Increased bilateral expression of α1-adrenoceptors on peripheral nerves, blood vessels and keratinocytes does not account for pain or neuroinflammatory changes after distal tibia fracture in rats.

In certain forms of nerve injury and inflammation, noradrenaline augments pain via actions on up-regulated α1-adrenoceptors (α1-ARs). The aim of this study was to use immunohistochemistry to examine α1-AR expression on peripheral neurons, cutaneous blood vessels and keratinocytes after distal tibia fracture and cast immobilization, a model of complex regional pain syndrome type 1. We hypothesized that there would be increased α1-AR expression on neurons and keratinocytes in the injured limb in comparison to the contralateral unaffected limb after distal tibia fracture, in association with inflammatory changes and pain. α1-AR expression was increased on plantar keratinocytes, dermal blood vessels and peripheral nerve fibers at 16weeks after injury both in the fractured and contralateral uninjured limb. Similar changes were seen in controls whose limb had been immobilized in a cast for 4weeks but not fractured. Neurofilament 200 (NF200), a marker of myelinated neurons, and calcitonin gene-related peptide (CGRP), a neuropeptide involved in neuro-inflammatory signaling, decreased 4weeks after fracture and casting but then increased at the 16-week time point. As some of these changes were also detected in the contralateral hind limb, they probably were triggered by a systemic response to fracture and casting. Soon after the cast was removed, intraplantar injections of the α1-AR antagonist prazosin released local vasoconstrictor tone but had no effect on pain behaviors. However, systemic injection of prazosin inhibited behavioral signs of pain, suggesting that fracture and/or casting triggered an up-regulation of α1-ARs in central nociceptive pathways that augmented pain. Together, these findings indicate that α1-AR expression increases in the hind limbs after distal tibia fracture and cast immobilization. However, these peripheral increases do not contribute directly to residual pain.

Expression of α1-adrenoceptors on peripheral nociceptive neurons.

The purpose of this study was to determine whether α(1)-adrenoceptors are expressed on primary nociceptive afferents that innervate healthy skin. Skin and dorsal root ganglia were collected from adult male Wistar rats and assessed using fluorescence immunohistochemistry with antibodies directed against α(1)-adrenoceptors alone or in combination with specific labels including myelin basic protein and neurofilament 200 (markers of myelinated nerve fibres), protein gene product 9.5 (a pan-neuronal marker), tyrosine hydroxylase (sympathetic neurons), isolectin B(4) (IB(4): non-peptidergic sensory neurons), calcitonin gene related peptide (CGRP) and transient receptor potential vanilloid receptor 1 (TRPV1) (peptidergic sensory neurons). Double labelling in dorsal root ganglia confirmed the expression of α(1)-adrenoceptors within sub-populations of CGRP, IB(4) and TRPV1 immunoreactive neurons. Myelinated and unmyelinated sensory nerve fibres in the skin expressed α(1)-adrenoceptors whereas sympathetic nerve fibres did not. The expression of α(1)-adrenoceptors on C- and A-delta nociceptive afferent fibres provides a histochemical substrate for direct excitation of these fibres by adrenergic agonists. This may help to explain the mechanism of sensory-sympathetic coupling that sometimes develops on surviving primary nociceptive afferents in neuropathic pain states.

Radiofrequency heating of painful annular disruptions: one-year outcomes.

OBJECTIVE: Although several studies have reported on outcomes following heating of annular tears with a thermoresistive catheter (SpineCATH), no data are available on the efficacy of thermal treatment with a flexible radiofrequency electrode (discTRODE). A prospective case-control study was conducted to determine the efficacy of radiofrequency heating of painful annular tears in the lumbar spine. METHODS: After at least 6 months of conservative treatment, 46 patients were studied for the presence of single-level painful annular tears with magnetic resonance imaging and provocative discography. Thirty-one patients underwent heating of their annular tears with a flexible radiofrequency electrode placed across the posterior annulus. The remaining 15 patients, who mostly could not obtain funding for the procedure, continued with conservative management and acted as a control group. The Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and Medication Quantification Score (MQS) were obtained before and at 3-monthly intervals after treatment. RESULTS: The VAS decreased significantly after the radiofrequency treatment, and this decrease persisted at 12 months of follow-up. The VAS did not change over 12 months in untreated control subjects. The decrease in VAS was significantly greater in the treated patients than the control subjects. The ODI also decreased in treated patients but not in control subjects. The MQS did not change in either group over the 12-month follow-up period. CONCLUSIONS: Radiofrequency heating of annular tears can lead to an improvement in the pain of internal disc disruption. The improvement gained by this treatment method is significantly better than that obtained from conservative management.

Persistence of pain induced by startle and forehead cooling after sympathetic blockade in patients with complex regional pain syndrome.

BACKGROUND: Stimuli arousing sympathetic activity can increase ratings of clinical pain in patients with complex regional pain syndrome (CRPS). OBJECTIVE: To determine whether the increase in pain is mediated by peripheral sympathetic activity. METHODS: The effect of sympathetic ganglion blockade on pain evoked by a startle stimulus and cooling the forehead was investigated in 36 CRPS patients. RESULTS: Loss of vasoconstrictor reflexes and warming of the limb indicated that sympathetic blockade was effective in 26 cases. Before sympathetic blockade, pain increased in 12 of these 26 patients when they were startled. Pain increased in seven of the 12 patients and in another five cases when their forehead was cooled. As expected, pain that increased during sympathetic arousal generally subsided in patients with signs of sympathetic blockade. However, pain still increased in three of 12 of patients after the startle stimulus and in six of 12 of patients during forehead cooling, despite indisputable sympathetic blockade. CONCLUSIONS: These findings suggest that stimuli arousing sympathetic activity act by a central process to exacerbate pain in some patients, independent of the peripheral sympathetic nervous system. This may account for the lack of effect of peripheral sympathetic blockade on pain in some CRPS patients.

Outcome of intrathecal opioids in chronic non-cancer pain.

Eighty-eight patients (58 women and 30 men; mean age 53.4 years) with chronic non-cancer pain present on average for 9.8 years were evaluated following treatment with intrathecal opioids for an average duration of 36.2 months. Outcome measures were global pain relief, physical activity levels, medication consumption, work status, intrathecal opioid side-effects, proportion of patients who ceased therapy and patient satisfaction. The most common diagnosis in this group was lumbar spinal or radicular pain after failed spinal surgery (n= 55, 63%). At the time of follow-up, mean pain relief was 60% with 74% of patients (36 of 49) reporting increased activity levels. Oral medication intake was significantly reduced (Medication Quantification Scale Score prior to implantation 31.0+/-2.6 and at follow-up 12.7+/-1.4; n= 48; p< 0.0001). These gains were not accompanied by a change in work status (43 of 50 working age patients not working at follow-up). There were frequent reports of opioid side-effects, including sexual dysfunction and menstrual disturbance. Technical complications occurred with the drug administration device, most often catheter related, requiring at least one further surgical procedure in 32 patients (40%). Patient satisfaction with intrathecal opioids was high, with 45 of 51 (88%) reporting satisfaction. Mean intrathecal morphine dose increased from 9.95+/-1.49 mg/day (mean+/-SEM) at 6 months to 15.26+/-2.52 mg/day 36 months after initiation of therapy. Drug administration systems were permanently removed in five patients (6%). Intrathecal opioid therapy appears to have a place in the management of chronic non-cancer pain. Therapy does not seem to be significantly inhibited by the development of tolerance.

Pain increases during sympathetic arousal in patients with complex regional pain syndrome.

OBJECTIVE: To investigate the effect of sympathetic arousal on pain and vasomotor responses in healthy control subjects and patients with complex regional pain syndrome (CRPS), and to determine whether pain increases in patients with particular symptoms. METHODS: In experiments 1 and 2, capsaicin was applied to the forearm of 24 healthy subjects to induce thermal hyperalgesia. Vascular responses were monitored and subjects rated thermal hyperalgesia before and after being startled (experiment 1), and before, during, and after mental arithmetic, breath holding, forehead cooling, the Valsalva maneuver, and a cold pressor test in experiment 2. In a third experiment, sensitivity to heat, cold, and mechanical stimulation was investigated in 61 patients with CRPS. Pain ratings and vascular and electrodermal responses were recorded after patients were startled and during forehead cooling. RESULTS: In experiment 1, thermal hyperalgesia decreased in healthy control subjects after they were startled, and digital blood vessels constricted symmetrically. In experiment 2, thermal hyperalgesia decreased during and after other forms of sympathetic arousal. However, in experiment 3, ratings of clinical pain increased during forehead cooling or after being startled in over 70% of patients with CRPS. Pain increased most consistently during forehead cooling in patients with cold allodynia or punctate allodynia. Digital blood vessels constricted more intensely on the symptomatic than the nonsymptomatic side in patients with CRPS during sympathetic arousal. CONCLUSIONS: Normal inhibitory influences on pain during sympathetic arousal are compromised in the majority of patients with CRPS. The augmented vasoconstrictor response in the symptomatic limb during sympathetic arousal is consistent with adrenergic supersensitivity. An adrenergic sensitivity in nociceptive afferents might contribute to pain and hyperalgesia during sympathetic arousal in certain patients with CRPS.

Hypogonadism in patients treated with intrathecal morphine.

OBJECTIVE: The objective of this study was to investigate the hypothalamic-pituitary-gonadal response to intrathecal opioids. PATIENTS: Thirty patients receiving intrathecal morphine for chronic nonmalignant pain were studied for clinical and biochemical evidence of hypogonadism. Ten men and 10 postmenopausal women with chronic pain of similar duration but who were not receiving any form of opioid therapy acted as control subjects. RESULTS: Men and both premenopausal and postmenopausal women had evidence of hypogonadism with low levels of serum testosterone or estrogen coupled with low levels of pituitary gonadotrophins. Control subjects had hormone levels in the expected range for their sex and age. Two men demonstrated recovery after ceasing intrathecal opioid therapy. CONCLUSIONS: Hypogonadotrophic hypogonadism is a common complication of intrathecal opioid therapy in both men and women.

The effect of problem-based learning on the academic performance of students studying podiatric medicine in Ontario.

OBJECTIVES: To investigate the effect of problem-based learning (PBL) on student achievement. DESIGN: Two cohorts of students studying podiatric medicine in Ontario were compared - one having undertaken the traditional lecture-based curriculum, and the other the problem-based learning programme. SETTING: The Michener Institute for Applied Health Sciences and The Toronto Hospital. SUBJECTS: Chiropody students. RESULTS: The performance of the students on the written Provincial Registration Examinations of Ontario was analysed utilizing independent t-tests and demonstrated that the PBL cohort of students achieved significantly higher overall examination scores (P < 0.005) than the traditional cohort. Further analysis revealed that no significant difference existed between student cohorts with respect to factual biomedical knowledge (P > 0.5), but that the PBL students performed significantly better in tests of deeper understanding and the cognitive skills related to patient management (P < 0.0005). Additionally, intragroup analysis using Spearman's rank order correlation indicated that there was no rank ordered association between performance on the multiple-choice and essay sections of the examination. CONCLUSIONS: The above results suggest that the PBL cohort of students was more knowledgeable than, and possessed superior cognitively related patient management skills, to their traditional counterparts.

Innervation of hyperalgesic skin in patients with complex regional pain syndrome.

OBJECTIVE: To look for anatomical and histochemical signs of interaction between sensory and sympathetic nerves in the hyperalgesic skin of patients with complex regional pain syndrome. SUBJECTS: Skin samples were obtained from eight patients whose condition developed after a suspected or confirmed peripheral nerve injury, and from nine patients with features of reflex sympathetic dystrophy (RSD) following a soft-tissue injury. A skin sample was also obtained from 18 control subjects of similar age and sex distribution to patients. DESIGN: In patients, skin samples were taken from an area of static mechanical hyperalgesia and from an equivalent site in the contralateral limb. In controls, skin samples were obtained from the dorsum of one hand or foot. HISTOCHEMICAL MARKERS: We used neuron-specific enolase for all classes of nerve fiber; tyrosine hydroxylase for noradrenergic fibers; vasoactive intestinal peptide for sympathetic sudomotor fibers; tyrosine hydroxylase co-existing with neuropeptide Y for sympathetic vasoconstrictor fibers; and calcitonin gene-related peptide with substance P or somatostatin for peptide-containing unmyelinated sensory fibers. RESULTS: In patients, the distribution of markers was similar in skin taken from an area of mechanical hyperalgesia and skin taken from an equivalent site contralaterally, and was unrelated to clinical features of RSD. The distribution of markers did not differ between patients and controls. Nerve tangles immunoreactive to neuron-specific enolase, but not to other markers, were detected in samples taken from four patients and two controls. The nerve tangles were present bilaterally in two patients, and only on the affected side in two other patients. The clinical condition was more fully developed in the four patients whose skin samples contained nerve tangles than in most other patients. CONCLUSIONS: A major difference in distribution or change in histochemical content of cutaneous autonomic or nociceptor fibers is unlikely to underly static mechanical hyperalgesia following a soft-tissue or peripheral nerve injury. The relevance of cutaneous nerve tangles for the pathophysiology of RSD is uncertain.

alpha 1-adrenoceptors in normal and hyperalgesic human skin.

1. Evidence of an adrenergic component of cutaneous hyperalgesia has recently been obtained in animal models of painful peripheral neuropathy. These findings have prompted speculation that an increased density or sensitivity of peripheral alpha-adrenoceptors contributes to sensory abnormalities and chronic neuropathic pain in conditions such as reflex sympathetic dystrophy. However, it is not known whether alpha-adrenoceptors are present at the site of nociception, either in hyperalgesic or normal skin. 2. We used the selective radioligand 125I-hydroxyphenyl-ethyl-aminomethyl-tetralone (HEAT) to label alpha 1-adrenoceptors, and quantitative autoradiography to assess the relative density of these receptors in skin samples from seven normal individuals and from the hyperalgesic and pain-free limbs of five patients with reflex sympathetic dystrophy. The distribution of autoradiographic grains over the epidermis and dermis was investigated in 10 microns serial transverse sections. 3. alpha 1-Adrenoceptors were identified in the epidermis and dermal papillae of normal individuals, and in the hyperalgesic and pain-free skin of patients with reflex sympathetic dystrophy. The density of alpha 1-adrenoceptors was greater in the epidermis and dermal papillae than further down in the dermis. 4. The mean density of alpha 1-adrenoceptors was significantly greater in the hyperalgesic skin of patients than in the skin of normal individuals (35.4 grains/1000 microns2 compared with 15.5 grains/ 1000 microns2, P < 0.01). The mean density of alpha 1-adrenoceptors in the pain-free skin of patients (26.9 grains/1000 microns2) fell midway between receptor density in hyperalgesic skin and in the skin of normal individuals, and did not differ significantly from either. 5. Our findings indicate that alpha 1-adrenoceptors are present in the epidermis, and suggest that their numbers may be increased in the hyperalgesic skin of patients with reflex sympathetic dystrophy. Further studies need to identify the dermal and epidermal cell types that express high densities of alpha 1-adrenoceptors, and to investigate their normal function and role in neuropathic pain.

Plasma neuropeptide Y in the symptomatic limb of patients with causalgic pain.

The aim of this experiment was to measure the concentration of neuropeptide Y (NPY), a vasoactive transmitter which co-exists with noradrenaline in sympathetic nerve terminals, in venous blood taken from the painful and contralateral limbs of 16 patients with features of reflex sympathetic dystrophy (RSD) or causalgia. In nine patients tapping the skin of the affected limb provoked pain (allodynia). In seven of the nine patients with allodynia the concentration of NPY was lower on the painful side; similar results were obtained in only two of seven patients without widespread allodynia. In addition, the concentration of NPY was generally lower in the painful limb if it was warmer than the contralateral limb. These findings suggest that a reduction in sympathetic activity might accompany allodynia and influence vasomotor disturbances in patients with causalgic pain.

Neck sprain.

Neck sprain is characterised by 'soft tissue' lesions in the cervical discs, synovial joints, muscles and sometimes the nerve roots. Peripheral nociception in the outer annulus, joint capsules, muscles, meninges, arteries and nerves can cause neck pain, with headache, or upper torso and upper limb pain. Careful physical examination, or accurately placed local anaesthetic injections, may localise the sources of pain.

Mapping the spread of epidural phenol in cancer pain patients by radionuclide admixture and epidural scintigraphy.

This study used a radionuclide imaging technique to map the spread and density contours of phenol in glycerin injected into the epidural space of cancer patients. Correlations were made between phenol injectate volume, sequence of injection, position of patient, and resultant epidural spread and analgesic outcome. Fifteen patients with cancer pain (average age of 61 years) were treated with serial epidural phenol in glycerin injections. Phenol in glycerin is miscible with [99mTc]sulfur colloid. An assumption was made that the admixture injected epidurally was inseparable prior to absorption and the spread was recorded by continuous gamma camera observations with computer collection for 30 min postinjection. The spread of injectate volumes of 2, 3, and 4 ml were compared and further correlations made between observed spread and sequence of injections (first to fifth in series within each patient) and position of patient. Small volumes of phenol may spread extensively in the epidural space (3 ml spreads a mean 13.6 segments) with wide variation among patients. Initial phenol injections spread further than subsequent injections. Maximum spread is achieved by 15 min postinjection and epidural distribution is mostly uniform, independent of patient position. Good analgesia was obtained in 14 patients (93%). Epidural neurolysis using serial injections of small volumes of phenol in glycerin is an effective, safe technique for cancer pain relief. Injectate volumes larger than 3 ml may be unnecessary and potentially dangerous.

Reflex sympathetic dystrophy: the significance of differing plasma catecholamine concentrations in affected and unaffected limbs.

In 26 patients with features of reflex sympathetic dystrophy, venous blood was collected from painful and unaffected limbs. Levels of plasma adrenaline, noradrenaline and its intracellular metabolite, 3,4-dihydroxyphenylethyleneglycol (DHPG), were measured by combined gas chromatography/mass spectrometry. Plasma DHPG was lower on the painful side. Concentration of plasma noradrenaline was also lower on the painful side in patients with widespread allodynia, and in those with hyperhidrosis in the affected hand or foot. These findings do not support the widely held view that autonomic disturbances in reflex sympathetic dystrophy are due to sympathetic overactivity. Rather, they suggest that sweating and changes in peripheral blood flow result from supersensitivity to sympathetic neurotransmitters. After injury, supersensitivity to noradrenaline may also contribute to spontaneous pain and allodynia by disrupting efferent sympathetic modulation of sensation. This would explain why pain and allodynia are relieved by sympathetic blockade, and why noradrenaline rekindles pain in sympathectomized skin.

Reflex control of facial flushing during body heating in man.

Facial temperature and amplitude of capillary pulsations from the forehead and cheeks were measured shortly before and after pharmacological blockade of the stellate ganglion in 9 patients with reflex sympathetic dystrophy of an upper limb, and in 1 other patient with erythromelalgia of all four limbs. Patients were then heated to determine the effect of sympathetic blockade on mediation of thermoregulatory facial flushing. Release of vasoconstrictor tone following stellate ganglion blockade was invariably followed by an increase in orbital and cheek temperature, and by similar but less consistent increases in temperature of the forehead, lips and chin. The amplitude of capillary pulsations recorded from the forehead and cheeks also increased on the side of stellate ganglion blockade. Flushing of the forehead and cheek on the sympathetically intact side during body heating far outweighed the extent of flushing after release of vasoconstrictor tone. The thermoregulatory response was prevented by sympathetic blockade, indicating that an active sympathetic vasodilator pathway had been interrupted. In contrast, the temperature of the orbit during body heating was not influenced by sympathetic blockade. Asymmetry of forehead temperature was detected before sympathetic blockade in 8 of 9 patients with reflex sympathetic dystrophy, suggesting that autonomic disturbances in this condition may influence cervical sympathetic outflow. The results indicate that sympathetic vasodilator fibres passing through the stellate ganglion mediate thermoregulatory facial flushing, and that release of vasoconstrictor tone has only a minor influence on this response in most areas of the face.

Endogenous opiates modulate release of growth hormone in response to electroacupuncture.

The effect of electroacupuncture on serum growth hormone levels was investigated in 5 normal subjects and in 10 patients with chronic musculoskeletal pain. Serum growth hormone did not change in the normal subjects but there was an approximate 5-fold increase in the chronic pain subjects. This effect was partially inhibited by prior administration of the opiate antagonist naloxone, suggesting that the rise in growth hormone was mediated via release of central nervous system opioids.