WO1999015184A1

WO1999015184A1 - New method of treatment

Info

Publication number: WO1999015184A1
Application number: PCT/SE1997/001591
Authority: WO
Inventors: Alf Sollevi
Original assignee: Item Development
Priority date: 1997-09-22
Filing date: 1997-09-22
Publication date: 1999-04-01
Also published as: CA2299320A1; EP1017400A1; AU4888397A

Abstract

The described invention relates to the treatment of hyperexcited sensory nervous function, e.g. neuropathic conditions in human subjects. The treatment is performed without inflicting painful side-effect to the patient, comprising intrathecal administration of the endogenous compound adenosine in a combination with a low dose of a local anaesthetic agent. It is demonstrated that the drug combination can intrathecally repeatedly be administered, providing inhibition of neuropathy without inducing side-effects from any of the two agents involved.

Description

NEW METHOD OF TREATMENT

D E S C R I P T I O N

Field of the Invention

The present invention relates to normalisation or allevation of a pathologically hyperexcited sensory nerve function in a conscious human subject without inflicting painful side-effects.

Background

The sensory nervous system projects signals to the central nervous system, mediating information from the periphery to the brain (CNS) . These comprise signals from sensors in peripheral tissues and other organs, sensitive for qualities like touch, reduced temperature, increased temperature, vibration, painful stimuli, pressure, vision, hearing, smell, taste and balance. This sensory nervous system is an important physiological control in the subject's relation to the environment. The sensory nervous system can be damaged by various types of trauma, such as infections and mechanical lesions. This can result in disturbance in the signal transmission into the CNS, leading to reduced perception of sensory signals (hypoestesia) as well as hyperfunction (more excited signals in the CNS) due to some largely unknown changes in the nerve transmission process (neuropathic damage) . The neuropathic condition with hyperexcitation is described as a "central sensi- tisation" phenomenon and often involves several of the above mentioned sensory functions. This may therefore be associated with decreased perception thresholds for touch and temperature (hyper- esthesia) , discomfort in the perception for touch and temperature (dysesthesia) , discomfort or pain with normally non-painful touch, pressure and/or temperature stimulation (allodynia) , and hyper- sensitivity to painful stimuli (hyperalgesia) . These types of hyperexcited sensory nervous function may develop after various types of trauma, and is called chronic when persistent for more than 3-6 months . Adenosine is an endogenous nucleoside present in all cell types of the body. It is endogenously formed and released into the extracellular space under physiological and pathophysiological conditions characterized by an increased oxygen demand/supply ratio. This means that the formation of adenosine is accelerated in conditions with increased high energy phosphate degradation. The biological actions of adenosine are mediated through specific adenosine receptors located on the cell surface of various cell types, including nerves (1) .

Adenosine is one of several endogenous compounds that are considered to induce pain in peripheral tissues, and exogenous application of adenosine to tissues causes pain (2,3) . In the central nervous system, adenosine acts differently. The latter conclusion is primarily based on animal data where adenosine is administered into the cerebrospinal fluid (intrathecally) of mice after chronic implantation of a catheter close to the spinal cord (4) . After intrathecal adenosine there is a transient latency in the withdrawal reflex to hot plate provocation. The duration of this effect is short (minutes) , and it is difficult to separate this effect on latency from an adenosine-induced influence on the motor nerve functions (control of movements of the animal) . Stable analogues of adenosine exert more long-lasting effects on these reflex latencies in rodents (4-7) , but this is often also associated with muscle paralytic effects in the extremities (5-7) . Further, endogenous adenosine has been proposed to be involved in the action of morphine, since this compound releases adenosine in the spinal cord of rats (see review 6) . In rats subjected to damage to the nervous system (lesion to the sciatic nerve) , causing a presumed painful behaviour, there are only studies using an analog of adenosine (8,9). This adenosine analogue R-phenyliso- propyl-adenosine (R-PIA) reduces sensory hyperexcitability for approximately one hour in these animals, suggesting reduced pain behaviour. Furthermore, one clinical case report demonstrate long- lasting pain relief in a patient with painful hyperexcited sensory nerves of the foot, receiving an intrathecal dose of R-PIA (10) . Consequently, there is evidence that administration of the adeno- sine analogue R-PIA to the CNS of rats, and in one patient, causes effects that counteract pathologically hyperexcited sensory nerves .

Adenosine is generally administered to human subjects for different purposes, such as vasodilation and treatment of arrhythmia. Adenosine is then given by continuous intravenous infusion or by bolus injections. Adenosine induces dose-dependent pain symptoms by intravenous infusion doses above approximately 70 μg/kg/min or by bolus injections (3,11-14). Thus, adenosine has been demonstrated to be an algogenic compound when given i.v. in humans but the pain symptoms are immediately reversible after discontinuation of administration. The pain symptoms are located in the chest, neck, throat, head, epigastrium, back, shoulder and arms (3,11- 14) . The incidence of dose-dependent pain at doses above 100 μg/kg/min is approximately 80% (15,16). Dose-dependent pain is produced when adenosine is infused into a peripheral arterial region in man (artery of the forearm, 12) . Intradermal injection of adenosine also causes pain in healthy volunteers (2,17) . Consequently, the knowledge regarding peripheral administration of adenosine to humans subjects demonstrates that it provokes dose- dependent pain symptoms at high doses. On the other hand, when the compound is infused intravenously at doses between 50-70 μg/kg/ min, pain relief has been documented, both in experimental human models (18-20) and in patients with hyperexcited sensory nerves (21-23) . Thus, available clinical data demonstrate that systemic adenosine infusion at low dose is associated with inhibition of hyperexcited sensory nerves in patients with neuropathy, while high doses causes dose-dependent pain symptoms from various peripheral parts of the body.

There are experimental data that suggest that endogenous adenosine may modify sensory input at the spinal level (24) . There is consequently experimental information suggesting that adenosine may act physiologically in the CNS to depress noxious stimuli of the intact nervous system. It has also been demonstrated that intravenous infusion of adenosine may reduce the surgical requirement of anaesthetic drugs (inhalational anesthetics, 25-28) suggesting an interaction with anaesthetic agents. Therefore, available data and proposals regarding the action of adenosine within the CNS relates to adenosine-induced depression of noxious stimuli, while the opposite is the case in the peripheral sensory nervous system in humans .

Regarding intrathecal administration of adenosine or analogues to the cerebrospinal fluid, there has not been indication of painful side-effects (such as vocalisation or writhing in rodents) upon intrathecal injection in any of the several animal studies (4-9) , or report of pain in the clinical case receiving the adenosine analogue R-PIA (10) . Further, there is no clinical information about actions of intrathecal administration of adenosine, neither with respect to its influence on pain mechanisms nor to its possible side-effects.

The administration of adenosine in combination with a local anaesthetic agent (lidocaine) has been suggested for the reduction myocardial reperfusion injury (muscle damage of the heart) in the treatment of a heart attack victim (29) based on experimentations in rabbits wherein the rabbits were treated by continuous intravenous infusion of adenosine at a dosage of 1 μg/min to 100 μg/min in combination with intermittent doses of lidocaine every four minutes (10 mg) for a total dose of 40 mg corresponding to 10-13 ^m<?/kg body weight .

Disclosure of the invention

The current invention relates to the alleviation or normalisation of a pathologically hyperexcited sensory nervous system in human subjects without being associated with painful side-effects, by combining intrathecal administration of the endogenous compound adenosine and a low dose of a local anaesthetic agent which is in the order of one hundreth of that used in the prior art combination of local anaesthetic agent and adenosine in reperfusion experiments on rabbits (29) . The current invention is based on the finding of specific effects of intrathecal adenosine administration to human subjects, demonstrating actions of the endogenous compound not previously recognized. As will be illustrated in detail below, applicant has discovered that adenosine injections to the CNS of humans is associated with marked side-effect consisting of pain (often severe) in the abdomen, inguinally and in both legs, lasting up to 3 hours. The effect is most prominent in patients with damage of the sensory nervous system (vide Examples 2 to 6 below) where the side-effect may be present at any dose, but the painful side-effect has also been demonstrated in healthy volunteers (vide Example 1 below) . The painful side-effect, which is dose-dependent, is so marked that clinical use of adenosine on its own for modulation of pathologically hyperexcited nervous system can not be performed by intrathecal administration. It is not known what mechanism is involved in the pain-inducing effect of adenosine, contrasting the non-painful synthetic analogue R-PIA (10), upon intrathecal injection in humans. Appparently, the endogenous compound adenosine produces an activation of sensory nerves involving pain perception at the spinal cord level, since the effect is initiated within minutes after administration.

It has been discovered by the present applicant, that combining adenosine with a low dose of a local anaesthetic agent upon intrathecal injection eliminates all painful side-effects of adenosine, without causing any detectable side-effect of the co- administered local anaesthetic agent. The drug combination does not affect the action of adenosine on pathologically hyperexcited sensory nerves. By applying the drug combination it has also been shown that adenosine together with a local anaesthetic agent can provide permanent inhibition of hyperexcited nerves of the sensory nervous system, both by continuous or intermittent administration, without being associated with pain-related or other side-effects.

On basis of the findings mentioned above the present invention, in accordance with one aspect thereof, comprises the use of adenosine for the manufacture of a pharmaceutical preparation for intrathecal administration in combination with a local anaesthetic agent for alleviation normalisation or diagnosis of pathologically hyperexcited nervous function in human patients without inducing painful side-effects.

As an example of a pathologically hyperexcited nervous function which can be subjected to alleviation, normalisation or diagnosis in a favourable way by means of such a pharmaceutical preparation is neurogenic pain in humans.

According to an embodiment of said aspect of the invention said pharmaceutical preparation is intended for the administration of adenosine in a dosage within the range of from 200 to 3000 μg, preferably 300 to 2500, more preferably 500 to 2000 μg when administered as an intrathecal injection.

According to another embodiment of said aspect of the invention said pharmaceutical preparation is intended for the administration of adenosine in a dosage within the range of from 20 to 200 μg/h, when administered as an intrathecal infusion.

Further in accordance with the present invention the adenosine is administered in combination with a local anaesthetic agent . The dosage of said local anaesthetic agent should be such as to be effective in preventing painful side-effects caused by adenosine but not to provide clinical spinal analgesia. Preferably the dosage is within the range of from 2 to 20%, more preferably 5 to 10% of that required for the specific anaesthetic agent to provide clinical intrathecal (spinal) analgesia.

Any type of local anaesthetic agent approved for spinal administration can be used in the present invention.

The local anaesthetic agent which is at present preferred for use in combination with adenosine in accordance with the present invention is a member selected from the group consisting of lidocaine, mepivacaine and bupivacaine. However, also other local anaesthetic agents which are at present or which will be available for clinical intrathecal use in the future are contemplated for use in the present invention.

According to another aspect of the present invention thereis provided a pharmaceutical preparation for alleviation, normalisation or diagnosis of pathologically hyperexcited nervous function in human patients, characterized in that it comprises adenosine in a concentration of 0.1-7.5 mg/ml , preferably 0.3-6 mg/ml, more preferably 0.5-5 mg/ml and a local anaesthetic agent in a concentration common for administration of said agent for spinal analgesia, and a pharmaceutically acceptable carrier for intrathecal administration, the adenosine and said local anaesthetic agent being present in said preparation in such a ratio to enable the administration of a dose of 200-3000 μg, preferably 300-2500 μg, more preferably 500-2000 μg of adenosine in combination with a dose of said local anaesthetic agent preferably corresponding to 2-20%, more preferably 5-10% of the dose required for providing clinical spinal analgesia on intrathecal administration of said local anaesthetic agent.

According to a further aspect of the present invention there is provided a method of alleviation, normalisation or diagnosis of pathologically hyperexcited sensory nervous function in human patients without inducing painful side-effects, which method comprises intrathecal administration of adenosine and a local anaesthetic agent.

The method according to the invention can in a favourable way be used especially in the alleviation, normalisation or diagnosis of neurogenic pain in humans.

Further details of the invention are illustrated in the following non-limiting examples. EXAMPLES OF TREATMENT

EXAMPLE 1

Ten healthy volunteers (age range 18 -52 years) , 7 females, were enrolled for intrathecal adenosine treatment. No one had any concomitant medication. No coffeinated beverage or smoking were allowed 12 hours before the experiment that was started in the morning, after a light breakfast. For the volunteer, all quantitative testing of sensory modalities were blinded. Statistic analysis by Wilcoxons Rank Test. The experiments were initiated by a series of control determination, followed by the intrathecal injection of adenosine and subsequent assessment of data, with escalation by doubling the dose after 5 experiments. Five subject received adenosine 1000 μg, and five 2000 μg i . t . If subjective side-effects of significance would occur at a dose level, no further escalation would be performed. The dura was punctured with a pencil-point spinal needle at the lumbar level L3-4.

Cold pain stimulus test

In order to test pain rating from cold challenge the subjects placed one foot (up to the ankle) in ice water (2-4 °C) during 60 s, rating their pain using the visual analogue scale (VAS, 0-100 intensity where 0 is no pain at all and 100 is worst imaginable pain) . The test was conducted prior to adenosine and at hourly intervals after treatment.

Tourniquet ischemic test

Ischemic pain of the forearm was obtained by a tourniquet applied to the upper arm on the nondominant side. The arm was raised for 3 minutes prior to occlusion in order to drain the venous system. A pressure exceeding the systolic blood pressure by 100 mmHg or a minimum of 250 mmHg was then applied. A weight of 3 kg was then during occlusion slowly and steadily lifted from the surface (females 15 times, males 20 times) as a submaximal effort during 90 s. After these contractions, representing time zero, pain was scored by the subjects every minute until reaching VAS 100 (when the tourniquet was deflated) , or for a maximum duration of 30 minutes, where the test was finished by deflating the tourniquet. The sum of pain VAS rating score over the 30 minute test was determined and represents the "sum of pain score" (SPS) , used for comparison between control occasion and treatment with adenosine. A training occasion were undertaken about 1 week before the adenosine experiment in order to demonstrate the procedure of the tourniquet test, and the data was not used for any comparison. The test was then performed 60-90 minutes after i.t. adenosine. The control test was thereafter conducted 7-10 days after the adenosine experiment.

Neurological examinations

Standard bedside reflex testing of the extremities as well as testing of muscle force was performed before, and at 1 and 4 hours after adenosine. Rombergs test for balance was also conducted. Subjective symtoms were throughout the whole procedure actively aske asked for.

RESULTS

Control situation

After MuO, the sensory parameters of the skin were altered, including allodynia to warmth and lowered thresholds to painful tactile stimulus (TPT) in both primary and secondary areas. Mean areas of secondary allodynia were 34 cm² (von Frey) and 24 cm² (brush) . Cold pain stimulus test showed mean basal VAS ratings ranging from 45 to 70 during the basal situation. SPS for the control tourniquet test in the absence of adenosine (7-10 days after the experiment) was 1522±660, with a range from 680 to 2390.

Adenosine treatment

Side-effects and neurological function:

There were no reports of unspecific subjective symptoms like tiredness, sedation or malaise. No influence on gross reflexes, motor function, balance or voiding reflex. One subject receiving

2000 μg adenosine experienced pain after injection, (maximal pain intensity VAS 70) continuous and circular around the lower part of the abdomen and the inguinal regions and legs, disappearing after 30 minutes. This side-effect terminated further dose-escalation in the study. Sensory testing:

The CDT, DT,HPDT and TPT thresholds on normal skin were not influenced by treatment. On MuO inflamed skin, CDT and HPDT were lowered in a similar manner as before treatment. In contrast to the control experiments, TPT was not significantly reduced by MuO, neither in primary or secondary allodynic areas. Furthermore, in the secondary allodynic areas the median value of TPT was elevated from 33 g before to 144 g after adenosine (p<0.05) . Areas of secondary allodynia to von Frey hair were reduced by more than 50% (p < 0.03), and a corresponding effect by brush stimulation was also seen (p < 0.06) . The cold pain stimulus test was not affected by adenosine, as indicated by stable VAS ratings throughout the experiment . The SPS during tourniquet test (nine tested subjects) was 1270±560 with a range from 530 to 2130 treatment, corresponding to 16% lower SPS than during the control test (p = 0.01) .

EXAMPLE 2

54 year female with a 31 year history of pain in both arms and in the upper thorax after a whiplash accident. Typical signs of neuropathy evolved over the years, including sympathetic dysfunction of both arms, tactile allodynia and radiating pain (resting VAS 60-80, evoked 100) . No effect of conventional drugs apart from side-effects. After responding to i.v. adenosine with warmth in arms / hands and marked pain relief including reduced allodynia, adenosine intrathecally caused an essential painfree state for 3-4 days. Upon injection of 1000 μg adenosine, the patient experienced pain inguinally and in both legs lasting for one hour. By combining adenosine with lignocaine (2.5 mg) along with adenosine 1000 μg, the treatment could be repeated without any side-effects. Similar effect was seen when combining adenosine with bupivacaine (1 mg) . EXAMPLE 3

50 year old female with a "failed back surgery syndrome" after surgery for a lumbar herniated disc, two years ago. The patient has radiating pain in the right leg and neuropathic pain over the lumbar region (tactile allodynia) with resting VAS score ranging from 60-75 and by load provoked pain up to 100. Adenosine intrathecally (500 μg) at lumbar L2-L3 level induced acute pain, rating VAS 95, slowly declining over several hours. The day after, the patient experienced more than 50 % pain relief compared to pre- treatment (VAS < 30) and she could move more freely. The allodynia over the back was abolished. The effect lasted for 3 days. When the patient was treated with adenosine (1000 μg) in combination with bupivacaine (1 mg) , there was no pain after injection, and the pain relief with respect to the neuropathy lasted for one week.

EXAMPLE 4

62 year female with 22 years of postoperative pain of the nervous cutaneus femoralis lateralis territory after a damage during an hysterectomy. There has been a marked upregulation involving the ipsilateral arm and shoulder. The condition is associated with marked tactile allodynia . Resting VAS 50-70 and provoked up to 100. Marked side-effects from all conventional pharmacological attempts. Spinal cord stimulation had no effect. Intrathecal adenosine injection (500 μg) made the patient totally painfree, with elimination of hyperexcited symptoms for the first time in 22 years. The duration of pain relief in the leg was 8 hours. Upon repeated treatment using adenosine 1000 μg, the patient experienced pain upon injection, inguinally and in both legs. The VAS intensity was 90. Thereafter, as low as 100 μg adenosine injections induced pain reaction. Combining adenosine with either lignocaine (2.5 mg) or bupivacaine (1 mg) , all symptoms of pain was eliminated, even when administering 1000 and 2000 μg of adenosine. Repeated daily treatments provided permanent pain relief without side-effects. The patient now have an implanted pump for intermittent adenosine with bupivacaine injections, patient-controlled administration.

EXAMPLE 5

44 years old female with dermatomyositis associated with allodynia and resting pain of neuropathic character of the right side of the body since more than 10 years. All therapeutic attempts had been without success. Adenosine injection (500 μg) induced immediate and severe pain, circular of the abdomen, lasting for 2 hours. Thereafter the treatment reduced the patients resting pain to VAS 0 and normalised the neuropathic allodynia for 5 days. The patient received intrathecal injection of adenosine (1000 μg) combined with bupivacaine (1 mg) . The treatment provide weeks of pain relief without any side-effect.

EXAMPLE 6

54 years old male with initial trauma to the right shoulder 9 years ago. Upregulation with severe neurogenic pain of the arm and shoulder, leading to neurosurgical implantation of electrodes for sensory stimulation. The surgical interventions caused series of complications of neurological and infectious origin during the period from 1991 to 1995. A severe pain state evolved, involving the neck, shoulder, both arms and the right leg (VAS intensity 60-100) , including marked tactile allodynia and loss of muscle strength of the right arm. All known pharmacotherapy has been tested without significant relief. Only morphine had some marginal effect . The implanted sensory stimulation equipment caused pain sensations. Adenosine intrathecally (750 μg) induced a 30 hours total pain relief as well as full functional recovery. However, the treatment was initially associated with pain of both legs (VAS 70), lasting for 2 hours. When combining adenosine (1000 μg) with bupivacaine (1.5 mg) , the injection was pain-free, and daily adenosine with bupivacaine injections was associated with permanent pain relief. The patient now has an implanted pump administering the intrathecal drug combination at a 24 hour interval. BIBLIOGRAPHY

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12. Sylven C, Jonzon B, Fredholm BB, Kaijser L. Adenosine injection into the brachial artery produces ischaemia like pain or discomfort in the forearm. Cardiovasc Res 1988;22:674-678.

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16. Abreu A, Mahmarian JJ, Nishimura S, Boyce TM, Verani MS, Tolerance and safety of pharmacologic coronary vasodilation with adenosine in association with thallium-201 scintigraphy in patients with suspected coronary artery disease, J Am Coll Cardiol 18 : 730 - 735 , 1991 .

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19. Segerdahl M, Ekblom A, Sollevi A. Influence of adenosine, ketamine, and morphine on experimentally induced ischemic pain in healthy volunteers. Anesth Analg 79, 787-791, 1994.

20. Segerdahl M, Ekblom A, Belfrage M, Sjόlund KF, Forsberg C, Sollevi A. Systemic adenosine attenuates touch evoked allodynia induced by mustard oil in humans. Neuroreport 6, 753-756, 1995.

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22. Belfrage M, Sollevi A, Segerdahl M, Sjόlund KF, Hansson P. Systemic adenosine infusion alleviates spontaneous and stimulus evoked pain in patients with peripheral neuropathic pain. Anesth Analg 81, 713-717, 1995.

23. Sollevi A. New method of treatment. "Adenosine receptor agonist treatment for alleviation of pathologically hyperexcited sensory nerves". WO/95/29680, published 9 november 1995.

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26. Segerdahl M, Ekblom A, Wickman E, Sandelin K, Sollevi A. Peroperative adenosine infusion reduces the requirement for isoflurane and postoperative analgesics. Anesth Analg 80, 1145- 11490, 1995.

27. Segerdahl M, Persson E, Ekblom A, Sollevi A. Peroperative adenosine infusion reduces isoflurane requirements during general anaesthesia for shoulder surgery. Acta Anaesth Scand 40, 792-797, 1996.

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Claims

C L A I M S

1. The use of adenosine for the manufacture of a pharmaceutical preparation for intrathecal administration in combination with a local anaesthetic agent for alleviation, normalisation or diagnosis of pathologically hyperexcited nervous function in human patients without inducing painful side-effects.

2. Use according to claim 1, wherein said pharmaceutical preparation is intended for the administration of adenosine in a dosage within the range of from 200 to 3000 ╬╝g, preferably 300 to 2500, more preferably 500 to 2000 ╬╝g when administered as an intrathecal injection.

3. Use according to claim 1, wherein said pharmaceutical preparation is intended for the administration of adenosine in a dosage within the range of from 20 to 200 ╬╝g/h, when administered as an intrathecal infusion.

4. Use according to any of claims 1 to 3 , wherein the adenosine is administered in combination with a local anaesthetic agent, the dosage of said local anaesthetic agent being effective in preventing painful side effects caused by adenosine but not providing clinical spinal analgesia, preferably a dosage within the range of from 2 to 20%, more preferably 5 to 10% of that required for providing clinical spinal analgesia.

5. Use according to claim 4, wherein said local anaesthetic agent is a member selected from the group consisting of lidocaine, mepivacaine and hupivacaine .

6. Use according to any of claims 1 to 5 , wherein said pharmaceutical preparation is intended for use in alleviation, normalisation or diagnosis of neurogenic pain in human patients without inducing painful side-effects.

7. The use of an intrathecally administrable local anaesthetic agent for manufacture of a pharmaceutical preparation for intrathecal administration in combination with adenosine for alleviation, normalisation or diagnosis of pathologically pyperexcited nervous function in human patients without inducing painful side-effect.

8. Pharmaceutical preparation for intrathecal administration for alleviation, normalisation or diagnosis of pathologically hyperexcited nervous function in human patients, characterized in that it comprises adenosine in a concentration of 0.1-7.5 mg/ml, preferably 0.3-6 mg/ml, more preferably 0.5-5 mg/ml and a local anaesthetic agent in a concentration common for administration of said agent for spinal analgesia, and a pharmaceutically acceptable carrier for intrathecal administration, the adenosine and said local anaesthetic agent being present in said preparation in such a ratio to enable the administration of a dose of 200-3000 ╬╝g, preferably 300-2500 ╬╝g, more preferably 500-2000 ╬╝g of adenosine in combination with a dose of said local anaesthetic agent preferably corresponding to 2-20%, or more preferably 5 to 10% of the dose repuired for providing clinical spinal analgesia on intrathecal administration of said local anaesthetic agent.

9. Pharmaceutical preparation according to claim 5, wherein said local anaesthetic agent is selected from the group consisting of lidocaine, mepivacaine and bupivacaine.

10. A method of alleviation, normalisation or diagnosis of pathologically hyperexcited sensory nervous function in human patients without inducing painful side-effects, which method comprises intrathecal administration of adenosine and a local anaesthetic agent .

11. A method according to claim 10, wherein said pathologically hyperexcited sensory nervous function is neurogenic pain.