CLINICAL APPLICATIONS OF MANNITOL IN
COMPLEX REGIONAL PAIN SYNDROME (CRPS)
H. Hooshmand, M.D.
Neurological Associates Pain Management Center
Vero Beach, FL 32960
The Mechanism of Action of Mannitol
Mannitol has been used as an effective intracellular type of
diuretic for more than four decades.
There are mainly two different types of diuretics: The first
type exerts it's effect in the plasma and acts as an extracellular diuretic by
excreting the extra water in the extracellular space through the kidney.
The best example of such a diuretic is Lasix. Also,
Hydrochlorothiazide (HCTZ) has been used for quite a few decades on the same
diuretic basis. Such diuretics only passively, and secondarily influence any
intracellular water retention.
The intracellular water retention is quite important,
especially in the following conditions:
In any condition that causes traumatic or toxic metabolic
water retention in the nerve cells, especially the brain, as well as in the
peripheral nervous system.
The best example of such as condition is water retention
secondary to disturbance of pituitary and adrenal hormones. This is seen in
conditions such as Diabetes Insipidus, hyper corticosteroid dysfunction such as
Cushing's Disease, hypothyroidism, and a condition Pseudotumor cerebri. In such
diseases, the water concentration in the nerve cells is selectively increased.
This causes water toxicity, increased intra-cranial pressure, and even death.
Another example of intercellular edema is glaucoma involving the eyes.
The third type of intercellular water retention is the
typical inflammatory changes seen in neuropathic pain, such as diabetic
neuropathy or complex regional pain syndrome (CRPS). The inflammation in
neuropathic pain causes the disturbance of permeability of the cell membrane
allowing the water, along with electrolytes such as sodium and calcium, to enter
the nerve cells. This cell membrane disturbance causes the death of nerve cells,
especially in the grey matter of the spinal cord, in the dorsal root
ganglia(DRG), and in the peripheral nerves.
The inflammation becomes manifested in the form of edema of
the extremities, severe vascular headaches, spontaneous cell membrane
permeability of the arterioles and venules resulting in cutaneous bleeding and
skin rash in absence of any kind of trauma.
Such water retention and disturbance of cell membrane
function causes edema of the brachial plexus, edema at the ankle or wrist, and
these conditions become mistaken for thoracic outlet syndrome, carpal tunnel
syndrome, tarsal tunnel syndrome, etc.
Traditionally, such compression neuropathies (entrapment
neuropathies) are treated surgically. Unfortunately, the trauma of the surgery
adds to the trauma of the neuropathic pain and neuropathic vascular dysfunction.
As a result, the inflammation undergoes a vicious circle of more neurovascular
damage, more inflammation, trauma of surgery, and secondary more inflammation.
One phenomenon noted after surgery for entrapment
neuropathies was the spread of CRPS to the opposite extremity. This was mistaken
for the development of carpal tunnel syndrome in the opposite extremity. This
was in spite of the fact that the nerve conduction times did not show any
definite entrapment neuropathy, but a mild reduction of the amplitude of nerve
Such erroneous interpretation of the spread of the CRPS
post-operatively leads to further unnecessary surgery, with dire consequences.
In 1969 and 1972 the research by my colleagues and myself
showed the efficacy of Mannitol in counteracting such intracellular edema [1-3].
Mannitol is very well tolerated. The only contraindications
are in patients who have practically total renal failure and in patients who
already have a dead space of intra-cerebral hemorrhage or necrotic brain tumor,
which can cause entrapment of the Mannitol in the dead space.
Mannitol Treatment vs. Surgery
In the past decade we have applied the treatment with
Mannitol to patients with compression neuropathies, as mentioned above
(conditions mimicking carpal tunnel syndrome, tarsal tunnel syndrome, thoracic
outlet syndrome and rotator cuff tear), as well as the patients who, due to
CRPS, suffer from severe edema, neurodermatitis, and trophic ulcers. There were
surgical candidates with the compression neuropathies who were divided into two
groups. Both groups were given the option of surgery or treatment with IV
Mannitol. The entire subject was discussed in detail with the patient and with
their referring physician. One group underwent surgery, and the other underwent
Mannitol treatment. After comparing 32 patients in each group, it became obvious
that Mannitol treatment was quite successful and would eliminate the necessity
The surgical group had a more rapid deterioration of their
CRPS post-operatively. The CRPS changed from stage II to stage III in 2/3 of
such patients, and the edema continued to show a tendency for further
The other equally comparable group of 32 patients, who
underwent Mannitol therapy, did not require surgery, and their condition
improved. The pain rating post-operatively dropped from an average of 6-9 prior
to treatment with Mannitol, to an average of 2-5 after treatment with Mannitol.
Medical Necessity for I.V. Mannitol Treatment
Many CRPS patients suffer from attacks of inflammation in the
form of edema in the extremities and bouts of reddish discoloration of the skin
over the extremities.
The sympathetic system has three main functions:
1. Control of the vital signs (BP, pulse and respiration)
2. Control of the temperature
3. Regulation of the immune system
The sympathetic dysfunction results in disturbance of the
immune system manifested by attacks of fever, swelling, skin rash and
spontaneous bruises. These symptoms cause clinical pictures identical to Carpal
Tunnel Syndrome, Tarsal Tunnel Syndrome or Thoracic Outlet Syndrome. Instead of
surgery, the patient should be treated with medications such as Mexitil 150 mg
bid, ACTH, Epsom Salt, as well as Mannitol. Surgery causes disastrous
deterioration of CRPS.
The patient needs to be treated with a specific type of
medication that counteracts inflammation without any side effects.
Mannitol, an inert sugar, is a selective, strong diuretic
which exclusively reduces the intracellular water retention. As such, it does
not cause electrolyte imbalance, weakness or fatigue.
The Mannitol is helpful in counteracting the neuroinflammation in
postoperative stage, and specifically in patients who cannot tolerate the
inflammatory response against hardware inserted surgically.
Necessity for Removal of
Because the patient has sympathetic dysfunction (CRPS), the
foreign body of devices such as screws, spinal cord stimulators, etc, is
considered by the immune system as an extraneous agent. The immune system is
stimulated (by sympathetic system) to mobilize WBC’s and macrophages to attack
the foreign body. This in turn leads to edema and osteopenia. Removal of the
foreign body, and treatment with I.V. Mannitol thru central line, as well as
staying active are effective treatments for this condition.
When CRPS patients are treated with this medication, the
swelling of the extremities is reduced and symptoms suggestive of Carpal Tunnel
or Thoracic Outlet Syndrome disappear. The treatment is done as an outpatient.
The dosage is 100 grams Mannitol in 500 cc D5W over 45-60 minutes. Usually 1 to
3 treatments are all the patient needs for inflammation of RSD.
In the past decade, we have noted the beneficial effect of
I.V. Mannitol in neuro-inflammation. This is especially true in patients
suffering from post herpetic neuralgia, CRPS, and other forms of neuropathic
pain. The common denominator in the various neuropathic pain is involvement of
thermoreceptor sensory nerves and the sympathetic system at some stage of the
disease. As you are well aware, the sympathetic system has three main functions.
1. Thermal regulation; 2.Control of vital signs; 3. Regulation and modulation of
the immune system function. In the neuropathic pain patients, it is not unusual
for the dysfunctional immune system to cause neuroinflammation accompanied by
intercellular and axonal edema. If such patients are treated with plasma
diuretics such as Hydrochlorothiazide or Lasix, these diuretics reduce the
plasma volume which can have the potential of causing edema ex-vacuole and
aggravate the neuroinflammatory edema.
On the other hand, intracellular dehydrants such as Mannitol
and Diamox selectively counteract neuroinflammation and reduce the intracellular
edema. On this basis, we in our clinic and as well as Doctor Veldman’s group in
Holland have applied IV Mannitol to counteract neurogenic edema[4,5]. Such
neurogenic edema is especially more prominent in patients who have undergone
surgery for sympathectomy, infusion pump treatment, and spinal stimulators. At
times the neuroinflammation is severe enough to cause a skin rash and
neurodermatitis as well.
As long as the patient has normal renal clearance (no protein
in the urine), the IV Mannitol treatment is quite safe. As the Mannitol has a
tendency to crystallize, the IV should be applied in 1-1 ½ hours. If the IV drip
is prolonged up to 4-6 hours, there is the risk of crystallization of the
Mannitol. Certainly, a filter should help prevent any such risk as well. The
usual dose is 100gm Mannitol in 500cc D5W.
1.Hooshmand H, Suter C, Dove J: The effects of mannitol and dexametheasone on
CSF pressure. Excerpta Medical International Congress 1969; Series
2.Hooshmand H, Dove J, Houff S, et al: Effects of diuretics and steroids in
CSF pressure, a comparative study. Arch Neurol 1969; 21: 499-509.
3.Hooshmand, H., Houff, S., and Quin, J.: Cerebrospinal fluid pressure
changes with chemotherapy for intracerebral hemorrhage. Neurology
4.Hooshmand H and Hashmi M: Complex regional pain syndrome (Reflex
sympathetic dystrophy syndrome): Diagnosis and Therapy - A Review of 824
Patients. Pain Digest 1999; 9 : 1-24.
5.Veldman PH, Goris RJ: Sequelae of reflex sympathetic dystrophy. Clinic
Aspects of Reflex Sympathetic Dystrophy. Thesis: 1995; Chapter 10, Pgs