WO2008001053A1

WO2008001053A1 - Treatment and/or prevention of pain using polyether polyols

Info

Publication number: WO2008001053A1
Application number: PCT/GB2007/002349
Authority: WO
Inventors: Gareth Ackland; Alexander V. Gourine
Original assignee: University College London Hospitals NHS Foundation Trust (UCLH)
Current assignee: University College London Hospitals NHS Foundation Trust (UCLH)
Priority date: 2006-06-27
Filing date: 2007-06-25
Publication date: 2008-01-03
Anticipated expiration: 2008-12-27
Also published as: GB0612749D0

Abstract

The present invention provides the use of an aqueous solution of at least one polyether polyol for the treatment and/or prevention of pain, particularly acute, chronic or neuropathic pain.

Description

TREATMENTAND/OR PREVENTION OF PAIN USING POLYETHER POLYOLS

Technical field

The present invention relates generally to a medicament for the treatment and/or prevention of pain and to the use of such a medicament for the treatment and/or prevention of pain.

Background art

Pain may be acute or chronic. Acute pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage [International Association for the Study of Pain]. Despite the availability of a variety of analgesics for the treatment of acute pain, recent studies demonstrate that about 50-70% of patients still experience moderate to severe pain after surgery [Best Pract Res Clin Anaesthesiol. 2007 ;21(1):3-13]. Acute pain usually resolves but may persist.

Chronic pain is defined as a persistent pain that is not amenable to treatments based upon specific remedies, or to the routine methods of pain control such as non-narcotic analgesics [International Association for the Study of Pain]. Diverse diseases and tissue trauma are associated with the development of chronic pain. Conservative estimates suggest that 5-20% of all patients undergoing a variety of elective surgical procedures will develop chronic pain. Chronic pain results in a systemic syndrome characterized by pain, prolonged psychological symptoms and the development of other medical problems, such as pain at other body sites, fatigue and cardiovascular disease. Chronic pain persists over a long period of time and is notoriously resistant to many analgesics and other medical treatments, rendering it as a leading cause of disability in the United States. Neuropathic pain is a complex, chronic pain state that may be accompanied by tissue injury. In this situation, the nerve fibres themselves may be damaged, dysfunctional or injured. These damaged nerve fibres send incorrect signals to those parts of the brain that control the sensation of pain. Many common diseases, such as post-herpetic neuralgia, trigeminal neuralgia, diabetes mellitus, cancer, stroke, and degenerative neurological diseases may produce neuropathic pain. Conventional analgesics fpain- killers") such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) and opioids (e.g. morphine) are often ineffective. Neuropathic pain accounts for 25-50% of pain clinic visits every year with an estimated prevalence of 4 million sufferers in the US alone (Curr Opin Anaesthesiol. 2005 Oct; 18 (5):548-54).

Pro-inflammatory cytokines released by immune cells can induce or facilitate pain. It is thought that pro-inflammatory cytokines contribute as much to the development and maintenance of pain as the initial damage itself. Studies using animal models have shown that up-regulation of chemokines is one of the mechanisms underlying the development and maintenance of chronic pain. Cytokine release results in neuroinflammation, where immune cells infiltrate the site of injury in response to damage to the nervous system. Neuroinflammation occurs in persistent pain states following peripheral and central nervous system injury, through neuroimmune activation involving endothelial cells, microglia and astrocytes. In particular, an excessive release of pro-inflammatory cytokines at the site of nerve injury manifests in behaviour suggestive of neuropathic pain (see e.g. DeLeo et al, The role of neuroinflammation and neuroimmune activation in persistent pain, Pain 90 (2001) 1-6).

After tissue injury, prolonged and/or excessive cytokine release continues to trigger cellular mechanisms responsible for perpetuating pain. Pain thresholds are not only lower, but also altered in that minor stimuli are sensed as excessively painful- hyperalgesic neuropathic pain. Furthermore, stimuli that are normally innocuous become painful - allodynic pain. Unfortunately, the development of chronic, neuropathic pain after surgery is a particularly undesirable yet common complication. This is exacerbated by the ineffectiveness of many analgesics, which have major side effects that limit both their use and efficacy. For example, the use of the most effective analgesic morphine is often limited by its strong tendency to provoke nausea and vomiting, excessive sedation and depression of breathing.

Thus it can be seen that novel ways of treating and/or preventing pain would provide a contribution to the art.

Disclosure of the invention

Polyether polyol, in particular polyether glycol, and most particularly polyethylene glycol, is a widely used substance for both household and industrial purposes. It possesses some remarkable properties that have been explored in several laboratory-based scenarios, although the mechanisms through which polyethylene glycol acts under different experimental conditions are unclear. Polyethylene glycol improves function in experimental transplant organs (JP Faure et al, American Journal of Transplantation 2004 vol 4; 495-504) reverses experimental spinal cord injury (R Borgens and R Shi, FASEB J. vol 14, 27-35, 2000) and protects against experimentally-induced colonic cancer (DE Corpet et al, Carcinogenesis vol.20 no.5 pp.915-918, 1999).

It is also known in the art to employ polyethylene glycol as a vehicle for therapeutic agents in a process known in the art as "PEGylation".

For example, a paper in the Journal of Surgical Research (1995), VoI 59, pp 153-158, entitled "PEG-BP-30 Monotherapy Attenuates the Cytokine-Mediated Inflammatory Cascade in Baboon Escherichia coli Septic Shock..." by Espat et al discloses the effects of soluble tumour necrosis factor receptors linked to polyethylene glycol used in a "PEGylation" technique to reduce immunogenecity and clearance and increase plasma half-life of the soluble receptor. Experimental design of this study, like of the vast majority of other studies involving peptides linked to polyethylene glycol, is flawed. This study fails to consider the most important control, namely determining the effect of polyethylene glycol per se.

As another example, a paper in Clinical Science (2004), VoI 107, pp. 263-272, entitled

"Plasma expansion by polyethylene-glycol-modified albumin" by Assaly et al discloses the effects of albumin linked to polyethylene glycol in a "PEGylation" technique to modify albumin. Experimental design of this study is also flawed: the most important control, namely administration of polyethylene glycol perse is missing.

FR-A-2316923 discloses complex solutions comprising a number of components (urethane, ethylene glycol, etc) including high molecular weight (6000) polyethylene glycol in a high concentration (2.5%). There is no evidence given that the beneficial effect of this solution is related to the properties of polyethylene glycol.

DE-A-10204696 discloses the use of polyethylene glycol in a nasal spray (comprising several other substances) to treat viral infections causing coughs and sneezes.

WO-A-2004/047778 discloses a solution based on a high molecular weight, at least 5,000 daltons, polyethylene glycol given in a very high concentration in an experimental model of microbe-mediated epithelial disorders. In the examples disclosed, the pathogen - A -

(Pseudomonas aeruginosa) was administered mixed with a polyethylene glycol solution. It is proposed that high molecular weight; high concentration polyethylene glycol prevents contact of pathogens with the epithelial surface. The disclosure has no relevance to the treatment or prevention of pain. Furthermore, polyethylene glycols are known for use as bowel purgatives in common clinical practice.

None of these prior disclosures addresses the treatment of acute and chronic pain in an individual, in particular for surgical and medical emergencies, for chronic post-operative pain and in particular, neuropathic pain.

There is a need for improved treatment of acute and chronic pain, in particular for surgical and medical emergencies, for preventing post operative pain and subsequent development of chronic pain and in particular, neuropathic pain. Where the word "preventing" is used below it will be understood that this does not necessarily circumscribe complete prevention or resolution, but encompasses rather mitigation, attenuation, pre-emption, or other palliative treatment of pain.

There is further a need for such a treatment that can be administered readily and effectively.

There is yet further a need for such a treatment that can be administered using as active component a readily available compound, known to be safe for use both in foods and in drugs for administration to humans.

The present invention at least partially aims to meet at least one, or more preferably all of those needs.

In a first aspect, the present invention provides the use of an aqueous solution of at least one polyether polyol for the treatment and/or prevention of pain.

The polyol polyether of the any aspect of the present invention can be of any suitable molecular weight for treating and/or preventing pain in a subject, but it is preferred that it has a molecular weight of from 100 to 10,000, preferably 200 to any one of 5,000, 6,000, 7,000 or 8,000, or most preferably, 200 to 4000. Thus, the molecular weight may be any one of 200, 400, 600, 800, 1 ,000, 1 ,500, 2,000, 2,500, 3,000, 3,500 or 4,000, and may be a range between any one of these points (i.e. 200 to 1,000). Molecular weight is represented in Daltons (Da).

The present invention may employ a "low molecular weight polyethylene glycol", meaning the range of molecular weight of the polyethylene glycols is from 200 to 1000, or alternatively the present invention may employ a "medium molecular weight polyethylene glycol", meaning the range of molecular weights of the polyethylene glycol is from 1000 to 4000. A mixture of such a "low molecular weight polyethylene glycol" and a "medium molecular weight polyethylene glycol" may alternatively be employed.

The polyol polyether of any aspect of the present invention can be of any suitable concentration for treating and/or preventing pain in a subject. Preferably, the concentration of the polyol polyether falls within the range of 0.01 to 1000 mg/ml, more preferably, 0.01 to 500 mg/ml, most preferably 0.01 to 100 mg/ml. In a most preferred embodiment, the polyether polyol is at a concentration of 0.01 to 10 mg/ml. For example, the polyether polyol can be present in the aqueous solution at a level of 0.01, 0.1 , 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg/ml, or a range including 2 or more of these points (i.e. 0.1 to 7 mg/ml). In any aspect of the invention, preferably the concentration of the at least one polyether polyol in the aqueous solution is from 1 to 10 mg/ml, more preferably 5 to 10 mg/ml.

The final dosage to be administered will depend on the precise mode of administration, but may preferably be such as to provide between 10 mg and 5 g to a typical subject of 70kg. Most preferably it will provide between 35 mg and 3.5g, or between 100 mg and 3g, or between 1g and 2g.

In a second aspect, the present invention provides the use of an aqueous solution of at least one polyether polyol for the manufacture of a medicament for treating and/or preventing pain.

In a third aspect, the present invention provides the use of a composition comprising at least one polyether polyol and an aqueous solution for administration to a mammal for the manufacture of a combined preparation for the simultaneous, separate or sequential use as a medicament for treating and/or preventing pain. In a fourth aspect, the present invention provides a composition comprising an aqueous solution of at least one polyether polyol for administration to a mammal as a combined preparation for use as a medicament, in particular for treating and/or preventing pain.

Preferably, the composition or medicament described herein is for administration to a mammal, the medicament or composition comprising at least one polyether polyol in aqueous solution, the at least one polyether polyol consisting of the sole active therapeutic constituent of the composition or medicament, wherein the at least one polyether polyol preferably has a molecular weight of from 200 to 4000 and is dissolved in an aqueous fluid selected from an aqueous solution of one or more crystalloids, an aqueous colloid suspension of one or more colloids, or a mixture of such an aqueous solution of one or more crystalloids and such a colloid suspension of one or more colloids.

Preferably the concentration of the at least one polyether polyol in the aqueous solution is from 0.01 to 10 mg/ml, more preferably from 1 to 10 mg/ml.

In accordance with these aspects of the present invention, the polyether polyol may comprise a single polyether polyol, or may comprise a mixture of at least two polyether polyols. The polyether polyol is preferably a polyether glycol, most preferably polyethylene glycol. The polyethylene glycol preferably has a molecular weight of from 200 to 4000, most preferably 200 to 2000, or 200 to 1000.

The invention most preferably has medical use for administration to human beings, although it may also have veterinary use for treating other mammals, such as domestic pets (cats, dogs, etc.), horses, farm animals (cattle, etc.).

The aqueous fluid for administration to a human being or a mammal is a medical-grade liquid, such as an aqueous intravenous (e.g. resuscitation) fluid or an aqueous fluid for intrathecal or intraperitoneal therapy which preferably comprises an aqueous solution of one or more crystalloids, an aqueous colloid suspension of one or more colloids, or a mixture of such an aqueous solution of one or more crystalloids and such a colloid suspension of one or more colloids. Preferred aqueous crystalloid solutions include Ringer's lactate solution, compound sodium lactate solution (for example comprisingi sodium 131 mmol/l, potassium 5 mmol/l¹, calcium 2 mmol/l, chloride 111 mmol/l, lactate 29 mmol/l; pH 6-7; osmolarity 278 mθsmol/l) and normal saline solution (for example 0.9% sodium chloride in water), or mixtures of two or more of these solutions. A most preferred fluid for administration contains sodium lactate. Preferred aqueous colloid suspensions include succinylated gelatine suspended in, for example 0.9% saline solution and starch based colloid preparations (including hydroxyethylated starch) in aqueous suspension. The preferred crystalloid-colloid solutions include one or more aqueous crystalloid solutions in admixture with one or more aqueous colloid suspensions.

The at least one polyether polyol is dissolved in the aqueous fluid for administration to a human being in a concentration (with respect to the volume of the initial aqueous fluid) of from 0.01 to 10 mg/ml, more preferably from 1 to 10 mg/ml.

In a fifth aspect, the present invention provides a method of treating and/or preventing pain, the method comprising administering to a patient an aqueous solution of at least one polyether polyol.

In a sixth aspect, the present invention provides the use of an aqueous solution of at least one polyether polyol as an analgesic. Preferably, the analgesic is for treating/preventing pain.

For treating and/or preventing pain, the medicament solution of the present invention can be administered in any suitable way, but is preferably administered orally, intravenously, intraperitoneal^ or intrathecal^ for central nervous system administration. The administration method is the same as for the conventional administration of an intravenous fluid or administration of intrathecal or intraperitoneal therapy. The administration may be in a single dose, or in plural doses administered over a period of time.

For situations in which the subject or patient (preferably a human) is undergoing surgery, the medicament solution or composition of the invention can be administered as a peri- operative fluid, most preferably intravenously. Alternatively, the medicament solution or composition can be administered as a pre-operative fluid and/or intra-operative and/or post-operative fluid, most preferably, intravenously.

In a most preferred aspect, the present inventors have found that low molecular weight polyethylene glycol administered in low concentration, of from 1-7 mg/ml, inhibits production and/or release of major endogenous pro-inflammatory mediators (cytokines) from immune cells directly implicated in pathophysiology of acute and chronic pain.

Without wishing to be bound by theory, the inventors postulate that the solutions of the present invention may act to reduce/prevent pain by reducing the production and/or release of pro-inflammatory cytokines that are involved with the initiation/development of pain. Thus, the solution is thought to act via attenuation of cytokine production/release.

Thus the present invention is predicated on the finding by the inventors that there is a marked benefit resulting from the administration of polyether polyol, in particular polyethylene glycol-saline solutions in experimental models of acute inflammation. The therapeutic application of this finding uses widely practiced, accepted means of maintaining/restoring organ function through administration of fluid, for example as a perioperative fluid, but with the additional benefit of anti-inflammatory, thus pain-relieving substance within that fluid.

The present invention therefore is based in part on the discovery of a new and unexpected medical use of a known compound, which, according to the experimental data obtained by the present inventors, has profound properties which decrease the production of the pro-inflammatory cytokines, which to the inventors' knowledge was previously unrecognised by those skilled in the art. In accordance with the present invention, the polyethylene glycol-saline solution can be administered easily, safely and effectively. The inventors believe that because polyethylene glycol has previously been recognised as being safe for human use, being used widely in foods and drugs (categorised as a "GRAS" (Generally Recognised as Safe) substance by The United States Food and Drug Administration), there is an immediate clinical opportunity to develop polyethylene glycol-saline solutions as an acute analgesic, and/or to prevent or treat chronic pain. Moreover, the administration of the polyether polyol-saline solutions may readily be achieved using a standard mode of care (fluid therapy) to deliver, in a resuscitation or peri-operative fluid, the additional pain-relieving benefit of the polyether polyol compounds.

The medicament of the present invention may be used for its pain-relieving properties for the treatment of pathophysiological states where there is acute and/or chronic pain. For example: acute pain may result from disease, inflammation, or trauma/injury to tissues. Chronic pain is associated with several medical conditions encompassing: alcoholism; amputation; back, leg, and hip problems; chemotherapy and/or following surgical procedures associated with post-operative pain. The pain may for example cancer (e.g. breast cancer), infection (e.g. otitis media, pelvic inflammatory disease, peptic ulcer disease), autoimmune disease (i.e. systemic lupus erythematosis), anatomical pathology (mechanical back, leg, and hip pain, including sciatica) and chronic inflammation (including hepatitis, pancreatitis, irritable bowel disease, chronic kidney failure, dysplasia, , repetitive strain injury , sickle cell anemia, rheumatoid spondylarthropathies, diabetes mellitus; facial nerve inflammation [Bell's palsy]; AIDS; multiple sclerosis and shingles (herpes zoster virus infection).

Other syndromes or diseases for which treatment of pain may be beneficial include headache, migraine, neuralgia, toothache and appendicitis, as well as toxic shock syndrome and/or thromboembolism, hernia, iritis, ischemia, lipedema, malaria, peripheral neuropathy, pinched nerve, ectopic pregnancy, menstruation, diverticulitis, urolithiasis, pyelonephritis, peptic ulcer disease, gastroenteritis, cholecystitis, aortic aneurysm, Osgood-Schlatter disease, cholestasis, and chondritis.

The composition, method or medicament of the present invention may thus be used to treat any condition, disease, injury, or infection that is associated with pain, particularly those associated with persistent or chronic pain. The present invention may be used to treat any one of those conditions listed above.

Any sub-titles herein are included for convenience only, and are not to be construed as limiting the disclosure in any way.

The invention will now be further described with reference to the following non-limiting Figures and Examples. Other embodiments of the invention will occur to those skilled in the art in the light of these.

The disclosure of all references cited herein, inasmuch as it may be used by those skilled ^■ in the art to carry out the invention, is hereby specifically incorporated herein by cross- reference.

Figures Figure 1 shows the relationship between body temperature and time, and thus demonstrating inflammatory response, for rats treated with a medicament in accordance with Example 1 of the present invention and in a comparative control sample.

Figures 2 (a), (b) and (c) show the relationship between blood plasma levels of the respective cytokines and composition of the injection for rats treated with a medicament in accordance with Example 2 of the present invention and in comparative control samples.

Figures 3 (a) and b) show responses to mechanical hyperalgesia in a neuropathic pain model . Animals were treated with saline [vehicle], morphine or PEG and response was demonstrated by force tolerated before paw withdrawal and time to paw withdrawal. Differences shown are between mean differences between paws ^*p<0.05 vs. before drug; #p<0.05 vs. before drug.

Figure 4 shows changes in mean paw volume vs. baseline (%) in the carrageenan inflammatory pain model - p<0.05 vs. vehicle; **p<0.01 vs. vehicle treated group.

Figure 5(a) shows the similar baseline response of rats to mechanical stimuli, before they receive carrageenan and then treatment [PEG or saline control]. Figure 5(b) shows the difference in responses to mechanical stimuli between paws 3 hours after one paw has been been injected with carrageenan resulting in acute inflammatory pain while the other paw serves as a control. The rats received either PEG or saline treatment 3 hours after the injection of the carrageenan, *p<0.01 vs. vehicle.

Figure 6(a) shows that the release of the inflammatory mediators MIP-1, lnterleukin-6 and PGE2 by human peripheral blood mononuclear cells [which are all centrally implicated in the pathogenesis of acute and chronic pain] is reduced when these immune cells are treated with a medicament in accordance with Example 1 of the present invention, but treated with control [vehicle] solution in a comparative control sample. Figure 6(a) also shows that at the same concentration, higher molecular weight PEG (>4000) was not so efficacious, but MW<2000 had a significant anti-inflammatory effect on cytokine production. Figure 6(b) shows that the most efficacious concentration of PEG that reduced prostaglandin E2 production was between 7-10mg/ml. * denotes significant difference (p<0.05). Examples

Example 1

An isotonic solution of polyethylene glycol in compound sodium lactate solution in accordance with the present invention was prepared. The solution had a concentration of 6.2 mg/ml of the polyethylene glycol in compound sodium lactate solution, and the polyethylene glycol had an average molecular weight of 200, and is available in commerce from the company Sigma, of Poole, UK (amongst many others). This polyethylene glycol solution is referred to hereinafter in these Examples as PEG 200- saline

In this Example, a PEG-200-saline solution (10% PEG-200 in a dose of 1 ml/kg) was injected intraperitoneally into rats (n=10) having had fever induced by intraperitoneal injection of E.coli endotoxin lipopolysaccharide, at an amount of 50 μg/kg bodyweight.

The temperature of the rats was measured for a period of two hours. As a comparison, the temperature was correspondingly measured in rats (n=9) injected intraperitoneally with a control saline solution after having had fever induced by intraperitoneal E.coli endotoxin lipopolysaccharide administration. The results are summarised in Figure 1.

The temperature data for each time measurement are presented as mean temperature values ± standard error of the mean value.

It was found that body temperature of rats treated with both polyethylene glycol 200- saline solution and lipopolysaccharide was significantly lower than of rats injected with saline and lipopolysaccharide (p<0.05). The data demonstrate that one of the major indicators of systemic inflammation, i.e. fever, is markedly reduced following a single intraperitoneal injection of polyethylene glycol-saline in accordance with the invention. The attenuation of inflammation was thus measured by the febrile response.

Example 2

In this Example it was found that bacterial endotoxin lipopolysaccharide (LPS)-evoked production and/or release of key pro-inflammatory mediator cytokines such as interleukin- 1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNFα) are markedly reduced¹ by polyethylene glycol 200-saline solution (the low molecular weight polyethylene glycol used in the first solution of Example 1) treatment in rats.

In this Example, rats were injected sequentially with either (a) saline and saline (n = 4); (b) the low molecular weight (200) polyethylene glycol-saline solution (10% PEG in a dose of 1 ml/kg) and saline (n = 4); (c) saline and bacterial endotoxin - E.coli lipopolysaccharide (LPS, 50 μg/kg) - dissolved in saline (n = 6); or (d) the low molecular weight (200) polyethylene glycol-saline solution and bacterial endotoxin - E.coli lipopolysaccharide (LPS, 50 μg/kg) - dissolved in saline (n = 6). Plasma IL-1β, IL-6 and TNFα concentrations were measured after a period of 1 hour following injection of the respective solutions (either containing LPS or not). The results are summarised in Figures 2 (a), (b) and (c), which show data presented as means + standard errors of the means. Numbers in parentheses indicate sample sizes.

It was found that IL-1β, IL-6 and TNFα levels in plasma of rats treated with both polyethylene glycol 200-saline solution and lipopolysaccharide were significantly lower than in plasma of rats injected with saline and lipopolysaccharide (p<0.05).

This Example shows that administration of a polyethylene glycol-saline solution in accordance with the present invention can substantially reduce the production and/or release of major pro-inflammatory cytokines during systemic inflammation in vivo from immune cells stimulated by bacterial endotoxins, similar to their response evoked by local and/or systemic trauma and injury.

Example 3

The purpose of this example was to evaluate the analgesic activity of PEG in the chronic partial sciatic ligation model for Neuropathic Pain in rats.

Materials were obtained as follows: Phosphate buffered saline (PBS) was supplied by Biological Industry. PEG 400 was supplied by Sigma. Morphine HCI was supplied by Teva Pharmaceutical Industry as a clear liquid. Catgut suture was supplied by SMI. Clorketam (for anesthesia) was supplied by vetoquinol. Xlyalzine was supplied by Medical Market. Ketamine Sodium (Clorketam) was dissolved in Saline to achieve a concentration of 7 mg/ml¹. Xylazine HCI was dissolved in Saline to achieve a concentration of 1.5 mg/ml. Both materials were injected IP at a volume of 10 ml/kg. PEG400 was diluted in PBS To achieve the desired concentration of 5mg/ml.

The test system employed rats (SD) from Harlan Laboratories, Israel. Young adult males were used having a weight of 200-22Og at the study initiation.

Animals were anesthetized with a combination of Ketamine Sodium 35 mg/kg IP and Xylazine HCI 8 mg/kg IP. A model of chronic sciatic nerve pain was produced by partial ligation of the right sciatic nerve. Two weeks later, the rats were tested for their pain threshold.

Rats [n=10 each group] were administered either vehicle (IV ), PEG (IV) or Morphine (which served as a positive control in this study, IP, 5mg/kg) once 15 minutes before the pain threshold test.

Mechanical pain threshold was measured using a Dynamic Plantar Von Frey apparatus which assesses the force that can be tolerated by both healthy and injured paws, before and after treatment. The lower the pain threshold, the lower the force is tolerated by the animal which promptly removes the paw undergoing testing.

This procedure was carried out 3 times: before surgery to determine baseline, 14 days post surgery before drug administration and 15 minutes post drug administration.

The results were analyzed and presented as the difference in the force between paws required for paw withdrawal from Dynamic Plantar Von Frey stimuli, both between within and between groups. Repeated measures ANOVA was applied on all data followed by Tukey-Krammer's multiple comparison test. Probability (p) value less than 0.05, was considered significant.

As shown in Figure 3, PEG400, administered once intravenously, reduced neuropathic pain induced in rats substantially [p<0.05]. Furthermore, in this model, PEG 400 was as effective as morphine, which served as a positive control in this study. All data are mean (95% confidence intervals).

Example 4 The purpose of this example was to demonstrate the analgesic activity of intravenous administration of PEG-400 in the acute carrageenan induced inflammatory pain model

Materials were obtained as follows: Phosphate buffered slaine (PBS) was supplied by Biological Industry. PEG 400 was supplied by Sigma, λ Carrageenan was provided by Sigma as an off-white lyophilized powder. PEG400 was diluted in PBS To achieve the desired concentration of 5mg/ml. A 2% solution of carageenan was prepared 24 hours prior to injection (in distilled water). The solution was stirred and heated during the process to 37 ⁰C to aid the solution preparation. The final solution was kept at 4 ⁰C, until half an hour before injection, when it was kept at room temperature

The test system employed rats (SD) from Harlan Laboratories, Israel. Groups of young adult males were used having average weights of around 186 to 189 g at the study initiation. 2% Carrageenan was injected into the planar surface of the right hind paw, resulting in inflammation, swelling and pain. The same volume of Saline was administered into the left hind paw. Both paw volumes (right and left) were measured before drug administration on study day 0 and served as baseline. The paws were measured again 3 hours post Carrageenan injection using a plethysmometer Paw volume and response to touch stimuli (mechanical hyperalgesia) were measured before treatment (study day 0) and 3 hours post Carrageenan injection. PEG400 was diluted in phosphate buffered saline to achieve a final concentration of 5mg/ml.

To test mechanical hyperalgesia the rat was placed in an enclosure positioned an the metal mesh surface and allowed to move freely. A straight metal filament was moved towards the rat paw such as to touch the planar surface and exert an upward force below the threshold of feeling. The force was increased until either the animal removed the paw or a preset force was met. This procedure was carried out before drug administration (to serve as baseline) and 3 hours after Carrageenan injection. The force required for paw withdrawal after Carrageenan injection was compared to the force required for paw withdrawal before Carrageenan injection between treatments.

As shown in Figure 4, injection of Carrageenan to the right paw resulted in a 10±5% increase in paw volume. PEG-400 at dose of 5 mg/ml prevented the carrageenann induced increase in paw volume (15±7% decrease in paw volume vs. vehicle; p<0.05). Rats receiving vehicle solution experienced more pain when mechanical force was applied to the inflamed paw only. The results in Figure 5(b) demonstrate the mean (95% confidence intervals) differences between the response of the carrageenan treated versus non- carrageenan treated paw for control and PEG treated animals. The pain response, demonstrated by delayed withdrawal response to a painful stimulus [withdrawal time], was reduced by intravenous PEG treatment (p<0.05; repeated measures ANOVA with Tukey-Krammer post hoc analysis).

Figures 6(a) and 6(b) show that pre-administration of a polyethylene glycol-saline solution in accordance with the present invention can substantially reduce the production and/or release of major pro-inflammatory cytokines and prostaglandins [PGE2] during systemic inflammation from immune cells stimulated by bacterial endotoxins, which is similar to their response evoked by local and/or systemic trauma and injury.

In summary, these Examples in accordance with the invention show that treatment with polyethylene glycol-saline solutions markedly reduces pain in both acute (carragenann) and chronic neuropathic (sciatic ligation) models of pain. Polyethylene glycol-saline inhibits the production and/or release of pro-inflammatory cytokines from immune cells involved in the response to pain. From these data the inventors conclude, without being bound by theory, that the effect of polyethylene glycol-saline infusion in acute and/or chronic pain is due to inhibition of overzealous production and/or release of harmful quantities of pro-inflammatory cytokines.

It is believed that the present Examples in accordance with the invention demonstrate that a polyethylene glycol-saline fluid decreases production of pro-inflammatory mediators protects cellular function and mitigates, prevents or treats pain. The implications of the data are far reaching, with immediate commercial and clinical applications, as would be apparent to medical practitioners.

Claims

1. The use of an aqueous solution of at least one polyether polyol for the treatment and/or prevention of pain.

2. The use of an aqueous solution of at least one polyether polyol for the manufacture of a medicament for treating and/or preventing pain.

3. The use according to any of claims 1 or 2 wherein the concentration of the at least one polyether polyol in the aqueous solution is from 0.01 to 10 mg/ml.

4. The use according to any foregoing claim wherein the concentration of the at least one polyether polyol in the aqueous solution is from 1 to 10 mg/ml.

5. The use according to any foregoing claim wherein the polyether polyol comprises a single polyether polyol, or a mixture of at least two polyether polyols.

6. The use according to any foregoing claim wherein the polyether polyol is a polyether glycol.

7. The use according to claim 6 wherein the polyether polyol is polyethylene glycol.

8. The use according to any preceding claim wherein the polyether polyol has a molecular weight of from 200 to 4000.

9. The use according to any preceding claim wherein the polyether polyol has a molecular weight of from 200 to 1000.

10. The use according to any foregoing claim wherein the aqueous fluid is an aqueous intravenous perioperative fluid for intravenous administration or an aqueous fluid for administration for intrathecal or intraperitoneal therapy.

11. The use according to any foregoing claim wherein the at least one polyether polyol consists of the sole active therapeutic constituent of the aqueous solution.

12. The use according to claim 11 wherein the aqueous solution consists of the at least one polyether polyol in an liquid selected from a saline solution, a Ringer's lactate solution, a compound sodium lactate solution, an aqueous colloid suspension or a mixture of two or more of those liquids.

13. Use of an aqueous solution of at least one polyether polyol, the at least one polyether polyol having a molecular weight of from 200 to 4000 and being dissolved in the aqueous solution in a concentration suitable for the treatment and/or prevention of pain for administration to a mammal, for the manufacture of a medicament for treating and/or preventing pain.

14. Use according to claim 13 wherein the concentration of the at least one polyether polyol in the aqueous solution is from 0.01 to 10 mg/ml.

15. Use according to claim 14 wherein the concentration of the at least one polyether polyol in the aqueous solution is from 1 to 10 mg/ml.

16. Use according to any one of claims 13 to 15 wherein the polyether polyol comprises a single polyether polyol, or a mixture of at least two polyether polyols.

17. Use according to any one of claims 13 to 16 wherein the polyether polyol is a polyether glycol.

18. Use according to claim 17 wherein the polyether polyol is polyethylene glycol.

19. Use according to claim 18 wherein the polyethylene glycol has a molecular weight of from 200 to 1000.

21. Use according to any one of claims 13 to 19 wherein the aqueous solution is an aqueous intravenous perioperative fluid for administration to a human being or an aqueous fluid for administration to a human being for intrathecal or intraperitoneal therapy.

22. Use according, to claim 21 wherein the aqueous solution consists of the at least one polyether polyol in an liquid selected from a saline solution, a Ringer's lactate solution, a compound sodium lactate solution, an aqueous colloid suspension or a mixture of two or more of those liquids.

23. Use according to any one of claims 13 to 22 wherein the at least one polyether polyol consists of the sole active therapeutic constituent of the aqueous solution.

24. A use or aqueous solution according to any preceding claim, wherein the pain is acute, chronic or neuropathic.