Erik Torebjörk

Noradrenaline-evoked pain in neuralgia

&NA; We have tested the effects of cutaneous application of noradrenaline in 35 patients presenting with neuropathic pain. Depending on the outcome of sympatholytic interventions the patients were considered to have sympathetically maintained pain (SMP; n = 25) or sympathetically independent pain (SIP; n = 10). Iontophoretic application or cutaneous injection of noradrenaline into symptomatic skin aggravated pain and mechanical or thermal hyperalgesia in Symbol SMP patients. Results from differential nerve blocks suggested that noradrenaline‐induced ongoing pain and heat hyperalgesia were signalled by unmyelinated afferents, while touch‐evoked pain and cold hyperalgesia were signalled by myelinated afferents. In none of the remaining Symbol SMP patients, 10 SIP patients or 18 normal subjects did application of noradrenaline result in any appreciable increase of pain. A follow‐up of 12 patients (initially 9 SMP, 3 SIP) after 12–16 years showed that one individual (previously SMP) was healthy, while 3 patients still suffered from SMP and 8 from SIP. Of the 5 SMP patients who had noradrenaline‐induced pain at the initial examination, only 1 SMP patient still responded to noradrenaline with pain and hyperalgesia. Three other patients had changed to SIP and 1 individual was healthy. None of these 4 and none of the 7 initially noradrenaline‐unresponsive patients experienced pain to the noradrenaline challenge at follow‐up. Thus, cutaneous noradrenaline application can aggravate the pain in some, but not all SMP patients. The abnormal noradrenaline reaction can change over time as can the pain relieving effects of sympatholytic therapy. Symbol. No caption available Symbol. No caption available

Psychophysical evidence of nociceptor sensitization in vulvar vestibulitis syndrome

&NA; Vulvar vestibulitis syndrome (VVS) is a long lasting disorder of superficial dyspareunia in young women. Quantitative sensory testing, including mechanical and temperature pain thresholds and warm/cold difference limen (WCL), was performed in the vestibular mucosa in 22 women (mean age 25.0 years) with vestibulitis and 20 control subjects (mean age 25.6 years). The tests were carried out on days 7–11 of the menstrual cycle. Patients had allodynia to mechanical testing with von Frey filaments, 14.3±3.1 mN in the symptomatic posterior area as compared with 158±33.5 mN in healthy subjects, P<0.0001. The pain threshold to heat was 38.6±0.6°C in patients and 43.8±0.8°C in controls, P<0.0001. In addition, pain threshold to cold was 21.6±1.2°C in patients whereas cooling down to 6°C was usually not painful in controls. WCL was 4.9±0.5°C in patients and 9.6±1.5°C in healthy subjects, P<0.01. The results are compatible with the hypothesis that patients with VVS have an increased innervation and/or sensitization of thermoreceptors and nociceptors in their vestibular mucosa.

Central suppression of cold-induced C fibre pain by myelinated fibre input

&NA; Changes in thermal sensibility for warmth, cold, heat pain and cold pain during nerve compression block of impulse conduction in myelinated fibres were studied in 20 healthy subjects. When mainly unmyelinated fibres were conducting, after 30–36 min of nerve compression, the pain threshold, induced by cold stimulation, was shifted towards higher temperatures (from 19.1° C to 22.8°C, mean values). Furthermore, the sensation of cold pain became more unpleasant and had a hot burning rather than a cold quality. These results indicate that a change in central decoding of the afferent input has occurred, possibly due to lack of inhibition normally exerted by concomitant activation of myelinated fibres. Whereas dramatic changes in the sensation of cold pain were observed during the course of nerve compression, no alteration in heat pain threshold was seen. This implies that heat pain threshold in hairy skin is due to activation of C nociceptor fibres without any significant contribution from myelinated nociceptor fibres. Furthermore, no gating from heat‐sensitive myelinated fibre input was evident on heat pain threshold.

Somatotopic organization along the central sulcus, for pain localization in humans, as revealed by positron emission tomography.

Abstract Regional cerebral blood flow was measured with positron emission tomography (PET) in six healthy volunteers at rest and during experimentally induced, sustained cutaneous pain on the dorsum of the right hand or on the dorsum of the right foot. Pain was inflicted by intracutaneous injection of capsaicin, providing a mainly C-fibre nociceptive stimulus. Statistical analysis showed significant activations along the central sulcus (SI) area when comparing pain in the hand to pain in the foot. Separate comparison of both pain states to a baseline revealed different locations along the central sulcus for hand pain and foot pain. The encountered differences are consistent with what is previously known about the somatotopics of non-painful stimuli. When comparing painful stimuli to baseline, the contralateral anterior cingulate gyrus, the ipsilateral anterior insular cortex and the ipsilateral prefrontal cortex were implicated. The results are consistent with an involvement of SI in the spatial discrimination of acute cutaneous pain.

Analgesic effect of vibration and cooling on pain induced by intraneural electrical stimulation

Abstract Psychophysical experiments were carried out on 16 human subjects to determine how low intensity mechanical and thermal skin stimuli interfere with the sensation of pain. Moderate or intense pain was induced by low frequency (2 Hz) electrical stimulation within cutaneous fascicles of the median nerve at wrist level, and vibration, pressure, cooling or warming were applied for short periods (usually 20–60 sec) within or outside the skin area to which the pain was projected. Vibration within the area of projected pain reduced the sensation of pain more efficiently than vibration outside that area. Moderate pain was sometimes completely inhibited but intense pain was only moderately reduced. Pressure and cooling produced some pain relief whereas mild warming had an ambiguous effect. Since the painful input derived from stimulation of fibres in the nerve trunk, and not from peripheral nociceptors, the pain suppressing effects of vibration and cooling are not explicable in terms of lowered excitability of the nociceptive nerve endings in the skin. Instead, the results indicate that activity in low threshold mechanoreceptive and cold sensitive units suppresses pain at central (probably segmental) levels.

Quantitative sensory testing before and after regional guanethidine block in patients with neuralgia in the hand

&NA; Using reference values from healthy volunteers, thermal and vibration‐induced pain thresholds and the sensibility for warm and cold were studied in 18 patients with neuralgia in one hand following a traumatic injury or surgery. All patients had spontaneous pain and allodynia to vibration. They were treated with intravenous regional guanethidine block (RGB). Quantitative sensory testing was performed on both hands before and 1–3 days after treatment. Eleven patients benefitted considerably from the block, with pain relief for 2 weeks or more. Ten of these 11 patients had mild nerve injuries caused by compressive trauma to the nerve. Before RGB they showed a moderate loss in temperature discrimination capacity; their heat pain thresholds were reduced and they exhibited allodynia to cold and vibration on the injured side. After RGB, the pain thresholds were normalised both to thermal and vibratory stimuli. These patients were classified as having sympathetically maintained pain (SMP). Seven patients reported no or only minor pain‐relieving effect of RGB lasting 1–5 days. Severe nerve injuries were most frequent in this group of patients. On the injured side, before RGB, their ability to discriminate between warm and cold was markedly impaired, thermal pain thresholds were normal, and they showed allodynia to vibration. After RGB, there was no change in thermal pain thresholds and the allodynia to vibration persisted. These patients were classified as having sympathetically independent pain (SIP). The results indicate that quantitative thermal sensory tests, together with clinical evaluation of the nerve trauma, can help to predict which patients will have long‐lasting pain alleviation after RGB treatment.

Effects of regional intravenous guanethidine block in posttraumatic cold intolerance in hand amputees.

In twenty-four patients with intolerance to cold after partial or complete finger amputations, lower skin temperature together with cold and vibration allodynia (allodynia = pain due to a non-noxious stimulus to neural skin) were found in the cold intolerant area compared with the corresponding area in the uninjured hand. When treated with regional intravenous guanethidine block nine patients became free from symptoms for up to twelve weeks, which is longer than would be expected from the duration of the known pharmacological effects of guanethidine. The patients had several features in common with reflex sympathetic dystrophies, and we suggest that neurogenic rather than vascular disturbances are mainly involved in the post-traumatic cold intolerance syndrome.

ATP responses in human C nociceptors.

&NA; Microelectrode recordings of impulse activity in nociceptive C fibres were performed in cutaneous fascicles of the peroneal nerve at the knee level in healthy human subjects. Mechano‐heat responsive C units (CMH), mechano‐insensitive but heat‐responsive (CH) as well as mechano‐insensitive and heat‐insensitive C units (CMiHi) were identified. A subgroup of the mechano‐insensitive units was readily activated by histamine. We studied the responsiveness of these nociceptor classes to injection of 20 &mgr;l 5 mM adenosintriphosphate (ATP) using saline injections as control. Because of mechanical distension during injection, which typically activates mechano‐responsive C fibres, interest was focused on responsiveness to ATP after withdrawal of the injection needle. Post‐injection responses were observed in 17/27 (63%) mechano‐responsive units and in 14/22 (64%) mechano‐insensitive units. Excitation by ATP occurred in 9/11 CH units and in 5/11 CMiHi units. ATP responsive units were found both within the histamine‐responsive and the histamine‐insensitive group of mechano‐insensitive fibres. ATP responses appeared with a delay of 0–180 s after completion of injection; responses were most pronounced during the first 1–3 min of activation, and irregular ongoing activity was observed for up to 10 or even 20 min. ATP responses were dose‐dependent, concentrations lower than 5 mM gave weaker responses. No heat or mechanical sensitisation was observed in any of the major fibre classes. In conclusion, we have shown that ATP injections at high concentrations activate C‐nociceptors in healthy human skin, without preference for mechano‐responsive or mechano‐insensitive units. ATP did not sensitise human C fibres for mechanical or heat stimuli. We discuss how various mechanisms might contribute to the observed responses to ATP.

Catecholamine-induced excitation of nociceptors in sympathetically maintained pain

Abstract Sympathetically maintained pain could either be mediated by ephaptic interactions between sympathetic efferent and afferent nociceptive fibers or by catecholamine‐induced activation of nociceptive nerve endings. We report here single fiber recordings from C nociceptors in a patient with sympathetically maintained pain, in whom sympathetic blockade had repeatedly eliminated the ongoing pain in both legs. We classified eight C‐fibers as mechano‐responsive and six as mechano‐insensitive nociceptors according to their mechanical responsiveness and activity‐dependent slowing of conduction velocity (latency increase of 0.5 ± 1.1 vs. 7.1 ± 2.0 ms for 20 pulses at 0.125 Hz). Two C‐fibers were activated with a delay of several seconds following strong endogenous sympathetic bursts; they were also excited for about 3 min following the injection of norepinephrine (10 μl, 0.05%) into their innervation territory. In these two fibers, a prolonged activation by injection of low pH solution (phosphate buffer, pH 6.0, 10 μl) and sensitization of their heat response following prostaglandin E2 injection were recorded, evidencing their afferent nature. Moreover, their activity‐dependent slowing was typical for mechano‐insensitive nociceptors. We conclude that sensitized mechano‐insensitive nociceptors can be activated by endogenously released catecholamines and thereby may contribute to sympathetically maintained pain. No evidence for ephaptic interaction between sympathetic efferent and nociceptive afferent fibers was found.

Dynamic adjustments of walking behavior dependent on noxious input in experimental low back pain.

The aim of this study was to explore whether accelerations of the lower back during walking are temporarily attenuated by experimentally-induced low back pain, as compared with normal walking. Transient low back pain was induced by injection of 1 ml 6% hypertonic saline in the longissimus dorsi muscle in 20 healthy subjects. Acceleration was measured during walking at self-selected speeds before and repeatedly after the injection by a portable, triaxial accelerometer positioned over the L3 region. Data were subsequently adjusted for differences in walking speeds between trials and subjects. Pain was reported on a 0-10 point scale during walking until pain was no longer present. Lumbar acceleration sample mean was attenuated for the anteroposterior (P=0.002) and mediolateral (P=0.002) sensing axes as well as for the vector sum (P=0.005) at maximal pain compared to pretest values. The vertical axis showed no significant changes. Values returned to pretest level when pain was no longer present. Regardless of the initial increase and subsequent decrease in pain after injection, there was a linear relationship between pain and acceleration in 15 of the 20 subjects (0.89>/=R(2)>/=0.36, P</=0.002), suggesting a continuous dynamic adjustment of motor behavior dependent on the noxious input. It appears that this new method is suitable for detection of continuous subconscious changes of body accelerations during walking in relation to pain.