A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain.

Peripheral neuropathic pain (PNP) poses a significant clinical challenge. The long-term efficacy of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was investigated in this 38-week open-label extension study. In total, 380 patients with PNP associated with diabetes or allodynia entered this study from two parent randomised, controlled trials. Patients received THC/CBD spray for a further 38 weeks in addition to their current analgesic therapy. Neuropathic pain severity was the primary efficacy measure using a pain 0-10 numerical rating scale (NRS). Additional efficacy, safety and tolerability outcomes were also investigated. In total, 234 patients completed the study (62 %). The pain NRS showed a decrease in score over time in patients from a mean of 6.9 points (baseline in the parent studies) to a mean of 4.2 points (end of open-label follow-up). The proportion of patients who reported at least a clinically relevant 30 % improvement in pain continued to increase with time (up to 9 months); at least half of all patients reported a 30 % improvement at all time points. Improvements were observed for all secondary efficacy outcomes, including sleep quality 0-10 NRS scores, neuropathic pain scale scores, subject global impression of change and EQ-5D questionnaire scores. THC/CBD spray was well tolerated for the study duration and patients did not seek to increase their dose with time, with no new safety concerns arising from long-term use. In this previously difficult to manage patient population, THC/CBD spray was beneficial for the majority of patients with PNP associated with diabetes or allodynia.

Individual choice of opioids and formulations: strategies to achieve the optimum for the patient.

The role of opioid therapy in chronic musculoskeletal disease continues to be controversial. However, recent years have seen a gradual shift towards the use of opioid therapy in chronic non-malignant pain (CNMP) following recognition that at least a subpopulation of such patients appears to benefit from long-term opioid treatment. Misconceptions about opioids and the associated risk of dependence stemmed from older research that was fundamentally flawed. More recent, rigorous research has yielded clearer statistics on opioid dependence and has highlighted the need for screening to identify individuals who may require closer monitoring during long-term opioid therapy. Controlled-release formulations (oral and transdermal) for the management of steady pain, in conjunction with fast-acting, immediate-release formulations for the management of breakthrough pain, may be available for a wide range of opioid analgesics, providing comprehensive therapy systems for use in CNMP. However, there are no universal criteria that can be confidently used to select CNMP patients who might profit from or be responsive to opioid therapy. Opioid treatment must therefore be individualised for each patient, based on a clear understanding of drug absorption, metabolism, toxicity and binding characteristics, using opioid switching strategies where appropriate. Practical guidelines for opioid therapy in CNMP include regular and systematic checks of treatment results to adjust therapy for each individual patient and to ensure optimum benefit.

Microvascular free-tissue transfers in elderly patients: the leeds experience.

Free-tissue transfer in the elderly has received increasing attention in the literature. Existing reports are limited by small samples or inadequate definition of the term elderly. This study reviewed 5 years' experience with free-tissue transfer in a geriatric population (mean age 75 years, range 70 to 83 years). Forty-nine free flaps were performed in 42 patients between 1986 and 1991. This review focuses on the 39 flaps undertaken in 33 head and neck cancer patients, the main indication being reconstruction after tumor resection (80 percent). In the head and neck cancer group, donor sites included the radial forearm (20), rectus abdominis (6), jejunum (5), and others (8). Thirty-four flaps (87 percent) were primarily successful. Reexploration was required in 10 patients (26 percent) for compromised flaps (5) and bleeding (5). Three of the compromised flaps were salvaged, giving an overall flap success rate of 95 percent. One patient (3 percent) died within 30 days of surgery. These results compare favorably with other published series in elderly patients, as well as with larger cohorts of younger subjects. Free flaps are safe in the elderly. Chronologic age alone should not be an exclusion criterion when selecting patients for free-tissue transfer.

Clinical pharmacokinetics of ondansetron. A review.

5-HT3 receptors are ubiquitous in the enteric, sympathetic, parasympathetic and sensory nervous systems and in the central nervous system (CNS) (Kilpatrick et al 1990). In man 5-HT3 receptors are mainly situated on enterochromaffin cells in the gastrointestinal mucosa, which are innervated by vagal afferents (Reynolds et al 1989), and the area postrema of the brain stem, which forms the chemoreceptor trigger zone. Ondansetron is a selective antagonist at 5-HT3 receptors. It is 100 times more potent than metoclopramide at this site (Tyers 1992). It shows limited binding to other receptors and has a wide therapeutic window. Ondansetron is a useful antiemetic which probably has both central and peripheral actions in patients undergoing radiotherapy, cytotoxic chemotherapy or general anaesthesia (Naylor & Rudd 1992). This paper reviews the pharmacokinetics of ondansetron in health and disease to provide information for clinicians; it might alter prescribing and alert them to possible drug interactions.

Prediction of outcomes in 150 patients having microvascular free tissue transfers to the head and neck.

Medical records of 150 patients who had undergone microvascular free tissue transfer to the head and neck (85% for malignancy) were retrospectively assessed to identify predictors of postoperative outcomes and complications. 5% of flaps failed and 20% required re-exploration. Surgical and medical problems occurred in 23% and 67% patients respectively; mortality was 4.7%. 132 records were analysed by logistic regression. Mortality and stroke were commoner in patients with previous myocardial infarction or steroid medication. Chest infection was commoner in men and with increasing age. Hypoxaemia was associated with bronchodilator therapy. Thromboembolism was commoner in patients on diuretics. Nutritional problems were more frequent in patients on opioids, with low weight or hypertension. Donor site infection was related to haemoglobin concentration, cerebrovascular disease, hypertension, opioid consumption or previous radiotherapy. Recipient site infection was associated with hypertension. Flap failure was related to nitrate or bronchodilator treatment. Re-exploration was associated with opioid or bronchodilator therapy. It was concluded that several factors predicted complications and death following microvascular surgery to the head and neck.

Medical student attrition: a 10-year survey in one medical school.

Medical student wastage leads to adverse emotional and social consequences for individual students and financial difficulties and morale problems for medical schools. This study retrospectively assessed the records of all students at Leeds School of Medicine who left the course prematurely between 1983 and 1992. The demographic data of the leavers were compared with those of all students entering the school during the 10 years studied. A-level examination choices and results of the leavers were compared with those of a control group of all students who entered the school in 1990. The attrition rate over the 10 years was 14% (283 students), with more males than females leaving. Fewer mature students than expected left the course. More leavers had A-level physics and lacked A-level biology compared with the control group. The leavers were academically less able than the controls. Fifty-three per cent of leavers were asked to withdraw from the course for academic reasons; the rest left voluntarily. Thirty per cent had personal problems, 9% had a combination of academic and personal problems and 8% had health problems (psychological difficulties were the commonest). Seventy-one per cent of leavers entered another degree course; science degrees were the most popular. Reasons for medical student wastage and possible solutions are discussed.

An audit of Björk flap tracheostomies in head and neck plastic surgery.

Patients undergoing head and neck surgery for malignancy especially resection of parts of the upper aerodigestive tracts need a secure airway intra- and postoperatively. A tracheostomy is an effective method of achieving this objective. In our unit the Björk flap technique1 has been the preferred type of tracheostomy. Ninety-five consecutive Björk flap tracheostomies performed by one surgeon preceding major head and neck resection for malignancy in patients aged 17-79 years (median = 61 years) were retrospectively evaluated. The technique was quick and provided a secure airway. The tracheostomy tubes were left in situ for a median of 5 days (range 1-17 days). After extubation subsequent stoma closure was uneventful, 60% healing within 1 week. No patient developed tracheal fistula, clinical tracheal stenosis or cosmetically unacceptable scarring. There was no tracheostomy-related mortality. It is concluded that the Björk flap tracheostomy technique can be safely used in head and neck cancer surgery in adults.

Management of spinal infusions in palliative care.

Spinal analgesia can provide excellent pain relief for a small group of patients in whom conventional modalities have failed. The role of spinal analgesia in the palliative care setting is discussed and illustrated by the experience at St Gemma's Hospice over a two-year period. Special emphasis is placed on the difficulties that may need to be overcome when using this form of analgesia. The management of spinal infusions can produce some unique problems to the hospice or home care team, but the benefits often far outweight the difficulties.

Development of a blood urea monitoring system for the closed loop control of dialysis.

Optimal hemodialysis prescription through real-time blood urea (BU) monitoring and closed loop control of urea removal would be of significant clinical value. Progress toward a bedside BU analyzer and a control system is described here. An Amicon Minifilter inserted into the arterial bloodline provides a 1 ml/min stream of protein free ultrafiltrate for analysis. In vitro tests with bovine blood have shown excellent correlation between plasma (CP) and ultrafiltrate (CU) urea levels: CP = 0.961CU + 0.071, (n = 34, r = 0.998). In clinical hemodialysis studies, CU accurately represented the decay in CP. The BU analyzer uses a standard UV endpoint assay with a proportioning roller pump. The absorbance of the reacted mixture is read in a spectrophotometer after a 5 min incubation. For future control system design, the transfer function (TF) of the BU analyzer was measured using multifrequency binary testing. The data indicated that the analyzer may be modeled by a second order TF with a pure time delay. The same form of TF was also found to describe the Minifilter. Control of the removal rate of NaCl (substituted for urea) through automatic dialysate flow adjustment has been achieved with a simulated dialyzer-patient circuit (using a conductivity probe in place of the BU analyzer). A modified BU analyzer using computer controlled precision syringes for improved sample processing time and accuracy is also reported.

Concentration of ondansetron in cerebrospinal fluid following oral dosing in volunteers.

This study measured the concentrations of ondansetron in plasma and cerebrospinal fluid (CSF) in six volunteers after oral dosing to steady state. Ondansetron concentrations ranged from 39.5-147 ng ml-1 in plasma and from 2.6-15.4 ng ml-1 in CSF. There was good correlation between plasma and CSF concentrations (r = 0.89, p = 0.017). CSF concentrations were less than 15% of plasma concentrations in all cases, indicating that the rate of penetration of the blood brain barrier by ondansetron is low.

Effect of addition of hyaluronidase to bupivacaine during axillary brachial plexus block.

We have studied in 22 patients the effect of adding hyaluronidase to bupivacaine during axillary brachial plexus block (BPB) in a double-blind design. Patients received BPB using bupivacaine 2 mg kg-1 with adrenaline 1 in 200,000, either with or without hyaluronidase 3000 iu, in a volume of 0.5 ml per 2.54 cm of the patient's height. The use of hyaluronidase did not increase the speed of onset of anaesthesia or reduce the incidence of inadequate nerve block. Hyaluronidase produced a significant reduction in the duration of anaesthesia. Changes in grip strength and skin temperature were useful in assessing the onset and progress of BPB.

Pain on injection of methohexitone. The use of lignocaine to modify pain on injection of methohexitone during anaesthesia for electroconvulsive therapy.

The present study was designed to assess the incidence of pain when methohexitone was administered to 35 depressed patients who had electroconvulsive therapy, and to determine whether the use of lignocaine could modify this, without affecting seizure duration. The same patients were studied during three separate treatment sessions; they received either methohexitone alone or mixed with, or preceded by, lignocaine 10 mg. Six (17%) patients spontaneously complained of pain during injection of methohexitone alone; the use of lignocaine prior to methohexitone reduced this to zero (p less than 0.05). A total of 49% patients reported pain during injection of methohexitone; the use of lignocaine either mixed with, or given prior to, methohexitone significantly reduced this to 23% and 20% respectively (p less than 0.05). Seizure duration was not significantly different during the three treatments.

An investigation of premedication with morphine given by the buccal or intramuscular route.

1. Premedication with 30 mg buccal morphine or 10 mg intramuscular morphine was evaluated in 40 healthy women undergoing major gynaecological surgery. 2. Buccal administration of morphine produced lower plasma morphine concentrations than intramuscular injection of morphine (P less than 0.01). 3. The mean systemic availability of the buccal tablet, during the first 5 h after administration, was approximately 3% relative to that of the intramuscular preparation. 4. Poor absorption of buccal morphine resulted in inadequate sedation prior to surgery and poor post-operative analgesia. 5. Patients experienced difficulty with the buccal formulation of morphine; tablet bitterness and failure to dissolve were particular problems.

Premedication with piroxicam in patients having dental surgery under general anaesthesia with halothane or isoflurane.

Pain, analgesic requirements, mouth opening and emesis were assessed in 60 patients who received either piroxicam 40 mg or placebo before dental surgery under general anaesthesia which included breathing either halothane or isoflurane. Patients went home on the day after surgery and completed a questionnaire concerning pain and emesis. There were four groups of 15 subjects: piroxicam-halothane, piroxicam-isoflurane, placebo-halothane or placebo-isoflurane. Pain increased at 2 and 4 h and had reduced by 18 h after surgery; there were no significant differences between the groups in pain scores. After operation, fewer patients in the piroxicam-isoflurane group required papaveretum compared with the piroxicam-halothane and placebo-halothane groups. Mouth opening was reduced between 2 and 4 h after surgery, but was less restricted after piroxicam-isoflurane than placebo-halothane. There was no difference between the groups in the incidence of emesis within 18 h of surgery. The postal questionnaire suggested that pain and emesis were reduced significantly during the 3 days after surgery in patients who had received piroxicam before surgery, compared with those who had received placebo.