Note: Descriptions are shown in the official language in which they were submitted.
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MIRTAZAPINE FOR THE TREATMENT OF NEUROPATHIC PAIN.
This invention relates to the use of mirtazapine for the treatment of
neuropathic pain.
There is both clinical and pre-clinical evidence that anti-
depressants are effective for the treatment of painful conditions. In
particular, it is
used for the treatment of chronic pain (Ansari, Harv Rev Psychiatry, 7 (2000)
257-
77; Carter and Sullivan, Curr Opin Investig Drugs, 3 (2002) 454-8; Reisner,
Curr
Pain Headache Rep, 7 (2003) 24-33; Mattia et al., Minerva Anestesiologica, 68
(2002) 105-114). Especially tricyclic antidepressants (TCAs) are well
established in
the treatment of difficult conditions such as neuropathic pain and tension
type
headache (Carter and Sullivan, Curr Opin Investig Drugs, 3 (2002) 454-8;
Lynch, J
Psychiatry and Neuroscience, 26 (2001) 30-36). However, as TCAs often have
severe side effects and lack safety in overdose (Reisner, Curr Pain Headache
Rep,
7 (2003) 24-33), a new generation of safer antidepressants with a better
tolerability
and fewer side effects is increasingly used for treating chronic pain (Ansari,
Harv
Rev Psychiatry, 7 (2000) 257-77). It has been suggested that 30% of tricyclic
antidepressant (TCA) prescriptions are written for the treatment of pain
conditions
(Su, X, Gebhart, GF (1998) Pain 76: 105-114) and are effective even in the
absence
of depression (Monks, R Psychotropic Drugs In Textbook of Pain (1994) Eds: PD
Wall & R Melzack, Churchill Livingstone, 963-989; McQuay, H.J. and Moore,
R.A.,
Br.Med.J., 314 (1997) 763-764). Indeed, more than 50% of the patients
attending
the Oxford Pain Clinic are taking antidepressant drugs. However, the
mechanisms
of the analgesic properties of antidepressants are poorly understood. As the
mechanism by which antidepressants exert their antinociceptive effect is still
unknown, it is unfortunately difficult to predict which antidepressants will
be
efficacious in the treatment of pain, and in particular the treatment of
neuropathic
pain.
Whilst the older tricyclics are known to have actions at a diversity of
receptors, the
more selective re-uptake blockers e.g. venlafaxine are also effective in the
treatment of pain (Sumpton, J.E. and Moulin, D.E., Annals of Pharmacotherapy,
35
(2001b) 557-559). Thus, it is possible that the analgesic effects of these
antidepressants are related to their ability to block the re-uptake of
serotonin and
noradrenaline within the central nervous system (CNS). The effectiveness of
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duloxetine (CymbaltaTM) in treating neuropathic pain (Goldstein et al., Pain
116 (1-2)
(2005) 109-118), a dual serotonin and noradrenaline reuptake inhibitor
supports
this hypothesis.
Mirtazapine is an antidepressive drug, which is marketed for
therapy as the racemic mixture, comprising the enantiomers R(-)-mirtazapine
and
S(+)-mirtazapine. There are some clinical indications which suggest that
mirtazapine might be useful in the treatment of pain in humans (Carter and
Sullivan,
Curr Opin Investig Drugs, 3 (2002) 454-8). Brannon and Stone, J Pain Symptom
Manage, 18 (1999) 382-5 report on treatment of a patient with chronic back
pain in
combination with depression. Bendtsen and Jensen, Neurology, 62 (2004) 1706-11
report on a trial to treat tension headache with mirtazapine.; Ansari, Harv
Rev
Psychiatry, 7 (2000) 257-77 report on treatment of chronic pain with
mirtazapine.
The use of mirtazapine in the treatment of pain in cancer patients is reported
by
Theobald et al, J Pain Symptom Manage, 23 (2002) 442-7. In none of these
disorders the role of damaged or irritated nerve cells as primary source for
the pain
is demonstrated. Neuropathic pain is thought to be a consequence of damage to
peripheral nerves or to regions of the central nervous system. Wang et al
(US2003/096805) mention mirtazapine in a list of options for topical or local
use in
combination with local anesthetics to reduce neuropathic pain.
The present invention provides for the use of the S(+)-enantiomer
of mirtazapine for the treatment of neuropathic pain.
In the context of the present invention, the term "essentially free
from R-enantiomer (or R(-)-mirtazapine)" means a content of R(-)-mirtazapine
of
less than 5%, 2%, 1%, 0.5% or 0.1% of the total amount of mirtazapine.
An embodiment of this invention is the use of pure S(+)-mirtazapine
for the manufacture of a medicament of the treatment of neuropathic pain. Pure
S(+)-mirtazapine in this context means essentially free from R(+)-mirtazapine.
In the context of the present invention, neuropathic pain means any
form of pain associated with a neuropathic disease or condition caused by
injury or
primary irritation of (part of) a nerve, including degenerative, toxic,
metabolic,
ischaemic and mechanical forms of injury. Neuropathic conditions include all
forms
of neuritis and polyneuritis. The neuropathic conditions can be hereditary,
such as
hereditary sensorimotor neuropathy and hereditary sensory and autonomic
neuropathy. Neuropathy can be secondary to diabetes, rheumatic disease or
viral
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infections (such as by the herpes virus; post-herpetic neuralgia). Myofacial
pain is a
form of neuropathic pain.
According to particular embodiments thereof, the present invention
relates to:
- the use of S(+)-mirtazapine for the manufacture of a medicament
for treatment of neuropathic pain;
- a pharmaceutical composition for treatment of neuropathic pain,
comprising S(+)-mirtazapine;
- a method of treatment of neuropathic pain comprising
administering to a subject in need of treatment for neuropathic pain a
therapeutically
effective dose of S(+)-mirtazapine.
In particular, S(+)-mirtazapine can be used for treatment of pain
caused by diabetic neuropathy, which can be a polyneuropathy, comprising all
forms of peripheral and central neurological conditions relating to chronic
diabetic
metabolism disease. In this context, the neuropathy is secondary to diabetes,
in that
diabetes causes damage to blood vessels providing nutrients etc. to nerves,
ultimately leading to damage to the nerves themselves. Therefore, the present
invention particularly relates to the use of S(+)-mirtazapine for treatment of
pain
caused by diabetic neuropathy, as well as to a pharmaceutical composition for
treatment of said pain, comprising S(+)-mirtazapine. The invention also
relates to a
method of treatment of pain caused by diabetic neuropathy, comprising
administering a therapeutically effective dose of S(+)-mirtazapine to a
subject in
need thereof.
S(+)-mirtazapine can, for the purpose of the invention, be used as a
free base or as one or more of the commonly accepted acid addition salts. Such
compounds can be used in pure form or in admixture with pharmaceutical
excipients. Preferred forms of mirtazapine are those in salt form which will
result in
stable pharmaceutical formulations as reported in W02005/051714, whereof the
maleate salt is preferred.
S(+)-mirtazapine can be prepared in several manners, e.g. by
purification from the racemic mixture mirtazapine. Mirtazapine may be prepared
using the method described in US 4,062,848. S(+)-mirtazapine can also be
obtained
by stereoselective synthesis (see W02005/005410).
In the context of the present invention, the subject is a patient,
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human or animal, suffering from a condition associated with any one or more of
the
aforementioned forms of neuropathic pain, to which S(+)-mirtazapine is
administered for treating said pain.
The amount of S(+)-mirtazapine, also referred to herein as the
active ingredient, which is required to achieve a therapeutic effect, that is
the
therapeutically effective amount, will vary with the particular compound, the
route of
administration and the age and other conditions of the subject. The amounts of
mirtazapine defined in this description refer to the amount of free base of
mirtazapine, unless indicated otherwise.
A suitable daily dose for humans will be in the range of 0.5 to 140
mg, calculated on the weight content of base, per recipient per day,
preferably in the
range of 5 to 90 mg of the base per recipient per day. In general, parenteral
administration requires lower dosages than other methods of administration
which
are more dependent upon absorption. However, the daily dosages in humans are
between 0.01 and 3 mg/kg body weight of the subject.
In the case of tolerance development, treatments can be further
optimized by increasing the dose up to 5 times in the course of a chronic
treatment
in humans. The desired dose may be presented as one, two, three or more sub-
doses administered at appropriate intervals throughout the day. A treatment
may be
for a single day, at discretion of the patient on an "if needed" basis or for
a limited
determined treatment period defined by a number of days, weeks or months.
While it is possible for the active ingredient to be administered as
such, it is preferable to present it as a pharmaceutical formulation.
Accordingly, the
present invention further provides a pharmaceutical formulation for use in the
treatment of neuropathic pain comprising pure S(+)-mirtazapine, together with
a
pharmaceutically acceptable carrier thereof and optionally other therapeutic
agents.
The carrier must be "acceptable" in the sense of being compatible with the
other
ingredients of the formulation and not deleterious to the recipients thereof.
The
invention further includes a pharmaceutical formulation, as hereinbefore
described,
in combination with packaging material suitable for the pharmaceutical
formulation,
said packaging material including instructions for use of the pharmaceutical
formulation in the treatment of pain.
Formulations include those suitable for oral or rectal administration.
The formulations may be prepared by any methods well known in the art of
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pharmacy. Such methods include the step of bringing into association the
active
ingredient with the carrier which constitutes one or more accessory
ingredients.
Such accessory ingredients include those conventional in the art, such as,
fillers,
binders, diluents, disintegrants, lubricants, colorants, flavoring agents and
wetting
5 agents.
Formulations suitable for oral administration may be presented as
discrete units such as tablets or capsules, each containing a predetermined
amount
of active ingredient; as a powder or granulates; as a solution or suspension.
The
active ingredient may also be presented as a paste, or may be contained within
liposomes or microparticles. The formulation may also be administered as a
bolus.
Formulations to be administered parenterally (for example
subcutaneously) may also be presented in a suitable sustained release form.
In the context of the present invention, the use of S(+)-mirtazapine
for treatment of neuropathy is as stand-alone therapy without any other
analgesic
co-medication or can be in combination with any other active compound for
treatment of the condition to be treated. The other active compound can be
administered before, simultaneously with, or after S(+)-mirtazapine. S(+)-
mirtazapine can even be combined together with the other active compound into
one pharmaceutical composition. The expert will recognise that, in each case
of
combined use or add-on therapy, the doses and/or formulations may have to be
adapted accordingly.
Example:
Effect of S(+)-mirtazapine in the Chung Neuropathic Model.
The Chung Neuropathic Model is an animal model of neuropathic
pain. Animals with tight ligation of the L5 spinal nerve develop hyperalgesia
and
allodynia that can be measured using standard behavioural paradigms.
Chung surgery: animals were anaesthetized with isoflurane
administered in oxygen. Under sterile conditions, a longitudinal incision
(about 5 mm
lateral from the midline) was made at the lower lumbar-sacral level, exposing
the
paraspinal muscles on the left. The paraspinal muscles were then isolated and
removed from the L4 spinous process to the sacrum using small blunt scissors.
This
opened up the space ventrolateral to the articular processes, dorsal to the L6
transverse process, and medial to the ileum. Small roungers were used to
remove
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the L6 transverse process as completely as possible. The L5 spinal nerve was
then
isolated and tightly ligated. Upon completion of the operation, haemostasis
was
confirmed and the wound closed in layers using silk sutures and metal clips.
Anaesthesia was then discontinued. Animals were kept in a cage with warm
bedding
until they had completely recovered from anaesthesia.
The rats' withdrawal threshold to a mechanical stimulus (calibrated
von Frey filaments) was measured (baseline reading). Rats were placed on an
elevated (- 40 cm) mesh floor in Perspex boxes and filaments of increasing
force
(2.6 - 167 mN) were applied to the plantar surface of the paw using an up and
down
method (Chaplan et al., 1994). The paw was touched with one of a series of 8
von
Frey hairs with logarithmically incremental stiffness. The von Frey hair was
presented perpendicular to the plantar surface with sufficient force to cause
buckling against the paw, and held for approximately 1 - 3 seconds. A positive
response was noted if the paw was sharply withdrawn. A cut-off of 15 g was
selected as the upper limit for testing, since stiffer hairs tend to raise the
entire limb
rather than buckling, substantially changing the nature of the stimulus.
Following baseline measurements each animal was anaesthetised
and the L5 spinal nerve tightly ligated. The animals were allowed to recover
from
the surgery for a period of at least five days. On the day of drug
administration, the
paw withdrawal thresholds were re-measured (0 min). Immediately after this
reading, the rats were injected subcutaneously with vehicle (1 ml/kg) or S(+)-
mirtazapine (0.3 - 120 pmol/kg) (see Table 1 for doses and group sizes).
Readings
were then made at regular intervals after compound injection.
Data were expressed as mean s.e.m. and compared between
groups using the Kruskal-Wallis one-way analysis of variance, a non-parametric
statistical test. Each of the treatment groups were then compared against the
vehicle group, using the non-parametric Dunn's test. The time of maximum
effect
(Tmax) was calculated.
Subcutaneous administration of S(+)-mirtazapine maleate salt
significantly attenuated the mechanical allodynia that develops in this animal
model
(see Table 1). After administration of the 120 pmol/kg of S(+)-mirtazapine
mechanical allodynia was reversed to 53% of the baseline, It was observed that
at
120 pmol/kg of S(+)-mirtazapine both vocalisation/struggle on injection (s.c.)
and
necrosis at site of injection were observed. Further, when rats were returned
to
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holding cages after testing, it was noted that animals in the 60 and 120
pmol/kg
group displayed hyperactive/excitable behaviour.
Table 1
Compound Route Dose Number of Tmax Withdrawal
(iamol/kg) animals threshold (g) at
tested Tmax
10% Tween 80 s.c. 1 ml/kg 9 60 1.2 0.2
S(+)-mirtazapine s.c. 0.3 8 60 1.8 0.4
S(+)-mirtazapine s.c. 3 8 60 1.7 0.3
S(+)-mirtazapine s.c. 30 8 60 1.3 0.4
S(+)-mirtazapine s.c. 60 9 60 5.8 1.0**
S(+)-mirtazapine s.c. 120 6 60 7.4 0.7**
Table 1 shows the dose groups and number of animals per group, for the
neuropathy-induced mechanical allodynia experiments. The table also shows the
Tmax for each group and the withdrawal threshold (g) at Tmax. ** denotes p <
0.01,
when vehicle-treated and compound-treated animals were compared.
Lack of effect of R(+)-mirtazapine in the Chung Neuropathic Model for
comparative
purpose.
Subcutaneous administration of R-mirtazapine (free base) (10-100 pmol/kg) had
no
effect on the mechanical allodynia induced by ligation of the L5 spinal nerve
in rats
(see Table 2).
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Table 2
Compound Route Dose Number of Tmax Withdrawal
(iamol/kg) animals threshold (g)
tested at Tmax
10% Tween 80 s.c. 1 ml/kg 5 30 2.3 0.4
R-mirtazapine S.C. 10 4 30 2.3 0.4
R-mirtazapine S.C. 30 3 30 2.1 0.3
R-mirtazapine S.C. 100 5 30 3.2 0.2
Table 2: shows the dose groups and number of animals per group, for the
neuropathy-induced mechanical allodynia experiments. The table also shows the
Tmax for each group and the withdrawal threshold (g) at Tmax. No significant
effect
was observed.
No side effects were observed after treatment with any of the doses.
Effect of Rac-mirtazapine in the Chung Neuropathic Model for comparative
purpose.
Racemic mirtazapine (10 and 30 pmol/kg) had a small but significant effect on
withdrawal
threshold (up to 4 g) 40 min after administration when compared to vehicle
treated rats
(Mann Whitney test, P < 0.05). However, this effect was not dose-dependent.
Conclusion
Anti-allodynic activity in rats having mechanical allodynia following L5
spinal nerve
ligation was observed with S-mirtazapine following 60 and 120 pmol/kg s.c.. In
contrast, administration of R-mirtazapine in doses up to 100 pmol/kg s.c. had
no
effect.
References:
Ansari, Harv Rev Psychiatry, 7 (2000) 257-77;
Bendtsen and Jensen, Neurology, 62 (2004) 1706-11
Brannon and Stone, J Pain Symptom Manage, 18 (1999) 382-5
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Carter and Sullivan, Curr Opin Investig Drugs, 3 (2002) 454-8;
Goldstein et al., Pain 116 (1-2) (2005) 109-118)
Lynch, J Psychiatry and Neuroscience, 26 (2001) 30-36)
Mattia et al., Minerva Anestesiologica, 68 (2002) 105-114).
McQuay,H.J. and Moore,R.A., Antidepressants and chronic pain-effective
analgesia
in neuropathic pain and other syndromes, Br.Med.J., 314 (1997) 763-764.
Monks, R Psychotropic Drugs In Textbook of Pain (1994) Eds: PD Wall & R
Melzack, Churchill Livingstone, 963-989;
Reisner, Curr Pain Headache Rep, 7 (2003) 24-33
Su X, Gebhart GF (1998) Effects of tricyclic antidepressants on
mechanosensitive
pelvic nerve afferent fibers innervating the rat colon. Pain 76:105-114.
Sumpton,J.E. and Moulin,D.E., Treatment of neuropathic pain with venlafaxine,
Annals of Pharmacotherapy, 35 (2001) 557-559.
Theobald DE. Kirsh KL. Holtsclaw E. Donaghy K. Passik SD. An open-label,
crossover trial of mirtazapine (15 and 30 mg) in cancer patients with pain and
other distressing symptoms. Journal of Pain & Symptom Management. Vol.
23(5)(pp 442-447), 2002.
Van der Burg US 4,062,848
Wang et al. (US2003/096805)
W02005/051714
W02005/005410
