Märta Segerdahl

Systemic Adenosine Infusion Alleviates Spontaneous and Stimulus Evoked Pain in Patients with Peripheral Neuropathic Pain

In seven patients with peripheral neuropathic pain, the effect of systemic adenosine infusion on pain symptoms was evaluated in a double-blind, placebo controlled, cross-over study. The study infusions, adenosine (50 micro gram centered dot kg-1 centered dot min-1) or placebo, were given intravenously (IV) during 45-60 min at two separate occasions. Before and during infusions, bedside examination of sensibility and quantitative sensory testing (QST), i.e., assessments of perception thresholds for touch, touch-evoked pain, cold, warmth, painful heat, and cold, were performed. In the neuropathic area, sensation magnitude was rated by a visual analog scale (100 mm VAS) using a pin and at perception threshold for touch-evoked pain using von Frey filaments. Adenosine infusion reduced spontaneous pain (P < 0.05), and caused an increase of the touch-evoked pain threshold from 10.8 +/- 5.3 to 22.2 +/- 6.9 g (P < 0.05), whereas placebo had no effect. Pain intensity at perception threshold for touch-evoked pain was, however, unaltered. Pinprick-evoked pain in the neuropathic areas was reduced from 53 +/- 11 to 29 +/- 10 mm (P < 0.05). No other sensory modality was consistently changed during adenosine infusion. In conclusion, the present study demonstrates that adenosine infusion alleviates spontaneous neuropathic pain, tactile allodynia, and pinprick hyperalgesia in patients with peripheral neuropathic disorders, probably by a central mechanism of action. (Anesth Analg 1995;81:713-7)

Systemic adenosine infusion: a new treatment modality to alleviate neuropathic pain.

Adenosine, an endogenous antinociceptive compound acting in the central nervous system, was infused intravenously (50-70 micrograms/kg/min) to 2 patients with peripheral neuropathic pain. In 1 subject, spontaneous pain was alleviated, and tactile allodynia was essentially relieved during 40 min of infusion. Allodynia to warmth and touch were abolished in the other subject. In addition, hyperalgesia to pinprick was markedly attenuated as was pressure-induced allodynia. The reported effects lasted for hours after termination of the infusion. Our preliminary encouraging data call for further controlled studies of the potentially relieving effect of adenosine in painful neuropathic conditions.

The influence of adenosine, ketamine and morphine on experimentally induced ischemic pain in healthy volunteers

Adenosine, intrathecally administered, produces antinociception in experimental studies on animals. The effect of intravenous (i.v.) adenosine on experimentally induced pain in humans has not been studied. The present single-blind, randomized, placebo-controlled study was conducted in nine healthy volunteers. The pain-reducing effects of adenosine (70 micrograms.kg-1.min-1 i.v.), morphine (0.1 mg/kg i.v.), ketamine (0.1 mg/kg i.v.), adenosine + morphine, and adenosine + ketamine were compared to each other and to placebo in random order. Ischemic pain was induced by the submaximum effort tourniquet technique. Pain was assessed using the visual analog scale (VAS, 0-100 mm). The sums of pain scores (SPS) were compared and found significantly 30%-40% lower for adenosine as well as for the other compounds and combinations (P < 0.03), compared to placebo. The number of subjects who reached VAS 100 within 30 min was significantly lower (P < 0.03) when receiving adenosine + morphine (0/9) and adenosine + ketamine (2/9) than when receiving placebo (7/9). This may indicate an additive effect on pain reduction when adenosine is given in combination with morphine or ketamine. In conclusion, the results indicate that i.v. adenosine, as well as morphine and ketamine, can reduce experimentally induced ischemic muscle pain in healthy volunteers.

The safety and efficacy of intrathecal adenosine in patients with chronic neuropathic pain

UNLABELLED: Adenosine and adenosine analogs decrease pain-like behavior in animal models of both acute nociceptive and neuropathic pain via adenosine receptor activation at spinal and/or supraspinal levels. This open study is the first in a series of intrathecal (IT) adenosine administration studied for the evaluation of efficacy and side effects in 14 patients. All had chronic neuropathic pain with tactile hyperalgesia and/or allodynia primarily of traumatic origin. The effects of IT adenosine (500 microg [n = 9] or 1000 microg [n = 5]) were evaluated. Approximate areas of tactile pain were mapped. Spontaneous and evoked pain (visual analog scale score 0-100) and tactile pain thresholds were assessed before and 60 min after injection. The injection caused transient pain (<60 min) in the lumbar region in five patients. There were no other side effects. Spontaneous and evoked pain was reduced (median score from 65 to 24 [P<0.01] and from 71 to 12 [P<0.01], respectively) in parallel with increased tactile pain thresholds in allodynic areas. Areas of tactile hyperalgesia/allodynia were reduced (median reduction 90%; P<0.001). Twelve patients experienced pain relief (median 24 h). We conclude that IT adenosine transiently causes lumbar pain in a subgroup of patients and may reduce various aspects of chronic neuropathic pain. IMPLICATIONS: This is the first series of patients with chronic neuropathic pain in which tolerability to spinal adenosine administration has been evaluated. A subset of patients reported transient low back pain as the only side effect. Spontaneous and evoked pain intensity decreased in most patients, an effect lasting for a median of 24 h.

Peroperative Adenosine Infusion Reduces the Requirements for Isoflurane and Postoperative Analgesics

The aims of this study were to investigate the influence of adenosine infusion, firstly, on postoperative analgesic requirements, and secondly, on peroperative isoflurane requirements.Seventy-five women, aged 18-70 yrs, ASA grades I and II, scheduled for breast surgery, were randomly assigned to peroperatively receive a double-blind intravenous infusion of either adenosine, 80 micro gram centered dot kg-1 centered dot min-1, or placebo, during surgery under isoflurane/N2 O/O2 anesthesia. The peroperative isoflurane requirements were significantly reduced at 30 and 90 min of surgery during adenosine treatment. The number of patients reporting pain when regaining consciousness after surgery was reduced by 57% in the adenosine group, 8/31 vs 19/32 (P < 0.02). Further, the postoperative 24-h opioid requirements were reduced by 27% in the adenosine group (P < 0.03). In conclusion, we found that a peroperative infusion of a small dose of adenosine during breast surgery, reduces the peroperative anesthetic requirements, and the demand for post-operative analgesics. (Anesth Analg 1995;80:1145-9)

Methadone, ciprofloxacin, and adverse drug reactions.

Ciprofloxacin, given to a patient successfully treated with methadone for more than 6 years, caused profound sedation, confusion, and respiratory depression. We suggest that this was caused by ciprofloxacin inhibition of CYP1A2 and CYP3A4 activity, two of the cytochrome p450 isozymes involved in the metabolism of methadone.

intrathecal Adenosine Administration : A Phase 1 Clinical Safety Study in Healthy Volunteers, with Additional Evaluation of Its Influence on Sensory Thresholds and Experimental Pain

Background Several animal studies show antinociceptive effects of intrathecally administered adenosine and its analogs. However, there is no clinical experience regarding the effects of intrathecal adenosine in humans. Methods The side effects and analgesic effects of intrathecal adenosine (500‐2,000 [micro sign]g) on experimental pain were studied in 12 healthy volunteers. Before and after adenosine was given, the authors evaluated the cold pain rating of the foot (submersion in ice water for 1 min), the forearm ischemic pain rating during a 30‐min tourniquet test, and the thermal and tactile pain thresholds on healthy and inflamed skin after application of mustard oil (4 min) to the calf. The areas of secondary allodynia surrounding the inflammation were also determined. The cerebrospinal fluid level of adenosine was determined before and after injection. Results Intrathecal adenosine caused a 1,000‐ to 2,000‐fold elevation of the cerebrospinal fluid concentration. One volunteer experienced transient (30 min) lumbar pain after injection at a dose of 2,000 [micro sign]g. There were no other complications in any other volunteers. Adenosine reduced, in a non‐dose‐dependent manner, the areas of secondary allodynia after skin inflammation (brush, P < 0.06; and von Frey hair, P < 0.03) and reduced the forearm tourniquet ischemic pain rating (P = 0.01). Tactile pain thresholds were significantly reduced by mustard oil inflammation during control, whereas adenosine treatment prevented this reduction. The ice water‐induced cold pain rating was not influenced by adenosine. Conclusions An intrathecal adenosine injection of 1,000 [micro sign]g lacked side effects in healthy volunteers. The compound attenuated different types of experimental pain.

Experimental pain by ischaemic contractions compared with pain by intramuscular infusions of adenosine and hypertonic saline

Deep tissue pain can be related to reduced muscle blood flow, which comprises the metabolic demand under muscle work. The tissues and receptors involved in nociception after ischaemic muscle contractions are not known. The concentration of adenosine is increased after ischaemic contractions and might act as an algesic substance. In 15 subjects, adenosine, hypertonic saline (algesic), and isotonic mannitol (placebo) were infused into the tibialis anterior muscle and compared with the pain caused by ischaemic contractions. The muscle pain intensity (visual analogue scale; VAS), distribution, and quality were assessed. Pressure pain thresholds were recorded to assess the deep tissue sensitivity. Adenosine did not induce more pain than the placebo. The maximal VAS score after hypertonic saline and ischaemic contractions was higher compared with adenosine/placebo infusions. The duration and area of pain were significantly increased after hypertonic saline infusions compared with ischaemic contractions. Higher scores on the McGill pain questionnaire were given to the “stabbing”, “burning”, “heavy”, and “exhausting” word categories after ischaemic contractions, and “cramping” was rated higher during hypertonic saline‐induced muscle pain compared with ischaemic contractions. During hypertonic saline infusions, the pressure pain threshold was decreased compared with before and immediately after the pain had vanished. The present study shows that pharmacological levels of adenosine in skeletal muscle did not induce pain. Excitation of muscle nociceptors by hypertonic saline evoked hyperalgesia, larger areas of pain, and a different quality of pain compared with ischaemic contractions, suggesting that the pain after ischaemic contractions is mediated by other populations of nociceptors in muscle and/or other tissues than excited by hypertonic saline.

Peripheral Neuropathic Pain: A mechanism-related organizing principle based on sensory profiles

Abstract Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profiles might respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroups with characteristic sensory profiles were identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders.

Children in day surgery: clinical practice and routines. The results from a nation-wide survey.

Background: Day surgery is common in paediatric surgical practice. Safe routines including parental and child information in order to optimise care and reduce anxiety are important. Most day surgery units are not specialised in paediatric care, which is why specific paediatric expertise is often lacking.