Title: Use for pain management
United States Patent: 6,395,291
Inventors: Isacsson; Goran (Ronninge, SE); Selander; Dag (Goteborg,
Assignee: Astra AB (Sodertalje, SE)
Appl. No.: 254382
Filed: March 2, 1999
PCT Filed: January 11, 1999
PCT NO: PCT/SE99/00012
371 Date: March 2, 2000
102(e) Date: March 2, 2000
PCT PUB.NO.: WO99/37301
PCT PUB. Date: July 29, 1999
Foreign Application Priority Data: Jan 21, 1998[SE]
The present invention is directed to the intramuscular use of
ropivacaine for the manufacture of a medicament for use in the treatment
of muskuloskeletal pain, in particular myofascial pain and tendinitis.
BACKGROUND AND PRIOR ART
The most common diagnosis in most pain clinics is a
disorder of skeletal muscle and connective tissue origin, which may stem
from previous trauma, muscle tension or postural abnormalities. The two
dominating muscle pain disorders are the generalized condition
fibromyalgia and the mainly localized myofascial pain. Myofascial pain
conditions are characterized by discrete tender loci known as trigger
points or tender points. These points are located by several methods
including digital palpation or pressure pain threshold algometer testing
and sometimes detection of skin loci with lowest electrical independence.
The pathophysiology of human myofascial pain remains unknown. However, it
has been suggested that myofascial tenderness may be the result of a
lowered pressure pain threshold, a stronger response to presuures in the
noxious range (Jensen K, Quantification of tenderness by palpation and use
of pressure algometers; In: friction Jr, Awad E., Advances in pain
Research and Therapy, Vol. 17, Raven press, New York, 199, 1990, pp.
165-181). The nociceptive processes are also qualitatively altered in
patients with chronic myofascial pain indicating that myofascial pain may
be mediated by low-threshold mechanosensitive afferents projecting to
sensitized dorsal horn neurons (Bendsten L., Jensen R, Oleson J.
Qualitatively altered nociception in Chronic Myofascial pain, Pain 1996;
65: pp. 259-264 ).
A wide range of therapeutic methods have been used over the years in order
to cure long lasting myofascial pain. The mostly used methods have been
massage, TENS, acupuncture, heat or cold packs, relaxation, unloading
aching structures, traction and manipulation. Various analgesics,
anti-inflammatory drugs and injected corticosteroids have also been used.
The various treatments often give initial relief of pain but the pain
often recurs thereby necessitating repeated treatments.
In a double-blind study of myofascial pain syndrome (MPS), the effect on
pain has been compared between bupivacaine (0.25%), lignocaine (1%), and
saline (Tschopp K P, Gysin C. Local Injection therapy in 107 patients with
myofascial pain syndrome of the head and neck; J. Oto-Rhino-Laryng &
Rel. Spec. 1996; 58: 306-310). No significant difference between these
compounds has, however, been reported.
Outline of the Invention
The problem underlying the present invention was to find a new way of
therapy for muskuloskeletal pain, in particular myofascial pain and
tendinitis. The inventors of the present invention have found that the
local anaesthetic ropivacaine is useful for the just mentioned therapy.
Ropivacaine refers to (S)-(-)-i-propyl-2',6'-pipecoloxylidide
hydrochloride known to be useful for injection. It is described, including
its long lasting local anesthetic effects, in EP 151 110 B1. In particular
ropivacaine can be used in the form of its monohydrate in high
enantiomeric purity, disclosed in EP 239 710 B1.
However, the routes of administration previously disclosed for ropivacaine,
are epidural administration, nerve block and peripheral infiltration.
Hitherto ropivacaine has not been disclosed for the therapeutic use in
accordance with the present invention.
The present invention is thus directed to a new use of ropivacaine for the
manufacture of a medicament for use in the treatment of muskuloskeletal
pain, in particular myofascial pain.
The medical indication "muskuloskeletal pain" is a well
established condition, and will be appreciated by a person skilled in the
The medical indication "myofascial pain" is defined as a
regional pain complaint; pain complaint or alterred sensation in the
expected distrubution of referred pain from a myofascial trigger point;
taut band palpable in an accessible muscle; exquisite spot tenderness at
one point along the length of the taut band; some degree of restricted
range of motion, when measurable. A person skilled in the art will however
appreciate the medical pain conditions belonging to this specific pain
A further specific medical condition which is within the scope of the
definition muskuloskeletal pain, is "tendinitis". A person
skilled in the art will appreciate what patients belong to this group, but
the following can however be mentioned as characterizing symptoms:
regional pain complaint; localized tenderness; increased pain on movement;
and limited range of motion.
"Trigger point" (TP) is a focus of hyperirritability in a muscle
or its fascia that causes the patient pain. It causes referred pain and
tenderness at rest, or with motion. The trigger point is always tender,
and is located in a palpable band of muscle fibers. It prevents full
lengthening of the muscle. It usually weakens the muscle, refers pain on
direct compression, and mediates a local twitch response of the palpable
band of muscle fibres when mechanically stimulated. Myofascial TPs can
initiate referred autonomic phenomena, which generally appear in the pain
A further aspect of the present invention is a method for the treatment of
muskuloskeletal pain, in particular myofascial pain and tendinitis,
whereby ropivacaine is administered intramuscularly to a patient suffering
from said pain condition.
The active substance ropivacaine which is used in accordance with the
present invention, is administered intramuscularly by injection in
muscular "tender and/or trigger points". A "tender
point" is defined as a point over a muscle/tendon which is tender and
elicits palpabral reflex on digital palpation. Although the definition of
tender points and trigger points differ slightly, the two words are used
Ropivacaine is administered as a formulation suitable for intramuscular
administration and in an amount effective to ameliorate pain.
Accordingly, 0.1-10 ml ropivacaine is injected intramuscularly, preferably
directly into each tender or trigger point. The concentration of
ropivacaine for administration intramuscularly is preferably 1-20 mg/ml,
more preferably 2-10 mg/ml. A concentration as low as 2-5 mg/ml may
advantageously be used.
Ropivacaine hydrochloride 7.5 mg/ml solution for injection was used (Naropin.RTM.,
Astra AB, Sweden). Ropivacaine was administered as a single dose
intramuscular tender point (TP) injection. Injection by means of one
needle insertion per tender point was preceded by aspiration before
infiltrating the study drug over the entire tender area. A standard
disposable syringe with a 0.4 mm diameter needle was used. Injection rate
was about 1 ml/30 sec. Injections were made at one occassion at a visit to
the clinic. Follow-up data were obtained at a study end visit to the
clinic 1 week after the injection.
(I) Patient Characteristics
Prior to the treatment the following information was recorded.
Demographic data: Date of birth, gender, race, body weight and height.
Past and current diagnoses: allergy and information related to significant
past or present medical and surgical diagnoses excluding minor
self-healing conditions with no obvious importance for the purpose of this
Active alcohol or drug abuse (yes/no).
A case history information including the duration of the present orofacial
muscle pain was collected. A clinical examination of the orofacial region
including digital palpation of the temporomandibular joints and
10 patients (5 men and 5 women) whose age varied from 19 years up to 69
years (mean 42.9 years of age) were included in this test. The duration of
complaints ranged from 1 month and up to 10 years (mean 26.5 months).
All patients were subjected to unilateral injections of ropivacaine into
tender points of the masseter muscle. Three patients received 1 ml, 5
patients received 2 ml, 1 patient received 3 ml and 1 patient received 4
ml of the study drug.
(II) Clinical Measurements
(i) Pain on Maximal Mouth Opening
The patient rated their pain on a 100 mm visual analogue scale (VAS). On
the VAS, 0 represents "no pain" and 100 represents "worst
pain imaginable". The primary efficacy variable was VAS pain score at
maximal mouth opening. The patient was asked to open the mouth as much as
possible and then they rated the experienced pain.
(ii) Pain at Rest
The non-functional pain (aw at rest) was also assessed by the patient on
the VAS scale. This parameter was rated before the rating of pain on
maximal mouth opening.
(iii) Tender Muscular Points
A tender point was defined as point over a muscle/tendon which was tender
and elicited a palpabral reflex on digital palpation. Bilateral digital
palpation of the temporalis muscle, the masseter muscle, the lateral
pterygoid muscle and the temporalis tendon was used for the registration
of tender points. The number and site of injected tender points and the
total amount of the study drug used were recorded. The assessment of
tender muscle points was made prior to the assessment of range of
(iv) Range of Movement
The distance between the edges of the right upper and the corresponding
lower medial incisor was used for the measurements of maximum mouth
opening. Both maximum opening with and without pain was registered.
The primary efficacy parameter, VAS rated pain at maximal mouth opening,
showed a dramatic reduction as a result of the treatment. The median VAS
value at baseline was 59.5 mm compared to 6 mm at the follow-up. The data
is shown in Table 1 below.
Pain ratings using a 100 mm graded VAS at baseline and at
Pain at maximal jaw
Pain at rest opening
Baseline Follow-up Baseline Follow-up
Median 19.5 3.5 59.5 6
Mean 33.3 3.7 59.3 27.3
Min 3 0 8 0
Max 89 16 95 75
S.D. 31.05 4.83 24.73 32.34
At baseline, 2 patients experienced pain every day and 8 patients pain
several times per week. At the follow-up 6 patients had not a single
episode with pain during the week prior to follow-up, 1 patient had pain
at one occasion during the week and the remaining 3 patients had pain
several times a week or every day.
Claim 1 of 5 Claims
What is claimed is:
1. A method for ameliorating myofascial pain in a patient, consisting of
intramuscularly administering to said patient a composition consisting of
ropivacaine as an active ingredient in an amount sufficient to ameliorate
said pain and wherein said composition is administered at a trigger point.
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