Donepezil provides positive effects to patients treated with gabapentin for neuropathic pain: an exploratory study.

BACKGROUND: The first-line medication gabapentin and the acetylcholinesterase inhibitor donepezil represent a new promising combination to improve treatment outcomes for patients with severe neuropathic pain. The drugs have previously shown synergism following co-administration in nerve-injured rats. METHODS: The clinical relevance of adding donepezil to existing gabapentin treatment in patients with post-traumatic neuropathic pain was explored in this open-label study. The study comprised two consecutive periods of minimum 6 weeks: (1) titration of gabapentin to the highest tolerable dose or maximum 2400 mg daily, and (2) addition of donepezil 5 mg once daily to the fixed gabapentin dose. Efficacy and tolerability were assessed by ratings of pain intensity, questionnaires for pain and health-related quality of life, and reporting of adverse events. Pain scores were also analysed using mixed-effects analysis with the software NONMEM to account for intersubject variability. RESULTS: Eight patients commenced treatment with donepezil, of which two withdrew because of adverse events. Addition of donepezil resulted in clinically relevant reductions of pain (> 11 units on a 0-100 scale) and improved mental wellness in three of six patients. The remaining three patients had no obvious supplemental effect. Mixed-effects analysis revealed that pain scores were significantly lower during co-administration (P < 0.0001 combination vs. monotherapy). CONCLUSION: Donepezil may provide additional analgesia to neuropathic pain patients with insufficient pain relief from gabapentin as monotherapy. The promising results support controlled clinical trials of the drug combination. The usefulness of mixed-effects analysis in small-scale trials and/or for data with high intersubject variability was also demonstrated.

Testing whether the epidural works: too time consuming?

BACKGROUND: When using epidural anaesthesia (EDA) for pain relief after major surgery, a failure rate of 10% is common. A crucial step in improving the care of patients with EDA is to define the position of the epidural catheter. The aim of this study was to investigate how much time it takes to determine whether the block is sufficient by assessing the extent of loss of cold sensation before induction of anaesthesia. METHODS: One hundred patients listed for abdominal surgery were included in the study. After an epidural catheter had been inserted and an intrathecal or an intravenous position had been made unlikely by the use of a test dose, the patient was given a bolus dose of local anaesthetic plus an opioid in the epidural catheter. The epidural block was tested every 2 min, starting at 5 min and ending at 15 min. When at least four segments were blocked bilaterally, the testing was stopped, the time was noted and the patient was anaesthetised. RESULTS: An epidural block was demonstrated after 5-6 min in 37 patients, after 7-8 min in 43 additional patients and after 9-10 min in 15 patients. In one patient, it took 12 min and in three patients, it took 15 min. In two patients, no epidural block could be demonstrated. CONCLUSION: Testing an epidural anaesthetic before the induction of anaesthesia takes only 5-10 extra minutes. Knowing whether the catheter is correctly placed means better quality of care, giving the anaesthetist better prerequisites for taking care of the patient post-operatively.

A double-blind trial of the analgesic properties of physostigmine in postoperative patients.

A double-blind clinical trial of the analgesic and antisedative effects of physostigmine was carried out on surgical patients (n = 60) during the first hours postoperatively. Pethidine and placebo were included for comparison in the double-blind study. The degree of pain and sedation was estimated when the patient demanded analgesics and immediately before the administration of the test drug. The dosage administered i.v. was: physostigmine salicylate 2 mg, placebo = saline, or pethidine chloride 50 mg. After this, the same parameters were recorded at regular intervals. In addition, ventilatory rate, pulse rate, systolic blood pressure and side effects, if any, were noted. The results showed that physostigmine caused analgesia that was of the same magnitude as pethidine during the first 15 min, after which it decreased to the level of the placebo at 30 min. An antisedative or arousal effect was recorded over a somewhat longer time period; after this, there was no difference between placebo and physostigmine. In contrast to pethidine, physostigmine caused no decrease in the ventilatory rate. The pulse rate and systolic blood pressure did not change in any of the groups. Although the durations of the analgesic and antisedative effects of physostigmine were short, the use of this drug may well be preferable to the use of e.g. naloxone when immediate alertness of the patient is wanted without causing an increase in postoperative pain.

Evaluation of possible spinal neurotoxicity of clonidine.

An experimental investigation was carried out concerning the potential neurotoxic effects of clonidine. For this purpose intrathecal or extradural catheters were implanted in dogs. Clonidine at a dose level of 25 micrograms/kg or 12.5 micrograms/kg, or placebo, was then administrated via the catheter once daily for 14 consecutive days. The spinal cord and the nerve roots were then taken for neuropathological analysis. Observation of the neurological behaviour of the animals and the results of the morphological investigation support the conclusion that clonidine under these circumstances does not have any significant neurotoxic effects.