Brain activity modifications following spinal cord stimulation for chronic neuropathic pain: A systematic review.

BACKGROUND AND OBJECTIVE: Spinal cord stimulation (SCS) is believed to exert supraspinal effects; however, these mechanisms are still far from fully elucidated. This systematic review aims to assess existing neurophysiological and functional neuroimaging literature to reveal current knowledge regarding the effects of SCS for chronic neuropathic pain on brain activity, to identify gaps in knowledge, and to suggest directions for future research. DATABASES AND DATA TREATMENT: Electronic databases and hand-search of reference lists were employed to identify publications investigating brain activity associated with SCS in patients with chronic neuropathic pain, using neurophysiological and functional neuroimaging techniques (fMRI, PET, MEG, EEG). Studies investigating patients with SCS for chronic neuropathic pain and studying brain activity related to SCS were included. Demographic data (age, gender), study factors (imaging modality, patient diagnoses, pain area, duration of SCS at recording, stimulus used) and brain areas activated were extracted from the included studies. RESULTS: Twenty-four studies were included. Thirteen studies used neuroelectrical imaging techniques, eight studies used haemodynamic imaging techniques, two studies employed both neuroelectrical and haemodynamic techniques separately, and one study investigated cerebral neurobiology. CONCLUSIONS: The limited available evidence regarding supraspinal mechanisms of SCS does not allow us to develop any conclusive theories. However, the studies included appear to show an inhibitory effect of SCS on somatosensory evoked potentials, as well as identifying the thalamus and anterior cingulate cortex as potential mediators of the pain experience. The lack of substantial evidence in this area highlights the need for large-scale controlled studies of this kind.

Spinal cord stimulation in the treatment of non-reconstructable stable critical leg ischaemia: results of the European Peripheral Vascular Disease Outcome Study (SCS-EPOS).

OBJECTIVE: To determine the effect of spinal cord stimulation (SCS) on limb survival in patients with non-reconstructable critical leg ischaemia, and the value of patient selection on the basis of transcutaneous oxygen pressure (TcpO2) measurements and trial screening. DESIGN: A prospective, controlled, European multicentre study. METHODS: Non-reconstructable patients with stable critical leg ischaemia were divided into three groups. The SCS-Match group comprised patients with a baseline forefoot TcpO2 of < 30 mmHg and both sufficient pain relief and sufficient paraesthesia coverage (> 75%) after a test stimulation period of at least 72 h. If baseline TcpO2 was < 10 mmHg, the TcpO2 should have exceeded 20 mmHg after test stimulation. The SCS-Match group was compared with patients not meeting these criteria, who were treated either with SCS (SCS-No-Match) or without SCS (No-SCS). RESULTS: At baseline, the mean (+/- SD) supine TcpO2 was 14.9 +/- 8.3 mmHg in the SCS-Match group (n = 41), 11.3 +/- 13.3 mmHg in the SCS-No-Match group (n = 32) and 15.3 +/- 17.1 mmHg in the No-SCS group (n = 39). In the SCS-Match group a significant improvement in pain relief (p < 0.005) and TcpO2 (p < 0.001) was seen. After 12 months, cumulative limb survival of patients treated with SCS was significantly better than that of patients not treated with SCS (p < 0.03), and limb survival in the SCS-Match group was significantly higher (p < 0.03) than that in the SCS-No-Match and No-SCS groups (78, 55 and 45%, respectively). CONCLUSION: SCS treatment of non-reconstructable critical leg ischaemia provides a significantly better limb survival rate compared with conservative treatment. Patient selection based on TcpO2 and the results of trial screening further increase the probability of limb survival after SCS therapy.

Efficacy and adverse effects of intravenous lignocaine therapy in fibromyalgia syndrome.

BACKGROUND: To investigate the effects of intravenous lignocaine infusions (IV lignocaine) in fibromyalgia. METHODS: Prospective study of the adverse effects of IV lignocaine in 106 patients with fibromyalgia; retrospective questionnaire study of the efficacy of IV lignocaine in 50 patients with fibromyalgia. RESULTS: Prospective study: Two major (pulmonary oedema and supraventricular tachycardia) and 42 minor side-effects were reported. None had long-term sequelae. The commonest was hypotension (17 cases). Retrospective study: Pain and a range of psychosocial measures (on single 11-point scales) improved significantly after treatment. There was no effect of the treatment on work status. The average duration of pain relief after the 6-day course of treatment was 11.5 +/- 6.5 weeks. CONCLUSIONS: Intravenous lignocaine appears to be both safe and of benefit in improving pain and quality of life for patients with fibromyalgia. This needs to be confirmed in prospective randomised controlled trials.

Long-term experience with implanted intrathecal drug administration systems for failed back syndrome and chronic mechanical low back pain.

BACKGROUND: Continuous intrathecal drug delivery has been shown in open studies to improve pain and quality of life in those with intractable back pain who have had spinal surgery. There is limited data on long term effects and and even less for patients with mechanical back pain without prior spinal surgery. METHODS: We have investigated spinal drug administration systems for patients with failed back syndrome and chronic mechanical low back pain by patient questionnaire study of the efficacy of this therapy and a case notes review. RESULTS: 36 patients (97% of 37 approached) completed questionnaires, 24 with failed back syndrome and 12 with chronic mechanical low back pain. Recalled pre-treatment levels with current post-treatment levels of pain and a range of quality of life measures (recorded on 11-point numerical rating scales) were compared. Pain improved significantly in both groups (Wilcoxan signed ranks test, p < 0.005). The majority of quality of life measures improved significantly in the failed back syndrome group (Wilcoxan signed ranks test, p < 0.005) although work interruption and the effect of pain on sex life did not change. There was a trend towards improvement in the majority of quality of life measures in the mechanical back pain group but this did not reach statistical significance due to the smaller numbers in this cohort (p > 0.005, Wilcoxan signed ranks test with Bonferroni correction).Diamorphine was used in all 37 patients, bupivacaine in 32, clonidine in 27 and baclofen in 3. The mean dose of diamorphine increased for the first 2 years but did not change 2-6 years post implant, averaging 4.5 mg/day. Revision surgery was required in 24% of cases, but reduced to 12% in the later years of our experience. CONCLUSIONS: We conclude that spinal drug administration systems appear to be of benefit in alleviating pain in the failed back syndrome and chronic mechanical low back pain but need to be examined prospectively.

Upper airway reactivity and upper respiratory tract infection: effect of nebulized lidocaine.

Patients presenting for elective anaesthesia and surgery may be suffering with, or recovering from, a recent upper respiratory tract infection. Airway reflexes are heightened and these individuals may be more likely to suffer airway complications on administration of general anaesthesia. We have examined the effect of nebulized lidocaine on upper airway reflexes in such subjects. Using dilute ammonia as a chemical stimulus to the upper airway, we measured upper airway reactivity in 15 volunteers (aged 22-43 yr) with symptoms of an upper respiratory tract infection for 4 days or less. The threshold concentration of ammonia producing a brief reduction in inspiratory flow was determined. Measurements were made before and after administration of a nebulized solution of 4% lidocaine 4 ml or saline. After a 2-h interval the procedure was repeated with the alternative solution. The order of administration was randomized. The observer was blind to the solution given. Ammonia threshold was found to increase in subjects after nebulized lidocaine, from a median value of 327 (range 76-878) ppm to 878 (251-1620) ppm (P = 0.0007, Wilcoxon); there was no significant change after nebulized saline. After a convalescence period of at least 4 weeks, with no return of symptoms in the preceding 2 weeks, ammonia threshold was reassessed. It was found to be increased in all 15 subjects. Comparison of the five different times of measurement showed a highly significant difference (P < 0.001, Friedman). Subsequent analysis showed significant differences (P < 0.05, Wilcoxon) between convalescent ammonia threshold and both baseline and post-saline nebulizer values. There was no significant difference between convalescent and post-lidocaine ammonia threshold. We conclude that in adult subjects, nebulized lidocaine attenuated the heightened airway reflex sensitivity associated with symptoms and signs of upper respiratory tract infection.

An investigation into the effects of midazolam and propofol on human respiratory cilia beat frequency in vitro.

OBJECTIVE: Patients in intensive care are known to be prone to both upper and lower respiratory tract infection. Respiratory mucus forms a barrier to infection. Mucus transport rate (MTR) depends upon both the physical properties of mucus and the action of respiratory cilia. Patients undergoing anaesthesia are known to have a reduced MTR that may be related to a depressant effect on cilia beat frequency (CBF) by anaesthetic drugs. The aim of this study was to investigate the effects of two commonly used intensive care sedative agents, midazolam and propofol, on CBF using human nasal turbinate explants in vitro. DESIGN: We exposed ciliated tissue from human nasal turbinate explants to midazolam and propofol in supraclinical concentrations (20 microM midazolam and 70 microM propofol) in a controlled and blinded manner for 90 min and measured CBF by the transmitted light technique. RESULTS: After 90 min, mean (SEM) CBF in the group exposed to midazolam and its control group were 13.0 (0.2) Hz and 12.9 (0.3) Hz, respectively. Mean (SEM) CBF in the group exposed to propofol was 13.6 (0.4) Hz and in the control group the value was 12.0 (0.6) Hz. There was no significant change in CBF (midazolam: p = 0.21, propofol: p = 0.31, MANOVA for repeated measures). CONCLUSIONS: We have found no effect of midazolam or propofol in supra-clinical concentrations upon CBF in human turbinate explants after a 90-min exposure. This contrasts with previous work that has shown a depressant effect of inhalational anaesthetic agents on CBF.

Comparison of isoflurane with propofol on respiratory cilia.

We have investigated the effects of two techniques of clinical anaesthesia on human respiratory cilia by measuring cilia beat frequency of nasal tissue. In a randomized, controlled study, 13 patients undergoing either inhalation anaesthesia with isoflurane or total i.v. anaesthesia with propofol and alfentanil had nasal ciliated epithelial samples removed at the beginning and after 1 h of anaesthesia. Mean cilia beat frequency in the group anaesthetized with isoflurane changed significantly from 11.5 (95% confidence interval (CI) 10.7-12.2) Hz to 9.1 (8.1-10.1) Hz after anaesthesia whereas in the group anaesthetized with propofol and alfentanil there was a change from 11.5 (10.7-12.2) Hz to 11.0 (10.2-11.8) Hz (ns). The difference between the anaesthetic agents on cilia beat frequency was significant (MANOVA, P < 0.01). These data suggest that different anaesthetic agents may impair respiratory defence mechanisms to differing extents.

Effect of an upper respiratory tract infection on upper airway reactivity.

Patients presenting for elective anaesthesia and surgery may be suffering with, or recovering from, a recent upper respiratory tract infection (URTI). It is a frequent clinical problem as to whether to postpone surgery in such patients as they may be more likely to suffer adverse respiratory events related to administration of general anaesthesia. Using dilute ammonia vapour as a chemical stimulus, we measured upper airway reactivity in 11 healthy volunteers (six males), mean age 39.8 (range 30-58) yr, who had symptoms of an URTI. Volunteers were recruited 24-72 h after symptoms first began, and followed-up at regular intervals for the next 8 weeks. Measurements of upper airway reactivity were made on the following days (+/- 24h) after commencement of URTI symptoms: 3, 6, 9, 15, 20 and 27. Additional measurements were obtained 56 days after symptoms first began, and these were regarded as baseline measurements. Upper airway reactivity was increased on days 3, 6 and 9 compared with baseline measurements (P < 0.01, Wilcoxon). There was no significant change in airway reactivity from day 15 onwards, by which time 10 of the 11 subjects were completely devoid of symptoms. All subjects were asymptomatic by day 20 and remained so until the study ended on day 56. We conclude that upper airway reactivity was increased during the acute phase of an URTI, and that this appeared to be related to the presence of symptoms.

Effect of nebulised lignocaine on the quality of induction of anaesthesia in cigarette smokers.

We have assessed the effect of nebulised lignocaine, given pre-operatively, upon the quality of induction of anaesthesia in cigarette smokers. Seventy-five patients were studied in a double-blind randomised fashion, receiving a nebuliser of either 4 ml 0.9% NaCl or 4 ml 4% lignocaine. All patients received a standardised anaesthetic consisting of thiopentone followed by progressive increments of enflurane. Thirty-three out of 38 patients (87%) who received nebulised lignocaine had induction without adverse events, compared with 25 out of 37 patients (68%) in the nebulised saline group (Chi-squared test p < 0.05). We conclude that the use of nebulised lignocaine, administered pre-operatively, improves the quality of induction of anaesthesia in cigarette smokers.

Configuration of the SCOTI device with different tracheal tubes.

We have evaluated the Sonomatic Confirmation of Tracheal Intubation device (SCOTI) by testing its ability to be correctly configured with a variety of tracheal tubes of differing internal diameter and length. The device only configured correctly for RAE tubes with internal diameter of 7.0 mm or greater and for armoured tubes of internal diameter 8.5 mm. For conventional tubes of varying internal diameter cut to different lengths, configuration was only successful with certain dimensions. The inability to configure the device correctly with all types and lengths of tracheal tubes limits its usefulness as a indicator of tracheal intubation.

Recovery of respiratory ciliary function after depression by inhalation anaesthetic agents: an in vitro study using nasal turbinate explants.

We have developed a human tissue preparation suitable for measurement of cilia beat frequency derived from nasal turbinates. Cilia beat frequency of turbinate explants from 11 patients did not change significantly over a 10-day observation period while maintained in an incubator, with mean cilia beat frequency of 13.1 (SEM 0.3) Hz to 14.4 (0.2) Hz (ANOVA for repeated measures, P = 0.168). We have used this preparation to investigate recovery of ciliary function after depression by inhalation anaesthetic agents. Eight or nine turbinate explants were exposed to three times the minimum alveolar concentration (MAC) of halothane, enflurane or isoflurane for a period of 1 h and thereafter to a period of air washout. After exposure to the inhalation agent there was a significant reduction in cilia beat frequency with all three agents: halothane 14.3 (0.4) Hz to 9.5 (0.3) Hz; enflurane 13.7 (0.6) Hz to 10.5 (0.5) Hz;isoflurane 15.9 (0.6) Hz to 10.6 (0.3) Hz. Cilia beat frequency returned to values after air washout that were not significantly different from baseline after 90 min of washout of halothane and 60 min of washout of enflurane and isoflurane (repeated measures ANOVA, unpaired t test; P = 0.01 at 60 min and P = 0.31 at 90 min washout for halothane; P = 0.83 at 60 min washout for enflurane; P = 0.26 at 60 min washout for isoflurane).

The effect of pre-incisional infiltration with lignocaine on postoperative pain after molar teeth extraction under general anaesthesia.

In a double-blind, placebo-controlled investigation, we studied the effects of pre-operative inferior alveolar nerve blockade and local anaesthetic intra-oral infiltration upon postoperative pain following third molar teeth extraction under general anaesthesia. Thirty six patients (12 male), mean (range) age 25.7 (18-40) years received an injection of 2% lignocaine 2 ml with 1:200,000 adrenaline around the inferior alveolar nerve and tissues adjacent to the third molar tooth on one side and of normal saline 2 ml in a similar fashion to the other side. We measured the pain on each side of the mandible on the 1st, 4th and 11th days after surgery using a visual analogue scale. The visual analogue pain score on the lignocaine and saline sides were 25/100 and 26/100 on day 1, 23/100 and 22/100 on day 4 and 0/100 and 1/100 on day 11. This study has a power of 80% to detect differences at the 5% level of significance of 11/100 on days 1 and 4 and 7/100 on day 11. We found no significant difference in the visual analogue scores between the lignocaine side and the saline side at any stage after the procedure.

Effects of topical benzocaine and lignocaine on upper airway reflex sensitivity.

We studied the degree and duration of effect on upper airway reflex sensitivity of oral benzocaine lozenges, nebulised lignocaine and lignocaine sprayed onto the vocal cords under direct vision, using low concentrations of ammonia as a stimulus to upper airway receptors. Ten minutes after the administration of oral benzocaine 20 mg the threshold response of the upper airway to ammonia (NH3TR) had risen significantly from baseline mean (SEM) of 680 (95) to 975 (109) ppm of ammonia with a return to baseline values after 25 min (n = 8, p < 0.05, repeated measures of ANOVA; p < 0.001, t-test). A direct spray of lignocaine 100 mg onto the vocal cords resulted in a significant elevation in NH3TR from a baseline mean (SEM) of 665 (81) to a maximum of 1600 (88) ppm of ammonia with a significant elevation in the threshold persisting for 100 min (n = 7, p < 0.001, repeated measures of ANOVA; p < 0.05, t-test). The application of 4% nebulised lignocaine 4 ml significantly increased NH3TR from a baseline mean (SEM) of 770 (56) to a maximum of 1190 (63) ppm of ammonia with a significant elevation in the threshold persisting for 30 min (n = 8, p < 0.001, repeated measures of ANOVA; p < 0.05, t-test). The maximum elevations in NH3TR with the two methods of lignocaine delivery were significantly different (p < 0.01, 2-way ANOVA).

Effects of morphine on human nasal cilia beat frequency in vitro.

Using human nasal cytological brushings, we have investigated the effects of morphine on ciliary function by measurement of cilia beat frequency in vitro, and we have also determined opioid receptor binding in these specimens. We obtained ciliated samples from seven volunteers, and measured cilia beat frequency using the transmitted light technique during exposure to morphine 10 mumol litre-1 for 4 h. Mean cilia beat frequency of the samples exposed to morphine was 11.1 (95% confidence interval 10.9-11.5) Hz and that of the controls 11.3 (11.1-11.7) Hz. There was no significant effect of morphine on human cilia beat frequency in vitro (MANOVA for repeated measures and nested, F = 0.61, P = 0.66). In a separate study, we obtained nasal brushings from 20 patients and measured the binding of the opioid antagonist tritiated diprenorphine ([3H]DPN). Mean disintegrations per minute (dpm) for total and non-specific binding were 9036 (8105-9967) dpm and 9130 (8054-10206) dpm, respectively. These values did not differ significantly (paired t test, t = 0.22, P = 0.83). We conclude that morphine had no effect on cilia beat frequency in vitro and we were unable to demonstrate any significant numbers of opioid receptors on nasal ciliated epithelium.

A perfusion system for in vitro measurement of human cilia beat frequency.

We have designed and built a perfusion system and perfusion chamber to allow investigation of the effects of anaesthetic agents on human cilia in vitro. Using this system, samples of human respiratory cilia can be maintained in a stable and controlled environment for several hours. We measured cilia beat frequency of nasal respiratory epithelium from 10 healthy volunteers; cilia beat frequency was constant over a 4-h period, and measurements were found to be in good agreement with previously published work [1]. In a separate study we investigated the effect of a sleep dose of propofol on cilia beat frequency in samples from six patients undergoing minor surgery; samples were obtained before and immediately after induction of anaesthesia with propofol 2-3 mg kg-1. There was no statistically significant difference in cilia beat frequency between data obtained before and after induction with propofol.

Effects of 3 MAC of halothane, enflurane and isoflurane on cilia beat frequency of human nasal epithelium in vitro.

We have measured the effects of three times the minimum alveolar concentration (MAC) of halothane, enflurane and isoflurane on cilia beat frequency of human nasal epithelial brushings from 18 healthy adult patients. Using the transmitted light technique and paired perfusion chambers, the cilia were exposed to 2.25% halothane, 5% enflurane or 3.6% isoflurane in air, or air alone, in a controlled and blinded manner. Over a 4-h observation period, cilia beat frequency of the samples exposed to inhalation anaesthetic agents demonstrated a significant reduction in frequency compared with controls exposed to air alone. Mean cilia beat frequency for the samples exposed to halothane was 9.3 (SEM 1.3) compared with its controls of 11.4 (1.0); for the samples exposed to enflurane, 10.9 (1.3) compared with its controls of 11.6 (1.2); and for the samples exposed to isoflurane, 10.8 (1.1) compared with its controls of 11.6 (1.2). There was a statistically significant difference between the samples exposed to all three volatile agents and their associated controls (halothane, P = 0.01; enflurane, P = 0.03; isoflurane, P = 0.01; nested repeated measures analysis of variance utilizing polynomial contrasts).

A combined high frequency oscillator and intermittent positive pressure ventilator.

A high frequency oscillator and its interface with the Siemens 900C ventilator form a combined high frequency oscillator and intermittent positive pressure ventilator. This combined high frequency ventilator is designed for use in selected cases of refractory hypoxaemia.