Dr. Jason Hughes ND & Dr. Brenden Cochran IV Mannitol – Expanding Perspectives for Use in Neurogenic Inflammation & Neuropathic Pain Dr. Jason Hughes ND & Dr. Brenden Cochran

Setting Expectations What this presentation will be; A brief overview of the history of use of IV Mannitol Review of generally accepted mechanisms of action Review of generally accepted clinical uses An introduction of potential new uses of IV Mannitol Particularly in view of mannitol’s mechanism of action on TRVP1 receptors in Neuropathic Pain A description of several cases where IV Mannitol has been used in from this new perspective.

Setting Expectations What this presentation won’t be; A conclusive review or “the final analysis” Neither of us have done exhaustive clinical trials with Intravenous Mannitol Hopefully this presentation will pique interest in experimentation with IV Mannitol within you, so as to help us all better understand its full clinical applications!

A Little Background... The 1st Masters Class... Both of us use Intravenous Therapies in our own practice. The idea of exploring the use of IV Mannitol grew out discussions around the dinner table between all of us present at the Inaugural Master’s Class Some initial research into the potential revealed a fair amount of history of use and several journal articles This lead to lots more exciting dinner conversations and the commitment to try this clinically to see if it was a viable treatment.

Mannitol: A Short History Mannitol is classified as a sugar alcohol; that is, it is derived from a sugar (mannose) by reduction A white, crystalline solid with the chemical formula C6H8(OH)6 Has been used in medicine as a INTRACELLUALR DIURETIC for many decades (Many studies go back to the 1940’s)

Mannitol: Generally Accepted Pharmacokinetics “Because orally administered mannitol is not absorbed, it must be administered parenterally. It distributes almost entirely in the extracellular fluid, very little penetrating cells. As a result, it is virtually inert, only 7 percent to 10 percent being metabolized, probably in the liver, while the rest is freely filtered by the glomeruli and excreted intact in the urine. About 7 percent is reabsorbed by the renal tubules. With normal kidney function, after a single intravenous dose, the half-life of mannitol in the circulating plasma is 15 minutes. Of an injected dose, 90 percent is recovered in the urine after 24 hours.” – Nissenson et al.

Mannitol: Generally Accepted Pharmacokinetics “With severe renal insufficiency the rate of mannitol excretion is greatly reduced and retained mannitol may increase extracellular tonicity leading to a shift of water out of cells, expanding the extracellular fluid as well as inducing an apparent hyponatremia with increased serum osmolality such as occurs in hyperglycemia. Therefore, mannitol should be used cautiously under these conditions.” – Nissenson et al.

Mannitol: Generally Accepted Physiological Effects Renal Can basically be used as an Osmotic Diuretic An almost ideal prototype, mannitol was used extensively in early physiological studies of osmotic diuresis. Osmotic diuretics are freely filtered at the glomerulus and poorly reabsorbed by the renal tubules. The resulting high urinary concentration profoundly affects renal water and sodium reabsorption.

Mannitol: Generally Accepted Physiological Effects Cardiovascular Intravenously injected mannitol is confined to the extracellular fluid space. The increased tonicity obligates water to move from the intracellular to the extracellular fluid to maintain osmotic equilibrium. With each 182 mg per dl increase in mannitol concentration, a 10 milliosmole increase in extracellular fluid osmolality occurs with the same proportionate dilution of all serum electrolytes as occurs in hyperglycemia.

Mannitol: Generally Accepted Physiological Effects Cardiovascular Various amounts of plasma volume expansion have been reported with mannitol infusion Ranging from 1 ml per kg of body weight per 5 grams of mannitol infused to 3 ml per kg of body weight per 5 grams of mannitol, depending upon body osmolarity With each 100 mg per dl increase in mannitol concentration in the extracellular fluid, serum sodium falls 1.6 to 2.6 mEq per liter.

Mannitol: Generally Accepted Physiological Effects Cardiovascular After the expansion of the extracellular fluid and blood volume by injection of mannitol mean arterial pressure, cardiac output, heart rate, coronary blood flow and left ventricular end diastolic pressure all increase.

Mannitol: Generally Accepted Physiological Effects Cerebrovascular Mannitol has several physiologic effects on the cerebrovascular system. Increased cerebral blood flow, increased cerebral oxygen consumption and decreased cerebrospinal fluid pressure have all been documented.

Mannitol: Generally Accepted Physiological Effects Cerebrovascular The decreased cerebrospinal fluid pressure, in spite of increased cerebral blood flow, is of interest. Since mannitol cannot cross the blood brain barrier, it causes water to move out of the brain into the extracellular fluid. This decrease in brain water is the cause of the fall in cerebrospinal fluid pressure. The movement of water out of the brain in response to the osmotic effect of mannitol decompresses the brain when cerebral edema is present.

Mannitol: Generally Accepted Physiological Effects Ocular Mannitol profoundly lowers intraocular pressure when given intravenously just as it lowers cerebrospinal fluid pressure. Can also be used topically to create ocular hypotensive effect!

Mannitol: Generally Accepted Clinical Uses Raised Intracranial Pressure Osmotherapy has been the cornerstone of the medical management of cerebral edema, irrespective of its aetiology, for decades, and mannitol is the most widely used agent. In a survey conducted in 1996, 100% of neurosurgical units in the UK used mannitol during the treatment of intracranial hypertension.

Mannitol: Generally Accepted Clinical Uses Reduction in raised intracranial pressure Preservation of perioperative renal function in patients undergoing major vascular and cardiac surgery and in those with jaundice To promote diuresis and minimize the risk of acute renal failure in patients after renal transplantation Preservation of renal function in rhabdomyolysis secondary to crush injuries and compartment syndrome Bowel preparation before colorectal surgery, colonoscopy, and barium enemas Promotion of urinary excretion of toxic materials

Mannitol: Generally Accepted Clinical Uses “Mannitol is a standard of care for the management of intracranial hypertension and is recommended by consensus guidelines. There is little evidence to support its continued use for other indications...” –Shawkat et al, 2012 Having said that, lets examine the history of “off label” uses and potential future “off label” uses.

Mannitol: History of Use In Pain Hooshang Hooshmand, M.D. Has been researching and publishing about IV Mannitol since at least 1969. It would seem that he is the person that innovated the use of IV Mannitol for Neurogenic Inflammation and Neuropathic Pain I have tried to contact him no less than 5 times, but unfortunately he is retired and not taking any calls!

Mannitol: Hooshmand’s Concept of Neuropathic Pain Mechanism Principally views IV Mannitol as an intracellular diuretic with action on the nerves as well “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.”

Mannitol: Hooshmand’s Concept of Neuropathic Pain Examples of Water Retention in Cells (Nerves) 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.

Mannitol: Hooshmand’s Concept of Neuropathic Pain Examples of Water Retention in Cells (Nerves) 3. 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.”

Mannitol: Hooshmand’s Concept of Neuropathic Pain Manifestations of Neurogenic Inflammation 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.

Mannitol: Hooshmand’s Clinical Observations “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 for surgery. “

Mannitol: Hooshmand’s Clinical Observations 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 recurrence. 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.

IV Mannitol Hooshmand’s Guidelines Safety Guidelines “As long as the patient has normal renal clearance (no protein in the urine), the IV Mannitol treatment is quite safe” - Hooshmand Treatment Strategies 100 g Mannitol in 500cc D5W over 40-60 min.

Mannitol & TRVP1 Receptors: Expanding Mechanism of Action? Expanding perspectives of use Can the only effect of Mannitol be as a intracellular diuretic? Cleared from the body very quickly, but effects are much longer lasting!

Mannitol & TRVP1 Receptors: Expanding Mechanism of Action? Could the mechanism of Mannitol’s effectiveness be also due to the response on TRVP1 receptors? If so, would the same amount or concentration need to be used? These are the questions that we are trying to answer!

Why we are excited about this... The cardiovascular system is one hell of a delivery system IV Mannitol could allow the treatment of system wide neurogenic inflammation! (Neurogenic Storm, FM, etc) IV Mannitol could allow the treatment of “hard to get” areas without the risk of deep injections! One poke beats many pokes So says every patient I’ve known. There is a known safety signature and a long history of use

Some Potential Drawbacks Its expensive and you potentially need to use a lot more of it to get the effect. It can be difficult to obtain. You may need to compound yourself or have a pharmacist do it. It takes longer to do a drip than subcutaneous injections, longer visit times

Storage Don’t store in the refrigerator due to crystallization Don’t store over 30 degrees Celsius MDV=Multiple dose vial Preservative and 28 day shelf life after opening SDV = Single dose vial Preservative free. Must be used no more then the day opened. Consider use of filter

Mannitol Concentrations (usually compounded or you have prepared by dilution) 225 mOsmol/L pH 4.5 – 7.0 10% mannitol (osmitrol) 550 mOsmol/L (Hypertonic) 20% mannitol (osmitrol) 1100 mOsmol/L (Very hypertonic) (OUCH!!!!)

Osmolarity Hemolysis: <145 mOsmol Hypotonic: <250 mOsmol Isotonic: 250 – 375 mOsmol Hypertonic: >375 mOsmol

Osmolarity Normal physiologic osmolarity range is 280 to 310 mOsmol/L 150-450: Low risk of phlebitis 450-600: Moderate risk of phlebitis 600 + : 100% risk of some phlebitis (Gazitua, et al) ** Remember: changing osmolarity (dilution) does not change pH. Both need to be assessed.

Contraindications Hypersensitivity Pre-existing plasma hyperosmolarity Heart Failure (CHF) Disturbances of the blood-brain barrier Anuria Pulmonary congestion/Pulmonary edema Active intracranial bleed Severe dehydration Progressive renal or heart damage

Cautions Electrolyte disturbances: Infusions of mannitol will cause depletion of sodium and potassium. Dehydration: osmotic diuresis If using with dextrose (hyperinsulinism), further potassium depletion.

Cautions Use in Pregnancy: (Category B2) Teratogenic Effects: unknown Lactation: Not known if excreted in breast milk Geriatrics: Dehydration and electrolyte disturbance

Cautions Interactions with other medications: Diuretics due to potentiation Concomitant cyclosporin due to nephrotoxicity Concomitant aminoglycosides (potentiation of ototoxicty) Anti-coagulants: reduce their effects by increasing clotting factors secondary to dehydration Digoxin: due to possible hypokalemia from mannitol

Adverse Side Effects Nausea and vomiting Local pain, thrombophlebitis, phlebitis Angioedema, allergy, anaphylactic shock Chills, dizziness, urticaria, fever, headache, blurred vision Hypotension, hypertension, tachycardia, arrhythmia, angina like pains, convulsions, CHF Nephrosis, diuresis, renal failure Acidosis, electrolyte imbalances Dehydration, cramps, thirst, dry mouth

Lab and other Work Up CBC CMP UA in office Vitals pre and post Patient is hydrating before and during infusion. Drip will last generally 1 – 3 hours depending on volume, strength and patient tolerance.

Dosing 250 – 500 ml 5% mannitol 250 – 500 ml 10 % mannitol 250/250 ml (10% mannitol: 10% Dextrose) Lower dosages are generally tolerated more and safer.

IV Mannitol Most patient’s report that they like having less injections. Better whole system treatment Best for fibromyalgia, CRPS, or other 4 quadrant pains. May benefit other neurological pathways. Possible calming agent: see CASE

IV Mannitol Consider in future neurological cases. Parkinson’s http://phys.org/news/2013-06-artificial-sweetener-potential-treatment-parkinson.html http://www.eurekalert.org/pub_releases/2013-04/gsoa-fma032913.php

Other IV agents Alapha lipoic acid EGCG Vitamin C Vitamin E Magnesium MSM DMSO MTHF

Other agents Topical magnesium, MSM, DMSO Injectable Vitamin D?

DIFFICULT TO DO!

% CFS/FMS Participants 26 13 10 25 Anderson, PS (2012, August). Active comparator trial of addition of MTHFR specific support versus standard integrative naturopathic therapy for treating patients with diagnosed Fibromyalgia (FMS) and Chronic Fatigue Syndrome (CFS). Poster Presentation, presented at the American Association of Naturopathic Physicians annual convention, Bellevue, WA. Incidence Data: Hetero A1298C Hetero C677T Compound Hetero Homo A1298C Homo C677T Study n = 88 23 12 19 9 22 % CFS/FMS Participants 26 13 10 25 % Normal population 43 15 11 % Incidence Difference - 40 - 70 + 53 - 1 + 44

Outcomes: Active comparator : Hetero A1298C Hetero C677T Compound Hetero Homo A1298C Homo C677T Intervention % (of n) 22 25 47 50 27 % outcome improvement + 55% + 75% + 56% + 71%

Approximately 45% of the population has 1 copy of the MTHFR C677T Wilcken B et al. J Med Genet 2003;40:619-625

Fibromyalgia 43 year old female fibromyalgia onset 2001 Tried pain medications, muscle relaxers, trigger point injections. Pelvic pain 8/10 (10- worst) B/L Jaw pain 5-6/10 (10- worst) B/L Hand pain 7/10 (10 worst) Burning aching pain Have done 3 – 4 sessions (PSI injections with 5% mannitol) have benefited but not holding.

Pressure algometry Pre-treatment Left pelvis: 0.13 kg/m2 Right thoracic lateral to T10- T11: 0.56 kg/m2 Right upper thoracic T4-5: 0.28 kg/m2 Other PE CV, Resp., reflexes WNL Vitals: BP 121/79, Pulse 94, RR 14

Infusion IV infusion: Infusion time 65 minutes. 250 ml 5% mannitol 250 ml 5% dextrose Infusion time 65 minutes. Patient reports feeling more relaxed during the IV

Pressure algometry Post-treatment Left pelvis: 0.13 kg/m2  0.34 kg/m2 Right thoracic lateral to T10- T11: 0.56 kg/m2  2.84 kg/m2 Right upper thoracic T4-5: 0.28 kg/m2  1.45 kg/m2 Other PE CV, Resp., reflexes WNL Vitals: BP 125/44, Pulse 97, RR 14

Depression/Fibromyalgia 63 year old female, depression flare, irritable and emotional Tried pain medications, muscle relaxers, responding well to PSI treatments Left cervical pain C3-C4 8/10 (10- worst) Left T7 pain 8/10 (10- worst) Left T10 pain 8/10 (10 worst) Aching pain

Pressure algometry Pre-treatment Left C3-C4: 1.13 kg/m2 Left thoracic T7: 1.10 kg/m2 Left throacic T10: 1.10 kg/m2 Other PE CV, Resp., reflexes WNL Vitals: BP 118/72, Pulse 76

Infusion IV infusion: Infusion time 60 minutes. 250 ml 5% mannitol Infusion time 60 minutes. Patient reports feeling more relaxed and very calm. Pain not as prominent.

Pressure algometry Post-treatment Left C3-C4: 1.13 kg/m2  1.13 kg/m2 Left thoracic T7: 1.10 kg/m2  1.55 kg/m2 Left throacic T10: 1.10 kg/m2  1.30 kg/m2 Other PE CV, Resp., reflexes WNL Vitals: BP 118/71, Pulse 70

Case History’s M.S. With Systemic Neuropathic Pain 65 y.o. Woman with M.S., Confined to wheelchair. Pain – Entire spine, hips. Noticeable edema both legs but worse right, Obese, Constipation Initial treatments Dietary changes, sensitivities, supportive GI protocol NPT – DRG relevant areas (thoracic / lumbar / cluneal) Significant benefit but recurring pain. Complained of “pain all over”

Case History’s 6 IV Treatments No significant cardiovascular history BP- WNL No protein in urine Started with 100cc 5% mannitol IV and worked up to 500cc 5% mannitol 100cc  200cc  300cc  400cc 500cc  500cc Infused over 45min

Case History’s Outcomes (to date) Initial treatment Headaches gone (didn’t report these) Lost significant weight (5 lbs) Observations over subsequent treatments Pain noticeably improved albeit still recurrent Weight loss (could be due to dietary factors as well as diuretic) Midway thru treatments she requested “just do the IV’s with me” no longer wanted the injections she felt the IV was more effective for systemic pain Noticeable improvement in peripheral edema and discoloration Noticeable relaxation during treatment as concentration increased

Case History’s 70 y o male – Fibromyalgia, systemic pain 36 y o female – Transverse Myelitis, HA’s

References 1.Hooshmand H, Suter C, Dove J: The effects of mannitol and dexametheasone on CSF pressure. Excerpta Medical International Congress 1969; Series No.193: 374-378. 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 22:56-61, 1972. 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. Shawkat H, Westwood M, Mortimer A: “Mannitol: a review of its clinical uses.” Continuing Education in Anaesthesia, Critical Care & Pain. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. 2012. 6. Nissenson A, Weston R, Kleeman C: “Mannitol.” The Western Journal of Medicine 131:277-282, Oct 1979