A Human Experimental Bone Pain Model

The aim of this study was to develop a human experimental bone pain model. Fourteen healthy men were included in two study sessions. Pressure pain threshold (PPT) was estimated using probes of different sizes. Computer‐controlled and hand‐held algometry were applied to the skin area covering right and left medial tibia before and after local anaesthesia (LA) of the skin and reproducibility was evaluated. Pain experience (McGill questionnaire) was compared between healthy volunteers and 12 patients with vertebral fractures. Computer‐controlled algometer: No differences in PPT between study sessions for 6 and 8‐mm probes (p = 0.43 and 0.32) were seen. There was a difference in PPT before and after LA for the 6‐mm probe (p = 0.008), but not for the 8‐mm probe (p = 0.26). Hand‐held algometer: A difference in PPT between study sessions was observed for 4‐ and 8‐mm probes (p = 0.03 and 0.007), but not for 2, 6 and 10‐mm probes (p = 0.19, 0.05 and 0.25). No differences in PPT were seen before and after LA for 2, 4, 8 and 10‐mm probes (p = 0.35, 0.15, 0.08 and 0.53), but LA significantly influenced PPT with the 6‐mm probe (p = 0.01). Similar words were chosen in the McGill pain questionnaire by healthy volunteers and patients, qualitatively describing the deep pain sensation. The pain evoked by hand‐held algometer and the 2‐mm probe was not influenced by LA, and PPT was reproducible between sessions and is recommended for studies of experimentally evoked bone‐associated pain.     

Placebo effect studies are susceptible to response bias and to other types of biases

Objective

Investigations of the effect of placebo are often challenging to conduct and interpret. The history of placebo shows that assessment of its clinical significance has a real potential to be biased. We analyze and discuss typical types of bias in studies on placebo.

Study Design and Setting

A methodological analysis and discussion.

Results

The inherent nonblinded comparison between placebo and no-treatment is the best research design we have in estimating effects of placebo, both in a clinical and in an experimental setting, but the difference between placebo and no-treatment remains an approximate and fairly crude reflection of the true effect of placebo interventions. A main problem is response bias in trials with outcomes that are based on patients’ reports. Other biases involve differential co-intervention and patient dropouts, publication bias, and outcome reporting bias. Furthermore, extrapolation of results to a clinical settings are challenging because of a lack of clear identification of the causal factors in many clinical trials, and the nonclinical setting and short duration of most laboratory experiments.

Conclusions

Creative experimental efforts are needed to assess rigorously the clinical significance of placebo interventions and investigate the component elements that may contribute to the therapeutic benefit.     

Guidelines for Reporting Reliability and Agreement Studies (GRRAS) were proposed

Objective

Results of reliability and agreement studies are intended to provide information about the amount of error inherent in any diagnosis, score, or measurement. The level of reliability and agreement among users of scales, instruments, or classifications is widely unknown. Therefore, there is a need for rigorously conducted interrater and intrarater reliability and agreement studies. Information about sample selection, study design, and statistical analysis is often incomplete. Because of inadequate reporting, interpretation and synthesis of study results are often difficult. Widely accepted criteria, standards, or guidelines for reporting reliability and agreement in the health care and medical field are lacking. The objective was to develop guidelines for reporting reliability and agreement studies.

Study Design and Setting

Eight experts in reliability and agreement investigation developed guidelines for reporting.

Results

Fifteen issues that should be addressed when reliability and agreement are reported are proposed. The issues correspond to the headings usually used in publications.

Conclusion

The proposed guidelines intend to improve the quality of reporting.     

Low-dose exposure to alkylphenols adversely affects the sexual development of Atlantic cod (Gadus morhua): acceleration of the onset of puberty and delayed seasonal gonad development in mature female cod

Produced water (PW), a by-product of the oil-production process, contains large amount of alkylphenols (APs) and other harmful oil compounds. In the last 20 years, there have been increasing concerns regarding the environmental impact of large increases in the amounts of PW released into the North Sea. We have previously shown that low levels of APs can induce disruption of the endocrine and reproductive systems of Atlantic cod (Gadus morhua). The aims of this follow-up study were to: (i) identify the lowest observable effect concentration of APs; (ii) study the effects of exposure to real PW, obtained from a North Sea oil-production platform; and (iii) study the biological mechanism of endocrine disruption in female cod. Fish were fed with feed paste containing several concentrations of four different APs (4-tert-butylphenol, 4-n-pentylphenol, 4-n-hexylphenol and 4-n-heptylphenol) or real PW for 20 weeks throughout the normal period of vitellogenesis in Atlantic cod from October to January. Male and female cod, exposed to AP and PW, were compared to unexposed fish and to fish fed paste containing 17β-oestradiol (E(2)). Approximately 60% of the females and 96% of the males in the unexposed groups were mature at the end of the experiment. Our results show that exposure to APs and E(2) have different effects depending on the developmental stage of the fish. We observed that juvenile females are advanced into puberty and maturation, while gonad development was delayed in both maturing females and males. The AP-exposed groups contained increased numbers of mature females, and significant differences between the untreated group and the AP-treated groups were seen down to a dose of 4 μg AP/kg body weight. In the high-dose AP and the E(2) exposed groups, all females matured and no juveniles were seen. These results suggest that AP-exposure can affect the timing of the onset of puberty in fish even at extremely low concentrations. Importantly, similar effects were not seen in the fish that were exposed to real PW.     

Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs

Pain models in animals have shown low predictivity for analgesic efficacy in humans, and clinical studies are often very confounded, blurring the evaluation. Human experimental pain models may therefore help to evaluate mechanisms and effect of analgesics and bridge findings from basic studies to the clinic. The present review outlines the concept and limitations of human experimental pain models and addresses analgesic efficacy in healthy volunteers and patients. Experimental models to evoke pain and hyperalgesia are available for most tissues. In healthy volunteers, the effect of acetaminophen is difficult to detect unless neurophysiological methods are used, whereas the effect of nonsteroidal anti-inflammatory drugs could be detected in most models. Anticonvulsants and antidepressants are sensitive in several models, particularly in models inducing hyperalgesia. For opioids, tonic pain with high intensity is attenuated more than short-lasting pain and nonpainful sensations. Fewer studies were performed in patients. In general, the sensitivity to analgesics is better in patients than in healthy volunteers, but the lower number of studies may bias the results. Experimental models have variable reliability, and validity shall be interpreted with caution. Models including deep, tonic pain and hyperalgesia are better to predict the effects of analgesics. Assessment with neurophysiologic methods and imaging is valuable as a supplement to psychophysical methods and can increase sensitivity. The models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. Knowledge obtained from this review can help design experimental pain studies for new compounds entering phase I and II clinical trials.     

Autologous patellar tendon and quadrupled hamstring grafts in anterior cruciate ligament reconstruction: a prospective randomized multicenter review of different fixation methods

ACL reconstruction with bone patellar tendon bone (BPTB) grafts has been shown to produce dependable results. Recently, reconstructions with double-looped semitendinosus gracilis (DLSG) grafts have become common. The prevailing opinion is that ACL reconstruction with patellar tendon graft produces a more stable knee with more anterior knee pain than DLSG grafts, while the functional results and knee scores are similar. The present study evaluates BPTB grafts fixed with metallic interference screws and DLSG grafts fixed with Bone Mulch Screw on the femur and WasherLoc fixation on the tibia. All else being the same, there is no difference in the outcome between the two grafts and fixation methods. This is a prospective randomized multicenter study. A total of 115 patients with isolated ACL ruptures were randomized to either reconstruction with BPTB grafts fixed with metal interference screws (58 patients) or DLSG grafts (57 patients) fixed with Bone Mulch Screws and WasherLoc Screws. Follow-up was at one and two years; the latter by an independent observer. At two years, one ACL revision had been performed in each group. Eight patients in the DLSG group and one in the BPTB group underwent meniscus surgery in the follow-up period (P = 0.014). Mean Lysholm score at the two year follow-up was 91 (SD ± 10.3) in the DLSG group and also 91 (SD ± 10.2) in the BPTB group. Mean KT-1000 at two years was 1.5 mm in the BPTB group and 1.8 mm in the DLSG group (n.s.). At two years, four patients in the BPTB group and three in the DLSG group had a Lachman test grade 2 or 3 (n.s.). More patients in the BPTB group had pain at the lower pole of the patella (P = 0.04). Peak flexion torque and total flexion work were lower in the DLSG group at one year (P = 0.003 and P = 0.000) and total flexion work also at two years (P = 0.05). BPTB ACL reconstruction fixed with interference screws and DLSG fixed with Bone Mulch Screws on the femur and WasherLoc Screws on the tibia produce satisfactory and nearly identical outcomes. Among our patients in the DLSG group, flexion strength was lower, and more patients underwent meniscus surgery in the follow-up period. The BPTB group has more anterior knee pain.