WO2002080893A1

WO2002080893A1 - Treatment of low back pain and whiplash associated disorder

Info

Publication number: WO2002080893A1
Application number: PCT/SE2002/000673
Authority: WO
Inventors: Kjell Olmarker; Björn Rydevik
Original assignee: A+ Science Invest Ab
Priority date: 2001-04-06
Filing date: 2002-04-05
Publication date: 2002-10-17
Also published as: SE0101258D0

Abstract

The use of a substance that inhibits disc-related nerve-irritating substances for the production of a pharmaceutical composition for treatment of low back pain and/or whiplash associated disorder (WAD) is disclosed. Also a method for treatment of low back pain and/or whiplash associated disorder (WAD) is disclosed.

Description

TREATMENT OF LOW BACK PAIN AND WHIPLASH ASSOCIATED

DISORDER

Field of the invention The present invention relates to substances, pharmaceutical compositions and methods for treatment of low back pain and whiplash associated disorders (WAD).

Background of the invention Low back pain affects approximately 80% of the population during their lifetime in most countries. Except for being extremely common, it is also one of the most costly disorders for the society. In Sweden alone, low back pain was estimated to cost 320.000.000 U.S. dollars in 1997 (Nachemson and Jons- son 2000). The major part of the cost relates to indirect costs such as sick- compensation and reduced productivity, and only a minor part is related to direct costs such as medical care and pharmacological substances.

In a minority of the cases (5%), there may be a known cause for the pain such as infra spinal tumors, rheumatic diseases, infections and more. In these cases the treatment may be specifically aimed at the cause. However, in the majority of the cases of low back pain, the cause remains unknown. At present there is no direct way to treat low back pain with an unknown cause and existing treatment modalities only aim at symptomatic relief.

Low back pain and sciatica

First it is necessary to make a distinction between low back pain and one specific condition that is often linked to low back pain called "sciatica". Sciatica refers to radiating pain into the leg according to the dermatomal inner- vation area of a specific spinal nerve root. The pain in sciatica is distinctly different from that of low back pain. In sciatica, the pain is sharp and intense, often described as "toothache-like", and radiates down into the lower extremities, below the level of the knee. The experience of the pain is closely related to the dermatomal innervation of one or more lumbar spinal nerve roots. Sciatica is also frequently related to neurological dysfunction in that specific nerve and may be seen as sensory dysfunction, reduced reflexes and reduced muscular strength. The sciatic pain thus seem to be a neuropathic pain, i.e. pain due to nerve injury, induced by sensitized axons in a spinal nerve root at the lumbar spinal level. The pain experienced by the patient at low back pain is more dull and is diffusely located in the lower back. There is never any radiating pain into the leg.

Sciatica is the result of nerve injury, and the cause of sciatica has an anatomical correlate. Since 1934 sciatica is intimately linked to the presence of a herniated intervertebral disc (Mixter and Barr 1934). However, although most patients with sciatica will display a herniated disc at radiological exami- nation, it is surprising that approximately 30% of an adult population at the age of 40-50 years of age with no present or previous sciatica also have disc herni- ations when assessed by magnetic resonance tomography, so called "silent" disc herniations(Wiesel, Tsourmas et al. 1984; Boden, Davis et al. 1990; Boos, Rieder et al. 1995; Boos, Dreier et al. 1997). The presence of silent disc herni- ations is intriguing to the spine research community and seems to contradict the relationship between disc herniations and sciatica.

Scientific knowledge of the pathophysiologic mechanisms behind low back pain It is well known that the outer part of the annulus fibrosus of the intervertebral disc and the posterior longitudinal ligament are innervated by C- fιbers(Bogduk, Tynan et al. 1981; Bogduk 1983; Kojima, Maeda et al. 1990; McCarthy, Carruthers et al. 1991; Ashton, Roberts et al. 1994; Cavanaugh, Kallakuri et al. 1995; Palmgren, Gronblad et al. 1999). Although there are no nerve fibers in the deeper part of the annulus fibrosus or the nucleus pulposus in normal discs, nerves may reach these parts in degenerated discs through annular tears (Carreon, Ito et al. 1997; Coppes, Marani et al. 1997; Freemont, Peacock et al. 1997).

Silent disc herniations

As presented earlier, it is known that approximately 1/3 of a normal adult population who never suffered from sciatica have radiological visible disc herniations. Since the presence of a disc herniation is so intimately linked to the symptom of sciatica this is surprising, and at present there is no valid explanation for this phenomenon. However, "silent" in this regard only implies that the disc herniations did not produce sciatica. One may assume though that they produce other symptoms.

Whiplash and whiplash associated disorders (WAD) About 10% to 20% of the occupants of a stricken vehicle in rear-end car collisions suffer from whiplash injury. The injury may also occur as a result of other types of accidents, such as train accidents, and sudden retardations. This injury is defined as a non-contact acceleration-deceleration injury to the head- neck system. It is most often caused by a rear-end car collision and there is no direct impact on the neck.

Presenting symptoms usually include neckpain, headaches, disequilibrium, blurred vision, paraesthesiae, changes in cognition, fatigue, insomnia and hypersensitiviy to light and sound. Dizziness described in a variety of terms such as imbalance, light-headedness and vertigo also occur frequently and these symptoms may be associated with long-term disability.

Although neurologic and orthopaedic examinations do not reveal abnormalities in the majority of patients, the characteristics of dizziness due to whiplash can be elucidated by means of ElectroNystagmoGraphic (ENG) evaluation. This examination is a method that is suitable for proving pathology in the oculo-vestibular system of whiplash-patients.

Until recently, the reason for the extent of injury was poorly understood. In addition, due to the legal and insurance issues, the veracity of complaints of neck pain and other symptoms by people who suffer from whiplash is commonly viewed as suspect. Whiplash injuries can be quite complex and may include a variety of related problems, such as joint dysfunction, and faulty movement patterns, chronic pain and cognitive and higher center dysfunction.

When the cervical spine (neck) is subject to a whiplash injury, there is usually a combination of factors that contribute to the pain. These factors must be addressed individually, while maintaining a "holistic" view of the patient. The most significant factors may include one or more of the following: joint dysfunction, muscle dysfunction, and faulty movement patterns.

Joint dysfunction This occurs when one of the joints in the spine or limbs loses its normal joint play (resiliency and shock absorption). It is detected through motion pal- pation, a procedure in which the doctor gently moves the joint in different directions and assesses its joint play. When a joint develops dysfunction, its normal range of movement may be affected and it can become painful. In addition, joint dysfunction can lead to a muscle imbalance and muscle pain and a vicious cycle. The loss of joint play can cause abnormal signals to the nervous system (there are an abundance of nerve receptors in the joint). The muscles related to that joint can subsequently become tense or, conversely, underactive. The resulting muscle imbalance can place increased stress on the joint, aggravating the joint dysfunction that already exists.

Muscle dysfunction

When joint dysfunction develops, muscles are affected. Some muscles respond by becoming tense and overactive, while others respond by becoming inhibited and underactive. In either case, these muscles can develop trigger points. Trigger points are areas of congestion within the muscle where sensitizing compounds accumulate. These sensitizing compounds can irritate the nerve endings within the muscle and produce pain. This pain can occur in the muscle itself or can be referred pain (perceived in other areas of the body). Muscle related mechanisms may also give rise to abnormal signaling to the nervous system. This event can subsequently cause disruption of the ability of the nervous system to properly regulate muscles in other parts of the body, leading to the development of faulty movement patterns.

Faulty movement patterns It is thought that the intense barrage of pain signals from a traumatic injury to the cervical spine can change the way the nervous system controls the coordinated function of muscles. The disruption of coordinated, stable movement is known as faulty movement patterns. Faulty movement patterns cause increased strain in the muscles and joints, leading to pain. They can involve the neck itself or can arise from dysfunction in other areas of the body such as the foot or pelvis. Instability is also considered part of faulty movement patterns. There are 2 types of instability that can occur in whiplash: passive instability — the ligaments of the neck are loosened, and dynamic instability — the nervous system disruption causes a disturbance in the body's natural muscular response to common, everyday forces. As a result of instability, even mild, innocuous activities can become painful. Summary of the invention It is now well known that sciatic pain does not develop unless there is both presence of disc-derived cytokines that sensitizes the axons in the nerve root to produce pain when mechanically deformed, and a mechanical compo- nent(01marker, Iwabuchi et al. 1998; Olmarker and Myers 1998). The herniated nucleus pulposus must be assumed to be semi-liquid and gelatinous at the time of hemiation. This would be a prerequisite for the nucleus pulposus to leak out, or to herniate, from the connective tissue capsule (annulus fibrosus) that separates it from the spinal canal under normal circumstances. The fi- brotic, hard nodule, i.e. the disc hemiation, that may be seen by radiology and that is excised at surgery, is not the same tissue as the freshly herniated nucleus pulposus. It must therefore be considered unlikely that the gelatinous tissue herniating from the disc space would exert any mechanical deformation on the nerve root at the time of hemiation. Therefore, we would not have the mechanical component that is essential for inducing the sciatic pain. One may instead assume that the semi-liquid nucleus pulposus after hemiation is just "smearing" the inside of the spinal canal rather than compressing a nerve root. At this time point, radiological investigation will not reveal any disc herni- ation. After some time the hemiation may heal, and the result will be a scar tissue formation that protrudes slightly from the annulus fibrosus into the spinal canal. This protrusion is now organized and comprises connective tissue and may be visualized by radiology and will thereby bear the characteristics of what is generally considered to be a disc hemiation. This scenario has also been seen in rats undergoing experimental disc hemiation. At the time of incision of the annulus fibrosus one may, after injection of air and slight manipulation of the spinal column, induce a leakage of nucleus pulposus, i.e. a disc her- niation. The nucleus pulposus is gel-like and easily be "smeared" onto the adjacent neural structures. When reoperating such rats after 4 weeks for harvest of nerve specimens, one may see a distinct nodule at the place of the incision. This nodule is hard and closely mimics the disc herniations that may be seen by radiology and that are excised at surgery in human cases.

Considering that there are nerves and nerve-receptors at the surface of the annulus one may assume that a leakage of nucleus pulposus, which com- prises a number of substances known to induce nerve irritation, will in fact induce irritation of these local nerves and thus induce low back pain. Although not producing sciatica, thus rendering it to be "silent" in this regard, the nucleus pulposus leakage induces low back pain according to the suggested pathophysiological mechanism.

Low back pain in relation to sciatica

It is known that sciatica is often preceded by a few days of low back pain. Sciatica is the result of a combination of sensitization of the nerve root by hemiated nucleus pulposus and mechanical deformation(01marker, Iwabuchi et al. 1998; Olmarker and Myers 1998). One may therefore assume that at disc hemiation, the hemiated nucleus pulposus will first reach the outer annulus and produce low back pain due to stimulation of the local nerves and nerve receptors and later induce sciatica when it may reach the nerve root. If we consider that all cases of sciatica and all cases of silent disc herniations have experienced low back pain at some point there will be a considerable number of cases. The life time prevalence of sciatica is 25%, and if 1/3 of all persons not having sciatica display "silent" disc herniations they will comprise 1/3 of 75% which would be 25%. Together the lifetime prevalence of low back pain due to hemiation of disc material should be 50% in an adult population. This relates well to the lifetime prevalence of low back pain that is 60-80%. The remaining 10-30% may be due to other causes such as tumor and infection.

Mechanism inducing the leakage of nucleus pulposus out into the spinal canal from the disc space

There may be various causes that may initiate a leakage of disc material out into the spinal canal. The most important prerequisite would be various degrees of disc degeneration. It is known that disc degeneration starts as early as 20 years of age and induce biochemical changes of the nucleus pulposus and a disintegration of the annulus fibrosus. It is also known that there are annular tears in the annulus fibrosus that may result in leakage of nucleus pulposus ma- terial out into the spinal canal(Hilton, Ball et al. 1980; Osti, Nemon-Roberts et al. 1992). Such leakage of nucleus pulposus material only results in a minor volume and is not equivalent to a disc hemiation. There would thus not be any sciatic pain but low back pain might occur as the result of stimulation of the infra spinal nerve-receptors. Another major cause of disc injury leading to leakage of disc-derived substances is spine trauma. Spinal injury may be acquired by axial loads, side bending, flexion-extension, axial compression or extension, torsion or as the combination of one or more of these motions. One particularly interesting cause is the "whiplash" injury that due to a quick whiplash movement induces high stresses on the intervertebral discs with obvious risks for disc injury. All these changes may result in leakage of disc material that may be the direct cause of both acute and chronic low back pain as well as whiplash associated disorder.

Primary and secondary changes in low back pain In low back pain patients it is very common to see muscular pain and tenderness. Muscular injury is probably not the primary cause of back pain but rather a secondary phenomenon to disc injury. It is well known that activation of visceral afferents may induce a secondary contraction of the skeletal muscles located superficial to the site of injury. It is therefore reasonable to think that activation of nerve receptors within the spinal canal may induce a reflec- tory contraction of the local muscles in the lumbar spine. The proper management of the muscle pain in such case would be to block the irritation of the nerve receptor and not by symptomatic treatment of the muscle or with stabilization or inacti vation achieved by orthoses. The inventors of the present invention have thus found that one common cause for low back pain and whiplash associated disorder (WAD) is due to or related to local stimulation and/or irritation of nerve fibers and receptors located in the spine and within the spinal canal, rather than to nerve injury per se. The inventors have found that this stimulation and/or irritation is due to leak- age of disc-derived substances, or nucleus pulposus material, from the intervertebral disc out into the epidural space of the spinal canal. These disc-derived substances will sensitize and irritate the local nerves and nerve-receptors within the spinal canal, primarily at the surface of the annulus fibrosus and the posterior longitudinal ligament. The leakage is the result of either degenerative changes of the intervertebral disc or the result of trauma.

There are several substances in the nucleus pulposus of the intervert- abral disc that may irritate the nerves in this way. Such substances include pro- inflammatory cytokines, such as TNF, IL-lα, IL-lβ, IL-6, eicosanoids, such as prostaglandins and leukotriens, and other substances such as metallopro- teinases, nitric oxide, hydrogen ions and glycoprotein. The inventors have found that it is possible to treat low back pain and whiplash associated disorder (WAD) by pharmacological inhibition of these disc related substances that may irritate local nerve fibers at the outer annulus fibrosus and other related structures such as the posterior longitudinal liga- ment.

The invention thus relates to the use of a substance that inhibits discrelated substances which have a nerve irritating effect for the production of a pharmaceutical composition for treatment of low back pain and/or whiplash associated disorder (WAD). The invention also relates to a method for treatment of low back pain, and/or whiplash associated disorder (WAD), wherein a substance that inhibits disc-related substances which have a nerve irritating effect is administered to a patient in an therapeutically effective amount.

The characterizing features of the invention will be evident from the following description and the appended claims.

Detailed description of the invention Also for the purpose of this disclosure, the terms "blocking agent", "blocking substance", "inhibitor" and "antagonist" are used interchangeably. The term "patient", as it is used herein, relates to any human or non- human mammal in need of treatment according to the invention, i.e. a human or non-human mammal suffering from low back pain and/or whiplash associated disorder (WAD).

The term "treatment" used herein relates to both treatment in order to cure or alleviate a disease or a condition, and to treatment in order to prevent the development of a disease or a condition. The treatment may either be performed in an acute or in a chronic way.

There are several different types of substances and pharmacological preparations that block substances that have irritant effect on nerves that may be used according to the invention:

^■ Specific Interleukin-1 alfa and beta (IL-lα and IL-1 β) blocking substances, such as:

- Monoclonal antibodies; - Soluble cytokine receptors;

- IL-1 type II receptor (decoy RII) - Receptor antagonists; IL-lra, (Orthogen®, Orthokin®)

- Antisense oligonucleotides;

■ Non-specific Interleukin-1 alfa and beta (IL-1 α and IL-1 β) blocking substances, such as - MMP inhibitors (i.e. matrix metalloproteinase inhibitors),

• Tetracyclines, for example Doxycycline, Trovafloxacin, Lymecy- cline, Oxitetracycline, Tetracycline, Minocycline, and synthetic tet- racycline derivatives, such as CMT, i.e. Chemically Modified Tetracyclines; • Prinomastat (AG3340)

Batimastat

Marimastat

BB-3644

KB-R7785 • TIMP- 1 , TIMP-2, adTIMP- 1 (adenoviral delivery of TIMP- 1), adTIMP-2 (adenoviral delivery of TIMP-2)

- Quinolones (chinolones), for example Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, Temafloxacin;

- Prostaglandins; Iloprost (prostacyclin);

- Phosphodiesterase I, II, III, IN, and N-inhibitors; CC-1088, Ro 20-1724, rolipram, amrinone, pimobendan, vesnarinone, SB 207499

■ Specific Interleukin-6 (IL-6) blocking substances, such as: - Monoclonal antibodies;

- Soluble cytokine receptors;

- Receptor antagonists;

- Antisense oligonucleotides;

■ Non-specific Interleukin-6 (IL-6) blocking substances, such as: - MMP inhibitors (i.e. matrix metalloproteinase inhibitors)

• Tetracyclines, for example Doxycycline, Lymecycline, Oxitetracycline, Tetracycline, Minocycline, and synthetic tetracycline derivatives, such as CMT, i.e. Chemically Modified Tetracyclines;

• Prinomastat (AG3340) • Batimastat

• Marimastat • BB-3644

• KB-R7785

• TIMP-1, TIMP-2, adTIMP-1 (adenoviral delivery of TIMP-1), adTIMP-2 (adenoviral delivery of TIMP-2) - Quinolones (chinolones), for example Norfloxacin, Levofloxacin,

Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, Temafloxacin,

- Prostaglandins; Iloprost (prostacyclin) - Cyclosporin

- Pentoxifyllin derivates

- Hydroxamic acid derivates

- Phosphodiesterase I, II, III, IN, and N-inhibitors; CC-1088, Ro 20-1724, rolipram, amrinone, pimobendan, vesnarinone, SB 207499 - Melanin and melancortin agonists; HP-228

^■ Specific Interleukin-8 (IL-8) blocking substances, such as:

- Monoclonal antibodies;

- Soluble cytokine receptors;

- Receptor antagonists; - Antisense oligonucleotides;

■ Non-specific Interleukin-8 (IL-8) blocking substances, such as:

- Quinolones (chinolones), for example Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, Temafloxacin,

- Thalidomide derivates, e.g. SelCID, i.e. Selective Cytokine inhibitors, such as; CC-1088, CDC-501, CDC-801 and Linomide (Roquininex®)

- Lazaroids

- Cyclosporin - Pentoxifyllin derivates

^■ Specific interferon-gamma (IFN-γ) blocking substances, such as:

- Monoclonal antibodies;

- Soluble cytokine receptors;

- Receptor antagonists; - Antisense oligonucleotides;

^■ Non-specific interferon-gamma (IFN-γ) blocking substances, such as: - MMP inhibitors (i.e. matrix metalloproteinase inhibitors)

■ Tetracyclines, for example Doxycycline, Trovafloxacin, Lymecy- cline, Oxitetracycline, Tetracycline, Minocycline, and synthetic tetracycline derivatives, such as CMT, i.e. Chemically Modified Tetracyclines;

Prinomastat (AG3340) Batimastat Marimastat BB-3644 • KB-R7785

TIMP-1, TIMP-2, adTIMP-1 (adenoviral delivery of TIMP-1), adTIMP-2 (adenoviral delivery of TIMP-2)

- Quinolones (chinolones), for example Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin,

Pefloxacin, Lomefloxacin, Temafloxacin, Rebamipide, and Nalidixic acid

- Lazaroids

- Pentoxifyllin derivates - Phosphodiesterase I, II, III, IN, and V-inhibitors; CC-1088, Ro 20-1724, rolipram, amrinone, pimobendan, vesnarinone, SB 207499 ^■ Specific nitric oxide blocking substances, such as:

- Monoclonal antibodies;

- Soluble cytokine receptors; - Receptor antagonists;

- Antisense oligonucleotides;

- ΝO-synthase inhibitors, such as

• Aminoguanidine and derivates

• Ν(omega)-nitro-L-arginine methyl ester (L-NAME) ^■ Non-specific nitric oxide blocking substances, such as:

- MMP inhibitors (i.e. matrix metalloproteinase inhibitors)

• Tetracyclines, for example Doxycycline, Trovafloxacin, Lymecy- cline, Oxitetracycline, Tetracycline, Minocycline and synthetic tetracycline derivatives, such as CMT, i.e. Chemically Modified Tetracy- clines;

• Prinomastat (AG3340) Batimastat Marimastat BB-3644 KB-R7785

- Quinolones (chinolones), for example Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, and Temafloxacin

- Thalidomide derivates , e.g. SelCID, i.e. Selective Cytokine inhibitors, such as thalidomide-derivate; CC-1088, CDC-501, CDC-801, and Li- nomide (Roquininex®);

- Lazaroids; - Pentoxifyllin derivates

- Phosphodiesterase III and IV-inhibitors; CC-1088 Amrinone, Pimoben- dan, Nesnarinone

- Melancortin agonists; HP-228

■ Specific eicosanoid blocking substances, such as: - Monoclonal antibodies;

- Soluble cytokine receptors;

- Receptor antagonists;

- Antisense oligonucleotides;

■ Non-specific eicosanoid blocking substances, such as: - MMP inhibitors (i.e. matrix metalloproteinase inhibitors)

• Tetracyclines, for example Doxycycline, Trovafloxacin, Lymecy- cline, Oxitetracycline, Tetracycline, Minocycline, and synthetic tetracycline derivatives, such as CMT, i.e. Chemically Modified Tetracyclines; • Prinomastat (AG3340)

Batimastat Marimastat BB-3644 KB-R7785 - Quinolones (chinolones), for examples Norfloxacin, Levofloxacin,

Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, and Temafloxacin;

- betalactamases; penicillium, fenoximethylpenicillium, cephalosporin;

- macrolids; sirolimus, spiramycin, tilmicosin, tylosin, kitasamicin, josamicin, erythromycin, oleandomycin;

- Thalidomide derivates, e.g. SelCID, i.e. Selective Cytokine inhibitors, such as thalidomide-derivate; CC-1088, CDC-501, CDC-801, and Li- nomide (Roquininex®);

- Cyclosporin ■ Inhibitors of eicosanoid synthesis enzymes, such as:

- Inhibitors of phospholipas A2 (PLA A2)

• Monoclonal antibodies

• Lidocaine

• Pyrrophenone ■ Mepacrine

- NSAID, i.e. non-steroidal anti-inflammatory dmgs, or inhibitors of cyclooxygenase 1 and 2 (COX) (prostaglandin synthesis inhibitors), such as:

Monoclonal antibodies • Ibuprofene

Indomethacine celecoxib, refecoxib, meloxicam corticosteroids acetylsalicylic acid • naproxene diclofenac

The substance or pharmaceutical composition according to the invention is administered once or repeatedly until a sustained improvement of the pa- tient's condition is observed. The substance or pharmaceutical composition according to the invention is administered in a therapeutically effective amount, i.e. an amount that will lead to the desired therapeutical effect and thus lead to an improvement of the patient's condition.

The pharmaceutical composition according to the invention may also comprise other substances, such as an inert vehicle, or pharmaceutical accept- able adjuvants, carriers, preservatives etc., which are well known to persons skilled in the art.

According to one preferred embodiment of the invention, the pharmaceutical composition is formulated as a sustained-release preparation. The sub- stance according to the invention may then, for example, be encapsulated in a slowly-dissolving biocompatible polymer.

The substances or pharmaceutical compositions according to the invention may be administered in any efficacious way. The substances or pharmaceutical compositions according to the invention may for example be injected via infra-articular, intravenous (i.v.), intramuscular (i.m.), intraperitoneal (i.p.), intrathecal (i.t), epidural, intracerebroventricular (i.c.v.) or subcutaneous (s.c.) routes by bolus injections or by continuous infusion. They may also be administered orally (per os), e.g. in the form of oral preparations, such as pills, syrups, or lozenges. Furthermore, they may be administered by inhalation. They may also be administered infranasally. Moreover, they may be administered transepidermally, e.g. in the form of topical preparations such as lotions, gels, sprays, ointments or patches. Finally, they may also be administered by geneti- cal engineering.

Examples of suitable doses for different administration routes are given below.

Per os 10-300 mg i.m. 25-100 mg i.v. 2.5-25 mg i.t. 0.1-25 mg daily - every 3 ^rd month inhalation 0.2-40 mg transepidermally 10-100 mg infranasally 0.1-10 mg s.c. 5-10 mg i.c.v. 0.1-25 mg daily - every 3^rd month eeppiidduurraallllyy 1-100 mg

Examples of suitable doses for different substances according to the invention are given below. Preferred More Most dosage preferred preferred dosage dosage

Iloprost i.v. 0.1-2000 1-1500 100-1000

(all doses given in μg/kg body weight/day) infranasally 50-250 100-150 100-150

(all doses given in μg/day) CC-1088

Per os 50-1200 200-800 400-600

(all doses given in mg/day) Linomide

(Roquinimex®)

Per os 0.1-25 5-20 10-15

(all doses given in mg/kg body weight/day)

HP-228 i.v. 5-100 10-50 20-40

(all doses given in μg/kg body weight)

Ariflo® SB 207499 Per os 10-100 30-60 30-45

(all doses given in mg/day)

KB-R7785 s.c. 100-500 100-300 150-250

(all doses given in mg/kg body weight/day)

Prinomastat (AG3340) Per os 1-250 5-100 10-50

(all doses given in mgfor administration twice daily)

Batimastat Per os 1-250 5-100 10-50

(all doses given in mgfor administration twice daily) Marimastat

Per os 1-250 5-100 10-50

(all doses given in mgfor administration twice daily)

CDC-501

Per os 50-1200 200-800 400-600

(all doses given in mg/day)

CDC-801

Per os 50-1200 200-800 400-600 (all doses given in mg/day)

It is possible to use either one or two or more substances according to the invention in the treatment of LBP. When two or more substances are used they may be administered either simultaneously or separately. The substances according to the invention may also be administered in combination with other drugs or compounds, provided that these other drugs or compounds do not eliminate the effects desired according to the present invention, to inhibit or block nerve-irritating disc-related substances.

It is understood that the response by individual patients to the sub- stances according to the invention or combination therapies, may vary, and the most efficacious combination of drugs for each patient will be determined by the physician in charge.

The invention also provides a diagnostic preparation and a method for diagnosis. According to this method the diagnostic preparation or a substance according to the invention is administered to a patient suspected of suffering from low back pain. An improvement of the patient's condition an indication of that the patient is afflicted with low back pain or whiplash associated disorder. The invention is further illustrated in the experiments and the example below, which are only intended to illustrate the invention and should in no way be considered to limit the scope of the invention.

Experiments I - Formation of a disc hernia in the rat following disc incision

A total of 15 Sprague Dawley rats were anaesthetized and a facetectomy of the left L4-5 facet-joint was performed. Through this exposure the L4-5 intervertebral disc was incised using a 0.4 mm diameter injection needle. The wound was closed and the rats were killed after 1 week (n=5), 2 weeks (n=5), and 4 weeks (n=5) for analysis. The analyses comprised a macro-anatomic assessment regarding degree of fibrosis at the operation site, inflammation at the site of operations, healing of the disc incision, height of the scar formed at the surface of the disc incision (disc hemiation tissue) from the disc surface, and consistency of this tissue. In selected cases the disc hernia was processed for light microscopic analysis.

Just after the incision there was of course no fibrosis, inflammation or healing of the incision. Neither was there any scar formation formed at the place of incision. In some cases the incision resulted in a slight leakage of the nucleus pulposus out into the spinal canal.

One week after the incision, there was no fibrosis and only one case with inflammatory reaction. Two of five discs were considered to be healed after the incision. Three of five discs displayed disc scars that resembled disc herniations.

Two weeks after the incision, fibrosis was more pronounced than after one week whereas inflammatory changes were similar. Healing of the disc was present in all five animals. Similar to the discs observed after one week, these discs showed scar tissue formation in three out of five discs. Four weeks after incision, slight fibrosis was seen in all animals but no inflammation. Four of the five discs showed healing and slight to pronounced formation of scar tissue resembling disc herniations. One disc was still open and had no scar formation.

Microscopic evaluation showed that the scar tissue comprised collagen and various cell- types. These were mainly fibroblasts but there were also inflammatory cells and chondrocyte-like cells, presumably disc cells. The results are illustrated in Table I below.

Table I ^■ - Disc incision in the rat

Disc

F I H h. c.

1 week:

0 0 0 0 0

0 0 + (+) +

0 0 + 0 0

0 0 0 ++ (+)

0 + 0 ++ (+)

2 weeks:

(+) 0 + (+) (+)

+ + + ++ (+)

0 0 + 0 0

0 0 (+) (+) (+)

(+) 0 + 0 0

4 weeks:

(+) 0 + ++ (+)

(+) 0 0 0 0

(+) 0 + ++ +

(+) 0 + + (+)

(+) 0 + (+) +

F = fibrosis, I = inflammation, H = healing of disk incision,

Disc h = height of formed disc hernia, Disc c = consistency of formed disc hernia.

F, I, H, Disc h Disc c

0 = no changes 0 = nothing

(+) = slight changes (+) = soft

+ = clear changes + = hard and elastic

++ = pronounced changes ++ = hard like bone

II - Fate of acutely injected nucleus pulposus into the epidural space of pigs Nucleus pulposus from intervertebral discs from pigs used for other purposes were harvested. The nucleus pulposus was mixed with barium sul- phate powder (Mixobar® High Density, Astra Tech, Molndal, Sweden) and a soluble iodine-contrast medium (Urografm®, Schering AG, Berlin, Germany). Approximately 0.5 teaspoon of Mixobar powder and 0.2ml of Urografm was added to the content of two intervertebral discs. Great care was taken to preserve the physical properties of the nucleus pulposus. In a total of three dead pigs used for other purposes the 3 lumbar vertebra was exposed through an abdominal approach. An injection needle (approximately 1 mm in diameter) connected to a syringe with the prepared nucleus pulposus was entered through the disc to the spinal canal under ffuoro- scopic guidance. The tip of the injection needle was placed in the spinal canal just outside the disc at the dorsolateral portion of the disc, i.e. where most disc herniations occur. The volume of 1 - 1.5 intervertebral discs of prepared nucleus pulposus was slowly injected into the spinal canal, thus performing an experimental acute disc hemiation. The distribution of the radiopaque nucleus pulposus was studied using a digital X-ray equipment and images were col- lected.

Contrary to what could be expected from the common understanding, the nucleus pulposus did not form a bulge or nodule that compressed the nerve tissue of the spinal canal. Instead, the nucleus pulposus was evenly spread in the spinal canal and did not compress the either the nerve root or the thecal sac.

III - Disc incision on the antero-ventral aspect of lumbar intervertebral discs in the pig

One pig was anaesthetized by an intramuscular injection of 20 mg/kg body weight of Ketalar (ketamine 50mg/ml; Parke-Davis, Morris Plains, New Jersey), an intravenous injection of 20 mg/kg body weight of Hypnodil (methomidate chloride 50 mg/ml; AB Leo, Helsingborg, Sweden), and 0.1 mg/kg body weight of Stresnil (azaperon 2 mg/ml; Janssen Pharmaceutica, Beerse, Belgium). Anesthesia was maintained by additional intravenous injections of 2 mg/kg body weight of Hypnodil and 0.05 mg/kg body weight of Stresnil.

Using a retroperitoneal approach, the antero-ventral aspect of the disc between the 4^th and 5^th lumbar vertebrae was exposed. The annulus fibrosus was incised using a scalpel. The wound was closed and one week later the pig was reanaesthetized and killed by an overdose of potassium chloride. The 4* and 5^th lumbar vertebrae including the incised disc were removed en bloc. Macroscopic examination revealed that the disc had healed with a fi- brotic scar. The scar was dense and mainly comprised collagen and various cell-types at microscopic examination. The cells were mainly fibroblasts, but there were also inflammatory cells and cartilage-like cells in the newly formed scar.

Summary of the data of the three experiments

It is generally assumed that when an intervertebral disc herniates, the viscous center of the disc (nucleus pulposus) is pressed out of the disc through an opening in the annulus fibrosus and forms a hard nodule at the surface of the disc that compresses the adjacent nerve root. This is thought to be the mechanism inducing nerve root pain (i.e. sciatica). However, it is not understood why disc herniations may be accidentally seen in almost a third of all persons undergoing radiological examination that has never had sciatica. Such asymptomatic disc herniations are called "silent disc herniations". The data from the three experimental studies clearly demonstrate that confrary to what is believed, acutely hemiated nucleus pulposus does not compress infra spinal nervous tissues since it is semi-fluid in consistency at the time of hemiation. Instead, the hard nodule that may compress a nerve root is a scar that is formed at the surface of the disc as the result of nucleus pulposus leakage. Since nerve root pain may only occur due to the combined action of sensitization of the nerve by nucleus pulposus derived cytokines and simultaneous mechanical deformation of the nerve tissue, nerve root pain will not occur since the acutely hemiated nucleus pulposus will not mechanically affect the nerve root. When a scar is formed at the disc surface, which may induce mechanical deformation of the adjacent nerve root, the cytokine-activity is no longer present in the herniated nucleus pulposus. In this situation we thus have a "silent disc hemiation" that may be observed by radiological examination. However, the next time there will be leakage of nucleus pulposus from the same or adjacent discs, we have a situation of both sensitization and mechanical deformation, which will result in nerve root pain.

Example A 38-year male presented at the department where the inventors work with radiating pain corresponding to the 5* lumbar nerve root on the right side since 3 days. He had a disc hemiation at magnetic resonance imaging (MRI) and was diagnosed as having sciatica due to disc hemiation. In addition, he had also pain in the region of the neck that radiated out into both arms after a vehicle accident 2.5 months earlier, which had been diagnosed as a Whiplash Associated Disorder. In order to try to reduce his sciatica he received an intravenous injection of 2.5 ml of Orthogen® (IL-1 ra, Interleukin-1 receptor antagonist) dissolved in 2.5 ml saline. The day after the injection the patient reported that the sciatic pain was markedly reduced. However, his problems in the neck region were also greatly improved. He reported that he only experienced minor stiffness in the neck and the radiating pain in the arms had more or less disappeared. At the follow-up examination 1 week later he reported that he only suffered minor pain in the legs and also in the neck. Four weeks after the injection he considered himself free of symptoms, and this was the case also at the final follow-up examination at 8 weeks.

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Claims

1. Use of a substance that inhibits disc-related nerve-irritating substances for the production of a pharmaceutical composition for treatment of low back pain and/ or whiplash associated disorder (WAD).

2. Use of a substance that inhibits disc-related nerve-irritating substances for the production of a diagnostic preparation for diagnosis of low back pain and/or whiplash associated disorder (WAD).

3. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a monoclonal antibody.

4. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a soluble cytokine receptor.

5. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a receptor antagonist.

6. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is an antisense oligonucleotide

7. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is an MMP inhibitor selected from the group consisting of tetracyclines, chemically modified tetracyclines, Prinomas- tat, Batimastat, Marimastat, KB-R7785, TIMP-1, TIMP-2, adTIMP-1 and ad- TIMP-2.

8. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is an quinolones selected from the group consisting of Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Te- mafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin,

Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, and Temafloxacin.

9. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a thalidomide derivate selected from the group consisting of CC-1088, CDC-501, CDC-801 and Linomide

10. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is selected from the group consisting of prostaglandins, phosphodiesterase I, II, III, IV, and V-inhibitors, cyclosporin, pentoxifyllin derivates, hydroxamic acid derivates, melanin and melancortin agonists, lazaroids, NO-synthase inhibitors, N(omega)-nitro-L-arginine methyl ester, inhibitors of eicosanoid synthesis enzymes, lidocaine, pyrrophenone, mepacrine and NSAID.

11. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a specific IL-l and/or IL-lβ block- ing substance.

12. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a non-specific IL-lα and/or IL-lβ blocking substance.

13. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a specific IL-6 blocking substance.

14. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a non-specific IL-6 blocking substance.

15. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a specific IL-8 blocking substance.

16. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a non-specific IL-8 blocking substance.

17. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a specific IFN-γ blocking substance.

18. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve- irritating substances is a non-specific IFN-γ blocking substance.

19. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a specific nitric oxide blocking substance.

20. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a non-specific nitric oxide blocking substance.

21. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a specific eicosanoid blocking substance.

22. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is a non-specific eicosanoid blocking substance.

23. Use according to claim 1 or 2, wherein said substance that inhibits disc-related nerve-irritating substances is an eicosanoid synthesis enzyme inhibitor.

24. A method for treatment of low back pain or whiplash associated disorder (WAD) wherein a therapeutically effective amount of a substance that inhibits disc-related nerve-irritating substances is administered to a patient.

25. A method for diagnosis of low back pain or whiplash associated disorder (WAD) wherein a diagnostically effective amount of a substance that inhibits disc-related nerve-irritating substances is administered to a patient, and an improvement of the patient's condition is an indication of that the patient is afflicted with low back pain or whiplash associated disorder.

26. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a monoclonal antibody.

27. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a soluble cytokine receptor.

28. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a receptor antagonist.

29. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is an antisense oligonucleotide

30. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is an MMP inhibitor selected from the group consisting of tetracyclines, chemically modified tetracyclines, Prinomastat, Batimastat, Marimastat, KB-R7785, TIMP-1, TIMP-2, adTIMP-1 and adTIMP-2.

31. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is an quinolones selected from the group consisting of Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin, and Te- mafloxacin.

32. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a thalidomide derivate selected from the group consisting of CC-1088, CDC-501, CDC-801 and Li- nomide.

33. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is selected from the group con- sisting of prostaglandins, phosphodiesterase I, II, III, IV, and V-inhibitors, cyclosporin, pentoxifyllin derivates, hydroxamic acid derivates, melanin and mel- ancortin agonists, lazaroids, NO-synthase inhibitors, N(omega)-nitro-L- arginine methyl ester, inhibitors of eicosanoid synthesis enzymes, lidocaine, pyrrophenone, mepacrine and NSAID.

34. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a specific IL-lα and/or IL-lβ blocking substance.

35. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a non-specific IL-lα and/or

IL-lβ blocking substance.

36. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a specific IL-6 blocking substance.

37. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a non-specific IL-6 blocking substance.

38. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a specific IL-8 blocking sub- stance.

39. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a non-specific IL-8 blocking substance.

40. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a specific IFN-γ blocking substance.

41. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a non-specific IFN-γ blocking substance.

42. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a specific nitric oxide blocking substance.

43. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a non-specific nitric oxide blocking substance.

44. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a specific eicosanoid blocking substance.

45. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is a non-specific eicosanoid blocking substance.

46. A method according to claim 24 or 25, wherein said substance that inhibits disc-related nerve-irritating substances is an eicosanoid synthesis enzyme inhibitor.