Acupuncture for 'frequent attenders' with medically unexplained symptoms: a randomised controlled trial (CACTUS study).

BACKGROUND: Medically unexplained physical symptoms (MUPS) are common and difficult to treat. AIM: To investigate the effectiveness of adding five-element acupuncture to usual care in 'frequent attenders' with MUPS. DESIGN AND SETTING: Randomised controlled trial in four London general practices. METHOD: Participants were 80 adults with MUPS, consulting GPs ≥8 times/year. The intervention was individualised five-element acupuncture, ≥12 sessions, immediately (acupuncture group) and after 26 weeks (control group). The primary outcome was 26-week Measure Yourself Medical Outcome Profile (MYMOP); secondary outcomes were wellbeing (W-BQ12), EQ-5D, and GP consultation rate. Intention-to-treat analysis was used, adjusting for baseline outcomes. RESULTS: Participants (80% female, mean age 50 years, mixed ethnicity) had high health-resource use. Problems were 59% musculoskeletal; 65% >1 year duration. The 26-week questionnaire response rate was 89%. Compared to baseline, the mean 26-week MYMOP improved by 1.0 (95% confidence interval [CI] = 0.4 to 1.5) in the acupuncture group and 0.6 (95% CI = 0.3 to 0.9) in the control group (adjusted mean difference: acupuncture versus control -0.6 [95% CI = -1.1 to 0] P = 0.05). Other between-group adjusted mean differences were: W-BQ12 4.4 (95% CI = 1.6 to 7.2) P = 0.002; EQ-5D index 0.03 (95% CI = -0.11 to 0.16) P = 0.70; consultation rate ratio 0.90 (95% CI = 0.70 to 1.15) P = 0.4; and number of medications 0.56 (95% CI = 0.47 to 1.6) P = 0.28. All differences favoured the acupuncture group. Imputation for missing values reduced the MYMOP adjusted mean difference to -0.4 (95% CI = -0.9 to 0.1) P = 0.12. Improvements in MYMOP and W-BQ12 were maintained at 52 weeks. CONCLUSION: The addition of 12 sessions of five-element acupuncture to usual care resulted in improved health status and wellbeing that was sustained for 12 months.

KATP channel subunits in rat dorsal root ganglia: alterations by painful axotomy.

BACKGROUND: ATP-sensitive potassium (KATP) channels in neurons mediate neuroprotection, they regulate membrane excitability, and they control neurotransmitter release. Because loss of DRG neuronal KATP currents is involved in the pathophysiology of pain after peripheral nerve injury, we characterized the distribution of the KATP channel subunits in rat DRG, and determined their alterations by painful axotomy using RT-PCR, immunohistochemistry and electron microscopy. RESULTS: PCR demonstrated Kir6.1, Kir6.2, SUR1 and SUR2 transcripts in control DRG neurons. Protein expression for all but Kir6.1 was confirmed by Western blots and immunohistochemistry. Immunostaining of these subunits was identified by fluorescent and confocal microscopy in plasmalemmal and nuclear membranes, in the cytosol, along the peripheral fibers, and in satellite glial cells. Kir6.2 co-localized with SUR1 subunits. Kir6.2, SUR1, and SUR2 subunits were identified in neuronal subpopulations, categorized by positive or negative NF200 or CGRP staining. KATP current recorded in excised patches was blocked by glybenclamide, but preincubation with antibody against SUR1 abolished this blocking effect of glybenclamide, confirming that the antibody targets the SUR1 protein in the neuronal plasmalemmal membrane. In the myelinated nerve fibers we observed anti-SUR1 immunostaining in regularly spaced funneled-shaped structures. These structures were identified by electron microscopy as Schmidt-Lanterman incisures (SLI) formed by the Schwann cells. Immunostaining against SUR1 and Kir6.2 colocalized with anti-Caspr at paranodal sites.DRG excised from rats made hyperalgesic by spinal nerve ligation exhibited similar staining against Kir6.2, SUR1 or SUR2 as DRG from controls, but showed decreased prevalence of SUR1 immunofluorescent NF200 positive neurons. In DRG and dorsal roots proximal to axotomy SLI were smaller and showed decreased SUR1 immunofluorescence. CONCLUSIONS: We identified Kir6.2/SUR1 and Kir6.2/SUR2 KATP channels in rat DRG neuronal somata, peripheral nerve fibers, and glial satellite and Schwann cells, in both normal state and after painful nerve injury. This is the first report of KATP channels in paranodal sites adjacent to nodes of Ranvier and in the SLI of the Schwann cells. After painful axotomy KATP channels are downregulated in large, myelinated somata and also in SLI, which are also of smaller size compared to controls.Because KATP channels may have diverse functional roles in neurons and glia, further studies are needed to explore the potential of KATP channels as targets of therapies against neuropathic pain and neurodegeneration.

ATP-sensitive potassium channels in rat primary afferent neurons: the effect of neuropathic injury and gabapentin.

ATP-sensitive potassium (K(ATP)) currents were examined in dorsal root ganglion neurons from neuropathic and control rats using whole-cell voltage clamp recordings. K(ATP) channel openers (diazoxide and pinacidil) enhanced, and the blocker glibenclamide inhibited an outward current in control neurons in a manner dependent on the pipette ATP concentration. Analysis of reversal potentials showed that this current is carried by K(+) ions. Outward current in cells from rats with peripheral nerve injury was not sensitive to modulators of K(ATP) channels. Gabapentin, a putative K(ATP) channel opener, had minimal effect on currents in either group of neurons. We conclude that normal primary afferent neurons express K(ATP) channels that conduct current which is eliminated by peripheral nerve injury. Gabapentin does not affect this current significantly.

Gabapentin decreases membrane calcium currents in injured as well as in control mammalian primary afferent neurons.

BACKGROUND AND OBJECTIVES: Neuropathic pain following injury to peripheral sensory neurons is a common clinical problem and frequently difficult to treat. Gabapentin (GBP), a novel anticonvulsant, has significant analgesic effects in clinical neuropathic states and in relevant preclinical models, but its mechanism of action remains unclear. Because calcium currents play a significant role in neuronal function, this study was designed to assess the effect of GBP on the membrane voltage-activated inward calcium currents (I(Ca)) in dorsal root ganglia (DRG) primary afferent neurons of neuropathic versus control rats. METHODS: Male rats were prepared according to the chronic constriction injury (CCI) model. The L4 and L5 dorsal root ganglia of those selected as CCI or control after appropriate behavioral testing were removed, and neurons were enzymatically dissociated. Fluorescent dye (DiI) placed at the injury site allowed identification of neurons projecting to that site. These were acutely studied using whole-cell, perforated (with beta-escin) patch-clamp recordings. Additionally, neurons from sham or nonoperated rats were also studied. RESULTS: Although there was marked variability among cells, concentrations of GBP ranging from 0.1 to 300 micromol/L decreased neuronal peak ICa in midsized neurons (30 to 40 microm) of both sham and neuropathic rats, in a fast, reversible, and concentration-dependent manner. Intergroup differences were not significant, however the concentration-response EC50s were 2.7 micromol/L for the sham and 16.5 micromol/L for the CCI neurons. The drug suppressed I(Ca) in nonoperated rats to a lesser degree, but changes did not differ significantly from the operated groups. Calcium currents in either small or large diameter neurons were also variably decreased by 10 micromol/L of GBP in sham and CCI neurons. Current inhibition by GBP was partly voltage dependent. CONCLUSIONS: GBP, at clinically relevant concentrations, results in significant reduction of I(Ca) in both sham and neuropathic neurons, while in nonoperated rats reduced I(Ca) to a smaller degree. Sensitivity to drug was not affected by neuropathy. This current inhibition is partly voltage dependent. Depression of I(Ca) may be partly related to the binding of the drug to the alpha(2)delta modulatory subunit of the voltage activated calcium channels (VACC). Analgesia may be due to diminished release of neurotransmitter by sensory neurons, a Ca(2+)-dependent process.