WO2002080891A1

WO2002080891A1 - Use of a tnf inhibitor for the treatment of low back pain

Info

Publication number: WO2002080891A1
Application number: PCT/SE2002/000671
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: SE0101256D0

Abstract

The use of a TNF inhibitor for the production of a pharmaceutical composition for treatment of low back pain and in particular of low back pain due to local irritation of annulus related nerve fibers by disc derived substances. Also a method for treatment of low back pain is disclosed.

Description

Use of a TNF inhibitor for the treatment of low back pain

Field of the invention The present invention relates to substances, pharmaceutical compositions and methods for treatment of low back pain.

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 intra 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 dif- ferent 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 examination, 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 herniations is intriguing to the spine research community and seems to contradict the relationship between disc herniations and sciatica.

Scientific knowledge ofthepathophysiologic 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- fibers (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 an- nular 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. 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 (Olmarker, 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 herniation. 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 herniation, 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 herniation. Therefore, we would not have the me- chanical component that is essential for inducing the sciatic pain. One may instead assume that the semi-liquid nucleus pulposus after herniation 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 herniation. After some time the herniation 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 herniation. This scenario has also been seen in rats undergoing experimental disc herniation. At the time of inci- sion 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 herniation. The nucleus pulposus is gel-like and could 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 comprises a number of substances known to induce nerve irritation, will in fact in- duce 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 nu- cleus 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 herniated nucleus pulposus and mechanical deformation (Olmarker, Iwabuchi et al. 1998; Olmarker and Myers 1998). One may therefore assume that at disc herniation, the herniated 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 herniation 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 material out into the spinal canal (Hilton, Ball et al. 1980; Osti, Nernon-Roberts et al. 1992). Such leakage of nucleus pulposus material only results in a minor volume and is not equivalent to a disc herniation. There would thus not be any sciatic pain but low back pain might occur as the result of stimulation of the intra 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.

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 manage- ment 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 inactivation achieved by orthoses.

The inventors of the present invention have thus found that one common cause for low back pain of unknown origin is due to or related to local stimula- tion 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 leakage 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 sensi- tize 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, and thereby produce low back pain. The leakage would be the result of either degenerative changes of the intervertebral disc or the result of disease or trauma. The inventors have found that it is possible to treat low back pain by pharmacological inhibition of the disc related substance TNF that may irritate local nerve fibers at the outer annulus fibrosus and other related structures such as the posterior longitudinal ligament.

Low back pain suitable for treatment according to the invention may be the result of unknown causes (idiopathic) or be related to various kinds of spine trauma, including whiplash injury. The treatment is also efficient in cases of low back pain where secondary changes are predominant, such as muscular tenderness.

The invention thus relates to the use of a TNF inhibitor for the production of a pharmaceutical composition for treatment of low back pain and in particular of low back pain due to local irritation of annulus related nerve fibers by disc derived substances.

The invention also relates to a method for treatment of low back pain and in particular of low back pain due to local irritation of annulus related nerve fibers by disc derived substances, wherein a TNF blocking agent or a TNF antagonist that is capable of reducing the effective amount of endogenous biologically active TNF, e.g. by reducing the amount of TNF produced, or by preventing the binding of TNF to its cell surface receptor, TNRF, is administered to a patient.

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

Detailed description of the invention For the purpose of this disclosure, TNF, tumor necrosis factor, denotes what earlier was known as TNF-α. Also for the purpose of this disclosure, the terms "TNF blocking agent",

"TNF blocking substance", "TNF inhibitor" and "TNF 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.

The "low back pain", or LBP, treatable according to the present invention is pain localized in the lumbar region, without radiation below the knees and without signs of neurological dysfunction.

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 TNF blocking substances and pharmacological preparations that may be used according to the invention: ^■ Specific TNF blocking substances, such as - Monoclonal antibodies, e.g. infliximab, CDP-571 (Humicade™), D2E7, and CDP-870;

- Soluble cytokine receptors, e.g. etanercept, lenercept, pegylated TNF- receptor type I, TBP-1 - TNF-receptor antagonists

- Antisense oligonucleotides; e.g. ISIS- 104838; on-specific TNF blocking substances, such as:

- MMP inhibitors (i.e. matrix metalloproteinase inhibitors, or TACE- inhibitors, i.e. TNF Alpha Converting Enzyme-inhibitors) • Tetracyclines, for example Doxycycline, Lymecycline, Oxitetracy- cline, 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, for example Norfloxacin, Levofloxacin, Enoxacin, Spar- floxacin, 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 derivative, for example CC-1088, CDC-501, CDC-

801, and Linomide (Roquininex®;)

- Lazaroids; nonglucocorticoid 21 -aminosteroids such asU-74389G (16- desmethyl tirilazad) and U-74500

- Prostaglandins; Iloprost (prostacyclin) - Cyclosporin

- Pentoxifyllin derivates

- Hydroxamic acid derivates

- Napthopyrans

- Phosphodiesterase I, II, III, IV, and V-inhibitors; CC-1088, Ro 20-1724, rolipram, amrinone, pimobendan, vesnarinone, SB 207499 (Ariflo®)

- Melancortin agonists; HP-228 ■ Others, such as:

- Lactoferrin, and peptides derived from lactoferrin such as those disclosed in WO 00/01730

- CT3 - ITF-2357

- PD- 168787

- CLX-1100

- M-PGA

- NCS-700 - PMS-601

- RDP-58

- TNF-484A

- PCM-4

- CBP-1011 - SR-31747

- AGT-1

- Solimastat

- CH-3697

- NR58-3.14.3 - RIP-3

- Sch-23863

- Yissum proj ect no . 11649

- Pharnia projects no. 6181, 6019 and 4657

- SH-636

The substance or pharmaceutical composition according to the invention is administered once or repeatedly until a sustained improvement of the patient'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 acceptable 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 substance 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 normally used to administer TNF inhibitors. The substances or pharmaceutical compositions according to the invention may for example be injected via intra-articular, intravenous (i.v.), intramuscular (i.m.), intraperitoneal (i.p.), intrathecal (i.t), epidural, intracere- broventricular (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 intrana- sally. 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 genetical 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 intranasally 0.1-10 mg s.c. 5-10 mg i.c.v. 0.1-25 mg daily - every 3^rd month epidurally 1-100 mg

Examples of suitable doses for different TNF inhibitors are given below.

Preferred More Most dosage preferred preferred dosage dosage Lenercept i.v. 5-200 10-100 30-80

(all doses given in mgfor administration once every 4^th week)

TBP-1

(all doses given in mgfor administration once every 4 i' week)

CDP-571

Humicade® i.v. 1-100 5-10 5-10

(all doses given in mg/kg body weight for administration as a single dose)

D2E7 i.v. 0.1-50 0.5-10 1-10 s.c. 0.1-50 0.5-10 1-10

(all doses given in mg/kg body weight for administration as a single dose)

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

(all doses given in μg/kg body weight/day) intranasally 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)

CDP-870 i.v. 1-50 2-10 3-8

(all doses given in mg/kg body weight for administration once every 4^{l l} week) s.c. 50-600 100-400 100-200

(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)

ISIS-104838

Per os 1-100 10-50 20-50

S.c. 1-100 10-50 20-50 i.v. 1-100 10-50 20-50 (all doses given in mg)

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, i.e. the effect on TNF.

It is understood that the response by individual patients to the substances 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 is an indication of that the patient has low back pain.

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 in- tervertebral 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 herniation 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 fϊbroblasts but there were also in- flammatory 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 + ++ -f^*

(+) 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, Mδlndal, Sweden) and a soluble iodine-contrast medium (Urografin®, Schering AG, Berlin, Germany). Approximately 0.5 teaspoon of Mixobar powder and 0.2 ml of Urografin 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^r 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 fluoro- 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 herniation. 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 contrary to what is believed, acutely herniated nucleus pulposus does not compress intra spinal nervous tissues since it is semi-fluid in consistency at the time of herniation. 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 herniated 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 herniation" 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 42-year old man was given infliximab, a selective monoclonal antibody that inhibits only TNF, at 5 mg/kg for treatment of Low Back Pain. The symptoms of his LBP were primarily pain in the lumbar region and muscular tenderness.

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Claims

I . Use of a TNF inhibitor for the production of a pharmaceutical composition for treatment of low back pain.

2. Use of a TNF inhibitor for the production of a diagnostic preparation for diagnosis of low back pain.

3. Use according to claim 1 or 2, wherein said low back pain is due to local irritation of annulus related nerve fibers by disc derived substances.

4. Use according to claim any one of the claims 1-3, wherein said TNF inhibitor is a specific TNF blocking substance.

5. Use according to claim 4, wherein said specific TNF blocking substance is an antibody.

6. Use according to claim 5, wherein said specific TNF blocking substance is a monoclonal antibody.

7. Use according to claim 6, wherein said monoclonal antibody is infliximab.

8. Use according to claim 6, wherein said monoclonal antibody is CDP-571.

9. Use according to claim 6, wherein said monoclonal antibody is CDP-870.

10. Use according to claim 6, wherein said monoclonal antibody is D2E7.

I I . Use according to claim 4, wherein said specific TNF blocking substance is a soluble cytokine receptor.

12. Use according to claim 11, wherein soluble cytokine receptor is etanercept.

13. Use according to claim 11 , wherein soluble cytokine receptor is lenercept.

14. Use according to claim 4, wherein said specific TNF blocking sub- stance is a TNF receptor antagonist.

15. Use according to claim 4, wherein said specific TNF blocking substance is an antisense oligonucleotide.

16. Use according to any one of the claims 1-3, wherein said TNF inhibitor is a non-specific TNF blocking substance.

17. Use according to claim 16, wherein said non-specific TNF blocking substance is an MMP inhibitor selected from the group consisting of tetra- cyclines, Prinomastat, Batimastat, Marimastat, BB-3644, KB-R7785, TIMP-1, TIMP-2, adTIMP-1 and adTIMP-2.

18. Use according to claim 16, wherein said non-specific TNF blocking substance is a quinolone selected from the group consisting or Norfloxacin, Levofloxacin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatiflox- acin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin, Lomefloxacin and Temafloxacin.

19. Use according to claim 16, wherein said non-specific TNF blocking substance is a thalidomide derivate selected from the group consisting of CC-1088, CDC-501, CDC-801, and Linomide.

20. Use according to claim 16, wherein said non-specific TNF blocking substance is selected from the group consisting of a lazaroids, nonglucocor- ticoid 21-aminosteroids, prostaglandins, cyclosporin, pentoxifyllin derivates, hydroxamic acid derivates, napthopyrans, phosphodiesterase I, II, III, IV, and V-inhibitors, elancortin agonists, lactoferrin, peptides derived from lactoferrin, CT3, ITF-2357, PD-168787, CLX-1100, M-PGA, NCS-700, PMS-601, RDP- 58, TNF-484A, PCM-4, CBP-1011, SR-31747, AGT-1, Solimastat, CH-3697, NR58-3.14.3, RIP-3, Sch-23863 and SH-636.

21. A method for treatment of low back pain wherein a therapeutically effective amount of a TNF inhibitor is administered to a patient.

22. A method for diagnosis of low back pain wherein a diagnostically effective amount of a TNF inhibitor 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.

23. A method according to claim 21 or 22 wherein said low back pain is due to local irritation of annulus related nerve fibers by disc derived substances.

24. A method according to claim 21 or 22, wherein said TNF inhibitor is a specific TNF blocking substance.

25. A method according to claim 21 or 22, wherein said TNF inhibitor is an antibody.

26. A method according to claim 21 or 22, wherein said TNF inhibitor is a monoclonal antibody.

27. A method according to claim 21 or 22, wherein said TNF inhibitor is infliximab.

28. A method according to claim 21 or 22, wherein said TNF inhibitor is CDP-571.

29. A method according to claim 21 or 22, wherein said TNF inhibitor is CDP-870.

30. A method according to claim 21 or 22, wherein said TNF inhibitor is D2E7.

31. A method according to claim 21 or 22, wherein said TNF inhibitor is a soluble cytokine receptor.

32. A method according to claim 21 or 22, wherein said TNF inhibitor is etanercept.

33. A method according to claim 21 or 22, wherein said TNF inhibitor is lenercept.

34. A method according to claim 21 or 22, wherein said TNF inhibitor is a TNF receptor antagonist.

35. A method according to claim 21 or 22, wherein said TNF inhibitor is an antisense oligonucleotide.

36. A method according to claim 21 or 22, wherein said TNF inhibitor is a non-specific TNF blocking substance.

37. A method according to claim 21 or 22, wherein said TNF inhibitor is an MMP inhibitor selected from the group consisting of tetracyclines, Pri- nomastat, Batimastat, Marimastat, BB-3644, KB-R7785, TIMP-1, TIMP-2, adTIMP-1 and adTIMP-2.

38. A method according to claim 21 or 22, wherein said TNF inhibitor is a quinolone selected from the group consisting or Norfloxacin, Levoflox- acin, Enoxacin, Sparfloxacin, Temafloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin, Grepafloxacin, Trovafloxacin, Ofloxacin, Ciprofloxacin, Pe- floxacin, Lomefloxacin and Temafloxacin.

39. A method according to claim 21 or 22, wherein said TNF inhibitor is a thalidomide derivate selected from the group consisting of CC-1088, CDC- 501, CDC-801, and Linomide.

40. A method according to claim 21 or 22, wherein said TNF inhibitor is selected from the group consisting of a lazaroids, nonglucocorticoid 21- aminosteroids, prostaglandins, cyclosporin, pentoxifyllin derivates, hydrox- amic acid derivates, napthopyrans, phosphodiesterase I, II, III, IV, and V- inhibitors, elancortin agonists, lactoferrin, peptides derived from lactoferrin CT3, ITF-2357, PD-168787, CLX-1100, M-PGA, NCS-700, PMS-601, RDP- , TNF-484A, PCM-4, CBP-1011, SR-31747, AGT-1, Solimastat, CH-3697, 58-3.14.3, RIP-3, Sch-23863 and SH-636.