 ml) spiked with racemic ketoprofen (2 microg ml(-1)) was dialysed against 1 ml of the four solutions of tissue homogenates (0.4 g ml(-1)). Ketoprofen enantiomers were quantified in buffer and tissue solutions by high-performance liquid chromatography. The distribution of ketoprofen enantiomers in the Bickel's multi-compartment model indicated that there was a non-stereoselective affinity of ketoprofen enantiomers for their potential target tissues. Despite the interindividual variability in articular tissues, the concentrations (+/-S.D.) of R- and S-ketoprofen were significantly higher in synovial membrane (8.69 (4.76) microg g(-1) for S, 9.14 (5.57) microg g(-1) for R), joint capsule (5.71 (2.49) microg g(-1) for S, 5.49 (2.62) microg g(-1) for R) and ligament (6.28 (3.61) microg g(-1) for S, 6.40 (3.64) microg g(-1) for R) than in articular cartilage (3.67 (1.75) microg g(-1) for S, 3.70 (1.67) microg g(-1) for R). There were no significant differences in the distribution of R- and S-ketoprofen between the solutions of joint capsule, synovium and ligament tissues. These data may be related to differences in ketoprofen affinity for the different constituents of joints. This in vitro distribution profile is similar to that reported in vivo for other non-steroidal anti-inflammatory drugs.

[Strong opioids for chronic non-cancer pain]. / Les opioïdes forts dans les douleurs chroniques non cancéreuses.

A CHALLENGING SITUATION: A number of patients experiencing chronic noncancer pain are unsatisfied with standard treatment modalities. This raises the question of whether there may be a place for strong opioids in the management of these patients. Randomised placebo-controlled trials of strong opioids generated rather disappointing results in this type of pain. Observational studies have indicated that strong opioids may improve comfort and function in some patients with intractable nociceptive or neuropathic pain. However, opioids may be ineffective in others and intolerable side effects, heightened pain and functional impairment as well as drug addiction may also occur. A PROMISING SOLUTION: Finally, strong opioids do not appear to be the issue to all intractable chronic nonmalignant pain states, but they may be a possible issue to a subset of selected and informed patients who agree on the goals of the treatment and accept regular monitoring.