EP1047414A1 - Gabapentin und seine derivate zur behandlungen von muskel und skelett-schmerzen - Google Patents

Gabapentin und seine derivate zur behandlungen von muskel und skelett-schmerzen

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Publication number
EP1047414A1
EP1047414A1 EP99904178A EP99904178A EP1047414A1 EP 1047414 A1 EP1047414 A1 EP 1047414A1 EP 99904178 A EP99904178 A EP 99904178A EP 99904178 A EP99904178 A EP 99904178A EP 1047414 A1 EP1047414 A1 EP 1047414A1
Authority
EP
European Patent Office
Prior art keywords
pain
gabapentin
day
muscular
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99904178A
Other languages
English (en)
French (fr)
Inventor
Leslie Magnus-Miller
Catherine A. Segal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
Original Assignee
Warner Lambert Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP1047414A1 publication Critical patent/EP1047414A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid

Definitions

  • the present invention relates to the use of analogs of glutamic acid and gamma-aminobutyric acid (GABA) for the treatment of muscular and skeletal pain. More particularly, the invention relates to the use of gabapentin for the treatment of non-neuropathic muscular and skeletal pain.
  • GABA gamma-aminobutyric acid
  • the compounds of the invention are known agents useful in antiseizure therapy for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, Parkinson's disease, tardive dyskinesia, and spasticity. It has also been suggested that the compounds can be used as antidepressants, anxiolytics, and antipsychotics. See WO 92/09560 (United States Serial Number 618,692 filed November 27, 1990) and WP 93/23383 (United States
  • WO 97/33858 teaches that compounds related to gabapentin are useful or treating epilespy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropathological disorders. WO 97/33858 does not specific what forms of pain are treated.
  • the compounds of the invention are known for treatment of neuropathic pain. For example, see Rosner H; Rubin L; Kestenbaum A.,
  • Gabapentin adjunctive therapy in neuropathic pain states Clin J Pain, 1996 Mar, 12:1, 56-8; Segal AZ; Rordorf G., Gabapentin as a novel treatment for postherpetic neuralgia. Neurology, 1996 Apr, 46:4, 1175-6; Wetzel CH; Connelly JF., Use of gabapentin in pain management. Ann Pharmacother, 1997 Sep, 31:9, 1082-3; Zapp JJ., Postpoliomyelitis pain treated with gabapentin [letter]. Am Fam -2- Physician, 1996 Jun, 53:8, 2442, 2445; Cheville A, et al., Neuropathic pain in radiation myelopathy: a case report.
  • Pain, 1997 Sept, 1393), pp. 251-3 discloses a retrospective review of patients that were treated with gabapentin. One of the groups of patients was reported to have low back pain. These patients did not report improved pain scores after using gapapentin.
  • Muscular and skeletal pain is caused by a variety of physical injuries or damage to the muscles, bones and tissues of the body.
  • a particularly debilitating form of this pain is chronic lower back pain.
  • Chronic lower back pain is a general condition of pain related to physical damage to the muscles (eg, muscle trauma or overexertion), bones (eg, osteoarthritis of the lumber spine) and/or tissues (eg, fibromyalgia) of the back.
  • Low back pain can also result from inflammation of the axial skeleton (eg, ankylosing spondylitis), conditions that create physical pressure on the nerves and tissues surrounding the spine (eg, sciatica and degenerative disk disease), or conditions/treatments that directly damage nerve -3- tissue (eg, postpoliomyelitis and chronic progressive radiation myelopathy [CPRM]).
  • inflammation of the axial skeleton eg, ankylosing spondylitis
  • conditions that create physical pressure on the nerves and tissues surrounding the spine eg, sciatica and degenerative disk disease
  • conditions/treatments that directly damage nerve -3- tissue eg, postpoliomyelitis and chronic progressive radiation myelopathy [CPRM]
  • neuropathic pain is chronic pain that can develop after alteration and/or injury to any level of the nervous system, peripheral or central.
  • the pain is typically burning and is associated with pressure on a nerve and/or actual damage to nervous tissue.
  • Some types of chronic low back pain can have a neuropathic component (eg, sciatica, postpoliomyelitis and CPRM).
  • Neuropathic conditions that have been treated with gabapentin include: postherpetic neuralgia, postpoliomyelitis, CPRM, HIV-related neuropathy, trigeminal neuralgia, diabetic neuropathy and Reflex Sympathetic Dystrophy (RSD). Of these, the cases of postpoliomyelitis and CPRM had pain associated with the back.
  • the main distinction between back pain that is neuropathy in nature, and muscular/skeletal lower back pain is that nerve damage itself is the cause of pain. In the other conditions, properly working nerves are detecting body tissue damage and pressure secondary to inflammation.
  • the two neuropathic conditions that reported a low back pain component clearly had the formation of anomalous nerve tissue or remodelling of the nerve pathway as the cause of pain.
  • Musculoskeletal pain is the unpleasant experience created by disease or dysfunction in the muscles, connective tissues, or by the stretching of the natural coverings of bones and joints. This type of condition can occur even when the associated sensory nerve fibers, by which the nociceptive impulses are sent from muscular tissue to the brain, are fully normal.
  • neuropathic pain is the sensation created when any combination of pathophysiological processes causes sensory nerves to function badly, or in a hyperexcitable manner.
  • One of the notable characteristics of neuropathic pain is that it can create the sensation that the source of symptoms is within its associated tissue, even when the nonneural tissue is perfectly healthy.
  • neuropathic pain There are patients whose low back pain may be predominantly musculoskeletal or neuropathic. In other patients the resulting symptoms are due to some degree of dysfunction of both types.
  • joints including the spinal facets, may be twisted and become inflamed.
  • Paraspinal muscles may be stretched to the point of having small penetrating vessels torn within the muscle tissue. Consequently the tissue repair response may create the lying down of multiple small areas of scar tissue within the muscle, which can stimulate further pain symptoms during contraction.
  • ligaments may be stretched and their sites of attachment may be torn away leaving microscopic hemorrhages and spinal instability.
  • Disc materials may be twisted in a manner where undue pressure from -5- above causing an actual internal shift of the nuclear material, resulting in a bulging or distortion of the shape of the disc.
  • disc capsules do not have adequate innervation to produce clinical pain when they are mechanically displaced, it has been confirmed that the posterior aspects of discs do indeed have innervation which creates pain when the disc capsule (annulus fibrosis) is stretched. Severe or sudden mechanical force can cause its jelly-like contents (nucleus pulpous) to shift and create pressure gradients against the inside wall of the disc capsule (annulus fibrosis) great enough for the disc to rupture.
  • the disc material Once the disc material is extruded outside its usual boundaries, it can put pressure on the nerve roots that are attempting to exit from the spinal canal. If enough of the disc material is ruptured or protruding, it may place true mechanical compression on the blood vessels which provide nutrition and oxygen to the nerve (versa nervure). The resulting schema will then make the nerve root dysfunctional, creating a specific form of neuropathic pain known as radiculopathy.
  • Reflex Sympathetic Dystrophy is a form of neuropathic pain that persists long after the cessation of cellular damage or healing of a physical injury. It is characterized by a severe burning pain secondary to autonomic (increased sympathetic activity) and/or dystrophic (skin and bone atrophy, increased hair and nail growth, cellular fibrosis, and possible alterations in cellular norepinephrine and sympathetic receptor sensitivity) changes in the tissue of the affected region. Such pain in the absence of any ongoing tissue damage along with the autonomic and/or dystrophic changes are distinguishing characteristics from conditions causing general low back pain. Moreover, the continued pain of RSD is typically out of proportion to the initial tissue damage and generally affects an extremity (eg, right shoulder and arm). -6-
  • the current treatments for lower back pain include exercise, spinal manipulation, bed rest, traction and/or drug therapy.
  • Drugs used to treat lower back pain include acetaminophen, tizanidine, mefenamic acid, chlormethoxazone, -paracetamol, ethoheptazine-aspirin-meprobamate, piroxicam, diflunisal, naproxen sodium, tricyclic antidepressants, indomethacin, cyclobenzaprine, baclofen and ibuprofen.
  • gabapentin which was originally used for treating the neurological disorder epilepsy, and has been further used to treat neurologically based pain (neuropathic pain), to treat muscular/skeletal based pain, such as chronic lower back pain.
  • neurologically based pain neuroopathic pain
  • muscular/skeletal based pain such as chronic lower back pain.
  • gabapentin been studied in low back pain conditions where the nervous system is functioning normally.
  • This invention provides a method for treating muscular and skeletal pain comprising administering to a subject suffering from such pain an effective amount of a GABA analog.
  • a preferred embodiment utilizes a cyclic amino acid compound of Formula I
  • R ⁇ is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof.
  • An especially preferred embodiment utilizes a compound of Formula I where Rj is hydrogen and n is 4, which compound is l-(aminomethyl)-cyclohexane acetic acid, known generically as gabapentin. -7-
  • the invention includes treating muscular and skeletal pain with a compound of Formula II.
  • Ri is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms; R is hydrogen or methyl; and
  • R3 is hydrogen, methyl, or carboxyl.
  • Preferred compounds of the invention are those wherein R3 and R 2 are hydrogen, and Rj is -(CH 2 )o- 2 -i C4H9 as an (R), (S), or (R,S) isomer.
  • the more preferred compounds of Formula II invention are (S)-3- (aminomethyl)-5-methylhexanoic acid and 3-aminomethyl-5-methyl-hexanoic acid, now known generically as pregabalin.
  • a GAB A analog is any compound derived from or based upon gamma-aminobutyric acid.
  • the compounds are readily available, either commercially, or by synthetic methodology well known to those skilled in the art of organic chemistry.
  • the preferred GAB A analogs to be utilized in the method of this invention are cyclic amino acids of Formula I. These are described in U.S. Patent 4,024,175, which is incorporated herein by reference.
  • Another preferred method utilizes the GABA analogs of Formula II, and these are described in U.S. Patent 5,563,175, which is -8- incorporated herein by reference.
  • All that is required to practice the method of this invention is to administer a GABA analog in an amount that is effective to treat the muscular and/or skeletal pain.
  • Such anti-pain amount will generally be from about 1 to about 300 mg per kg of subject body weight. Typical doses will be from about 10 to about 5000 mg per day for an adult subject of normal weight. It is expected that common doses that might be administered for muscular and skeletal pain could be from 100 mg. Three times a day up to 600 mg. Four times a day.
  • Commercially available capsules of 100 mg, 300 mg, 600 mg and 800 mg of gabapentin can be administered. Alternate forms include liquids and commercially available film- coated tablets.
  • the compounds of the present invention may form pharmaceutically acceptable salts with both organic and inorganic acids or bases.
  • the acid addition salts of the basic compounds are prepared either by dissolving the free base in aqueous or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution.
  • pharmaceutically acceptable salts are hydrochlorides, hydrobromides, hydrosulfates, etc. as well as sodium, potassium, and magnesium, etc. salts.
  • the compounds of the Formula II can contain one or several asymmetric carbon atoms.
  • the invention includes the individual diastereomers or enantiomers, and the mixtures thereof.
  • the individual diastereomers or enantiomers may be prepared or isolated by methods already well known in the art.
  • Formulating the active compound in dosage unit form with a pharmaceutical carrier produces pharmaceutical compositions useful in the present invention.
  • dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses. -9-
  • suitable pharmaceutical carriers are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations.
  • the compositions of the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts.
  • the compositions can, if desired, also contain other therapeutic agents.
  • the percentage of the active ingredients in the foregoing compositions can be varied within wide limits, but for practical purposes it is preferably present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition.
  • the most satisfactory compositions are those in which a much higher proportion of the active ingredient is present.
  • a useful intravenous dose is between 5 and 50 mg and a useful oral dosage is between 20 and 800 mg.
  • the dosage is within the dosing range used in treatment of pain or as would be with the needs of the patient as described by the physician.
  • a unit dosage form of the GAB A analog to be used in this invention may also comprise other compounds useful in the treatment of pain.
  • the advantages of using the compounds of Formula I and II, especially gabapentin and pregabalin, in the present invention include the relatively nontoxic nature of the compounds, the ease of preparation and the fact that the compounds -10- are well-tolerated. Gabapentin has few interactions with major classes of drugs since it is not metabolized in the liver, but rather excreted unchanged from the body. Further, the drugs are not metabolized in the body.
  • the subjects treated with the method of the present invention are mammals, including humans.
  • This 50 year old Caucasian female patient was referred for diagnosis and management of her chief complaint of aching and fatigue and persistent muscle -11- pain on a daily basis, with secondary or comorbid complaints of her legs jerking at night, as well as an intermittent band like pain around her head.
  • the headache was described as band-like.
  • the timing was continuous, with frequent variations in severity.
  • the pain intensity of most areas was reported, using a standard Numeric Rating Scale (NRS-11, with zero being no pain and 10 representing the worst pain imaginable) as 4-6.
  • the pain was made worse with exercise, during cold weather and generally increased at night. No specific agents or activities made the pain any better.
  • Other symptoms included tingling of both feet.
  • Past medical history was positive for the usual childhood illnesses, but otherwise negative.
  • Family history was positive for arthritis, heart disease and hypertension.
  • Social history was negative for tobacco or alcohol.
  • the allergy history was positive for codeine, meperidine (Demerol), carisoprodol (Soma) and penicillin.
  • the patient's weight was 150 pounds, height was 5'1".
  • Vital signs at the initial visit were: Pulse-68 per minute, BP (Right arm sitting)- 122/70, -12- Respirations- 12 and p.o. Temperature- 97.2 F
  • Myofascial pain syndrome versus fibromyalgia syndrome Myofascial pain syndrome versus fibromyalgia syndrome, paraspinal muscle spasm, cervical radiculopathy, lumbar radiculopathy.
  • musculoskeletal pain (Myofascial pain syndrome vs. fibromyalgia) with radiographic evidence for degenerative changes of the cervical spine, with secondary independent root irritation created by the associated neuroforaminal narrowing.
  • the patient had previously been unresponsive to OTC preparations such as acetaminophen and ibuprofen, and had been allergic to codeine, meperidine and carisoprodol. While diagnostic tests were being conducted she was provided a therapeutic trial of tizanidine hcl (Zanaflex) for her painful muscle spasms. This was titrated upward over several days from 1 mg three times a day to 4 mg three times a day. At her follow-up appointment six weeks later she stated that she had noticed some improvement (up to 25% pain reduction)in her myofascial symptoms, but she could not tolerate the usual dose due to significant drowsiness. She therefore had to reduce the tizanidine hcl to 1 mg at breakfast and lunch and 4 mg at bedtime, which reduced the effectiveness of the treatment.
  • OTC preparations such as acetaminophen and ibuprofen
  • This 67 year old Caucasian female patient was referred for diagnosis and management of her chief complaint of multiregional pain involving intrascapular, thoracic and lumbar areas, with secondary or comorbid complaints of generalized weakness, as well as right sided neck pain and upper extremity paresthesias.
  • Past medical history was positive for the usual childhood illnesses, headaches, hypertension and arthritis.
  • Family history was positive for arthritis, heart disease and hypertension.
  • Social history was negative for alcohol but the patient does smoke one ppd.
  • the allergy history was positive for morphine, meperidine (Demerol), tetracycline and "all arthritis medications”.
  • the patient's weight was 170 pounds, height was 5 '5".
  • Vital signs at the initial visit were: Pulse-64 per minute, BP (Right arm sitting)-148/88,
  • Cranial nerves including fundi, were normal. Upper extremity bulk, power, tone and range of motion were normal. Power was 4/5-5/5 in most muscle groups, but pain and soreness were noted by the patient. Reflexes were mildly reduced in both upper extremities, but patellars were reduced and achilles reflexes were absent bilaterally. Plantar reflexes were normal. Sensory examination revealed local hyperesthesia to touch and light palpation but was within normal limits to cold and pin. Vibration was mildly reduced bilaterally below the ankles. Stance and gait were within normal limits.
  • Myofascial pain syndrome versus fibromyalgia syndrome Myofascial pain syndrome versus fibromyalgia syndrome, paraspinal muscle spasm, cervical radiculopathy, lumbar radiculopathy.
  • Needle EMGs of the upper extremities revealed mild C5-6 root irritation on the left and mild C3-4 irritation on the right, but lower extremity EMGs were normal. Nerve Conduction Velocity studies of both upper and both lower extremities were fully normal. MRI revealed prominent bulging discs at C4-5 and C5-6, and moderately bulging discs at C3-4 and C6-7, but no disc herniation or spinal stenosis.
  • musculoskeletal pain (Myofascial pain syndrome vs. fibromyalgia) with radiographic evidence for changes of the cervical spine associated with bulging intervertebral discs.
  • Treatment -17- The patient had previously been unresponsive to OTC preparations such as acetaminophen, and had not had any significant benefit from codeine containing compounds (Tylenol # 3, four times a day). She had been taking Robaxin 750 mg twice a day, which was tapered and discontinued due to its ineffectiveness. While diagnostic tests were being conducted she was provided a therapeutic trial of tizanidine Hcl (Zanaflex) for her aching and for painful muscle spasms. This was initiated at a low dose ( lmg three times a day) due to the patient's concerns about drowsiness.
  • the patient indicated that, since she had reduced her gabapentin from 1500 mg a day to 1200 mg a day that she noticed some slight and transient return of her symptoms. She requested that she be permitted to increase it back to 1500 mg a day. She has since remained essentially asymptomatic on the previous schedule. Her personal and pharmacy records indicate that she is not taking any narcotic analgesics.

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EP99904178A 1998-01-23 1999-01-22 Gabapentin und seine derivate zur behandlungen von muskel und skelett-schmerzen Withdrawn EP1047414A1 (de)

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US7239798P 1998-01-23 1998-01-23
US72397P 1998-01-23
PCT/US1999/001290 WO1999037296A1 (en) 1998-01-23 1999-01-22 Gabapentin and its derivatives for the treatment of muscular and skeletal pain

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