Jannick Brennum

Measurements of human pressure-pain thresholds on fingers and toes

Pressure-pain thresholds (PPT) were measured on fingers and toes with a hand-held electronic pressure algometer in 15 males and 15 females. The pressure algometer offered easy control of pressure application rate. The intra-individual coefficient of variation, based on repeated PPT measurements with a 1 week interval was 14%. The inter-individual coefficient of variation was 28% for females and 33% for males. In the course of 10 consecutive PPT measurements with short intervals (10 and 20 sec), no significant change in PPT was observed. PPT was found to be 50% higher in males than in females (P less than 0.0001). Slightly but significantly higher PPT values were found on the dominant compared to the non-dominant side (P less than 0.005).

Electrophysiological and psychophysical quantification of temporal summation in the human nociceptive system

Animal experiments have shown that the nociceptive reflex can be used as an indicator of central temporal integration in the nociceptive system. The aim of the present study on humans was to investigate whether the nociceptive reflex, evoked by repetitive strong electrical sural nerve stimuli, increased when summation was reported by the volunteers. The reflexes were recorded from the biceps femoris and rectus femoris muscles in eight volunteers following a series of stimulations at 0.1, 1, 2, and 3 Hz. Each series consisted of five consecutive stimuli. Using 0.1- and 1-Hz stimulation, the reflex was not facilitated in the course of the five consecutive stimuli. Following 2- and 3-Hz stimulation, the reflex size (root mean square amplitude) increased significantly during the course of the fifth stimulus. This reflex facilitation was followed by a significant increase (summation) in the pain magnitude when compared with 1- and 0.1-Hz stimulation. Furthermore, the threshold for psychophysical summation could be determined. This threshold (stimulus intensity) decreased when the stimulus frequency (1–5 Hz) of the five consecutive stimuli was increased. The nociceptive reflex and the psychophysical summation threshold might be used to clarify and quantify aspects of temporal summation within the human nociceptive system.

The effect of pre- versus postinjury infiltration with lidocaine on thermal and mechanical hyperalgesia after heat injury to the skin

&NA; The aim of the study was to evaluate the effects of pre‐ and postinjury infiltration with lidocaine on alterations in mechanical and thermal sensitivity after heat injury to the skin. In the first part of the study, burn injuries (15 × 25 mm rectangular thermode, 50°C, 7 min) were produced twice in each subject on the medial side of the left and right calves at least 24 h apart in 8 healthy, unmedicated male volunteers, in order to investigate the effects of the injury on sensitivity in untreated skin. In the second part of the study, burn injuries (15 × 25 mm rectangular thermode, 50°C, 6 min) were produced twice in each subject on the medial side of the left and right calves at least 24 h apart (n = 10). This was preceded by subcutaneous (s.c.) infiltration with 5–6 ml of 1% plain lidocaine (pre‐injury block) on one day, and the same block was performed 35 min after injury (postinjury block) on the other day. Warm detection thresholds (WDT) and heat pain detection thresholds (HPDT) were determined within and outside the injury before and at regular intervals after injury. Areas of hyperalgesia to pinprick and brush were determined at regular intervals after injury. In the first part of the study, it was observed that both WDT and HPDT were decreased within but not outside the injury, and areas of hyperalgesia to pinprick and brush were found in‐ and outside the injury in all subjects. These findings were relatively constant throughout the study period and reproducible between the 2 days of examination. In the second part of the study, it was observed that pre‐injury infiltration with lidocaine reduced hyperalgesia to pinprick and brush outside the injury more effectively than postinjury block, but only for the first 70 min after injury, while no significant difference was observed 100–190 min after injury. Likewise, there was no difference in thermal thresholds inside the injury between pre‐ and postinjury treatment at the end of the study period. It is concluded, that a shortlasting ‘preemptive’ infiltration with lidocaine may postpone but not prevent the occurrence of hyperalgesia outside a thermal injury.

Capsaicin evoked pain and allodynia in post-herpetic neuralgia

&NA; The hypothesis that the pain and allodynia associated with post‐herpetic neuralgia (PHN) is maintained by a combination of input from preserved primary afferent nociceptors and sensitization of central pain transmitting neurons was examined in 17 subjects with PHN. Pain, allodynia, thermal sensory function, cutaneous innervation, and response to controlled application of 0.075% capsaicin were measured. Compared to mirror‐image skin, applying capsaicin on a 9 cm2 area of PHN skin significantly increased overall PHN pain and allodynia in 11 of 17 subjects. These ‘capsaicin responders’ were characterized by higher average daily pain, higher allodynia ratings, and relatively preserved sensory function at baseline compared to the non‐responders. In three of the ‘capsaicin responders’ the area of allodynia expanded into previously non‐allodynic and non‐painful skin that had normal sensory function and cutaneous innervation. These observations support the hypothesis that allodynia in some PHN patients is a form of chronic secondary hyperalgesia maintained by input from intact and possibly ‘irritable’ primary afferent nociceptors to a sensitized CNS.

PHASE II TRIAL TO EVALUATE THE ACTIGAIT IMPLANTED DROP-FOOT STIMULATOR IN ESTABLISHED HEMIPLEGIA

OBJECTIVE To evaluate a selective implantable drop foot stimulator (ActiGait) in terms of effect on walking and safety. DESIGN A phase II trial in which a consecutive sample of participants acted as their own controls. SUBJECTS People who had suffered a stroke at least 6 months prior to recruitment and had a drop-foot that affected walking were recruited from 3 rehabilitation centres in Denmark. METHODS Stimulators were implanted into all participants. Outcome measures were range of ankle dorsiflexion with stimulation and maximum walking speed and distance walked in 4 minutes. Measurements were applied before implantation, at 90 days and at a long-term follow-up assessment. Changes over time and with and without stimulation are reported. Safety was evaluated by nerve conduction velocity and adverse events. RESULTS Fifteen participants were implanted and 13 completed the trial. Long-term improvements were detected in walking speed and distance walked in 4 minutes when stimulated, and the orthotic effect of stimulation showed statistically significant improvement. The device did not compromise nerve conduction velocity and no serious device-related adverse events were reported. Technical problems were resolved by the long-term follow-up assessment at which further improvement in walking was observed. CONCLUSION This trial has evaluated the safety and performance of the device, which was well accepted by patients and did not compromise safety.

Effect of Preemptive Nerve Block on Inflammation and Hyperalgesia after Human Thermal Injury

Background Postoperative pain relief may be improved by reducing sensitization of nociceptive pathways caused by surgical trauma. Such a reduction may depend on the timing and efficacy of analgesia and the duration of the nociceptive block versus the duration of the nociceptive input. We examined whether a prolonged nerve block administered before a superficial burn injury could reduce local inflammation and late hyperalgesia after recovery from the block. Methods The effects of a preemptive saphenous nerve block on primary and secondary hyperalgesia, skin erythema, and blister formation, were compared to the opposite unblocked leg for 12 h after bilateral thermal injuries (15 x 25 mm, 49 degrees C for 5 min) in 20 healthy volunteers. Recovery from the block was identified by return of sensation to cold. Results Six subjects were excluded because of insufficient initial block (2 subjects) or because the block lasted beyond the study period (4 subjects). The remaining 14 subjects experienced significantly reduced primary (P = 0.005) and secondary hyperalgesia (P = 0.01) in the blocked leg after return of cold sensation compared to the unblocked leg. Erythema intensity and blister formation were not significantly affected by the blockade (P = 0.94 and P = 0.07, respectively). Conclusions These data suggest that a prolonged, preemptive nerve block reduced late hyperalgesia after thermal injury, whereas the erythema and blister formation were not significantly affected.

Evidence for central summation of C and Aδ nociceptive activity in man

&NA; Using two different stimulators, we have induced activity in A&dgr; and C afferents in order to investigate a possible summation of nociceptive activity from these two fiber types. We used nociceptive electrical stimulation to evoke activity in A&dgr; fibers. High‐intensity light from a xenon lamp, focused into a liquid light guide which was positioned on a spot painted black under the sole of the foot, resulted in a characteristic delayed burning sensation, indicating selective C‐fiber activation. By varying the delay between radiant heat and electrical stimuli (0–3000 msec), sensations evoked by these stimuli were brought to coincide. When we elicited the electrical stimulation during on‐going burning pain, corresponding to a delay of approximately 1 sec between the stimulations, we found a significantly higher nociceptive withdrawal reflex in tibialis anterior (P < 0.01) and a higher overall pain rating (P < 0.05). The existence of a summation mechanism at the spinal cord is the most likely explanation for our findings. Furthermore, the results demonstrate that the nociceptive reflex may be modulated by on‐going C‐fiber activity.

Sumatriptan has no clinically relevant effect in the treatment of episodic tension-type headache

In a randomized, multi‐centre, double‐blind, placebo‐controlled, parallel group study, the efficacy of 100 mg oral sumatriptan was compared with that of placebo in the treatment of episodic tension‐type headache. The patients were recruited from the general population in the vicinity of the study centres, by randomly mailed invitations. One or more attacks were treated with sumatriptan by 54 patients and with placebo by 57 patients. A seven‐point verbal rating scale was used for hourly assessments of headache relief, 1–4 h after treatment According to the predefined primary end‐point of the study, which was moderate or complete relief of headache 2 and 4 h after treatment of the first attack, there was no significant difference between sumatriptan and placebo treatment Sumatriptan did perform statistically significantly better than placebo at some time points, but the effect was not considered clinically relevant We conclude that sumatriptan should not be used in treatment of tension‐type headache. The marked difference in effect of sumatriptan in treatment of migraine and tension‐type headache argues against the idea that migraine and tension‐type headache are part of a continuum of headache disorders.

The Effect of Naloxone on Ketamine-induced Effects on Hyperalgesia and Ketamine-induced Side Effects in Humans

BACKGROUND The (NMDA) receptor plays a significant role in wind-up and spinal hypersensitivity and is involved in the occurrence of secondary hyperalgesia. Ketamine is an NMDA-receptor antagonist and has proven effective in alleviating secondary hyperalgesia in humans. Although it is disputed, the actions of ketamine have been ascribed not only to NMDA receptor antagonism, but also to opioid receptor agonism. A study therefore was designed in which the abolishment of a previously demonstrated effect of ketamine on secondary hyperalgesia was sought by pretreatment with naloxone. METHODS Twenty-five volunteers were subjected to three treatment regimens. A standardized first-degree burn injury was induced. On appearance of primary and secondary hyperalgesia, one of the following infusion schemes was applied in a randomized, double-blind, cross-over fashion: (1) infusion of naloxone (0.8 mg/15 min followed by 0.4 mg/h), succeeded by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); (2) infusion of placebo, succeeded by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); and (3) infusion of placebo, succeeded by infusion of placebo. Heat-pain detection thresholds, magnitude of secondary hyperalgesia around the burn injury, and side effects were determined. RESULTS Ketamine reduced secondary hyperalgesia. Naloxone did not affect the action of ketamine. The magnitudes of side effects were equal if the subjects received ketamine, regardless of preceding infusion of naloxone. CONCLUSIONS In this experimental setting, opioid receptor blockade does not inhibit ketamine-induced reductions of secondary hyperalgesia.

Experimental evaluation of the analgesic effect of ibuprofen on primary and secondary hyperalgesia

Abstract The analgesic effect of systemic ibuprofen was investigated with two human experimental pain models: (i) static mechanical stimulation of the inter digital web between the 2nd and 3rd finger and (ii) primary and secondary hyperalgesia induced by a 7‐min burn injury on the calf. In each double‐blind, randomized, two‐way cross‐over study 20 healthy male volunteers received either ibuprofen 600 mg or placebo tablets. Ibuprofen reduced pain evoked by static mechanical pressure in normal skin and by motor brush stimulation in the area of secondary hyperalgesia following burn injury. In contrast, ibuprofen did not reduce the area of secondary hyperalgesia to either pinprick or stroke following burn injury. Previous human experimental studies concerning the analgesic effect of NSAIDs are reviewed. Based on the previous literature and the present results we suggest that NSAIDs inhibit progressive tactile hypersensitivity but not the central sensitization itself.