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Neuropathic Pain, Complex Regional Pain Syndrome, and Gabapentin Therapy

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First Poster Presentation:  Complex Regional Pain Syndrome & Gabapentin (Neurontin)

Benefits of Gabapentin Therapy

  • Low toxicity-benefit ratio

  • No dependency risks

  • Enhanced sleep quality

  • Few adverse drug

 

Neurontin was first introduced as an anticonvulsant in 1994. It had been researched for 10 years but its pain relieving qualities was not recognized until Dr. Mellick prescribed gabapentin for the very first time on Friday May 20, 1994. Gabapentin was not a particularly strong anticonvulsant and was not expected to gross more than $500,000 annually. What ensued was an amazing saga that is ongoing. It began with a $20,000 dollar bonus to the drug representative for the best first year sales in any United States territory. The use of anticonvulsants such as gabapentin has evolved into a new paradigm of pain therapy and an entirely new direction for neuropathic pain research. This research has successfully launched new neuropathic pain therapeutics such as Lyrica (pregabalin) and others resulting in a skyrocketing multibillion dollar pain and psychotropic drug industry.

The first Gabapentin Poster: Successful Treatment of Reflex Sympathetic Dystrophy with Gabapentin (Neurontin).  13th Annual Scientific Meeting of the American Pain Society, Miami Beach, Florida, November 10-13, 1994

 
Initial Clinical Experience
       Reflex Sympathetic Dystrophy (CRPS Type I)
       Phobic Disorder

Subsequent Clinical Experience
       Neuropathic and Cancer
Pain
       Other Acute & Chronic Pain Syndromes      
       Sleep Disorders (RLS, PLMD) 
Complex Regional Pain Syndrome and Gabapentin Therapy

Complex Regional Pain Syndrome

On May 20, 1994, Dr. Gary Mellick was the first person to discover and publish the value of the anticonvulsant Neurontin in the use of CRPS and Neuropathic pain. Gabapentin (Neurontin) is used world wide for pain management.

Case Reports  

REFLEX SYMPATHETIC DYSTROPHY (RSD) TREATED WITH GABAPENTIN (NEURONTIN)  

 

Gary A. Mellick , D.O. and Larry B. Mellick, M.D.

Abstract.  We report our experience with the recently released anticonvulsant, gabapentin (Neurontin), in the treatment of severe and refractory reflex sympathetic dystrophy (RSD) pain in six patients ranging from 42 to 68 years of age.  Satisfactory pain relief obtained in all six of our patients who took gabapentin (Neurontin) suggests that this medication is an effective medical treatment for RSD pain.  In addition to pain control, early evidence of disease reversal is suggested in our patients.  Specifically, we have noted reduced hyperpathia, allodynia, hyperalgesia, and early reversal of skin and soft tissue manifestations.  Gabapentin (Neurontin) was chosen because it has properties similar to other anticonvulsant drugs and because previous studies have shown that it is well tolerated and appears to have a benign efficacy-to-toxicity ratio.  It was considered an acceptable therapeutic choice since previous medical and surgical approaches had been ineffective for these patients.  In view of encouraging results in these and other RSD patients, we believe that further scientific investigation is needed to delineate the role of gabapentin in the treatment of reflex sympathetic dystrophy.  Presently, the mechanism of pain relief in these patients is unknown.  In this paper we discuss the pathophysiology of RSD and propose a mechanism by which gabapentin provides pain relief.  These patients represent the first case series documenting the use of gabapentin for pain management.

(Key Words: Pain, Reflex sympathetic dystrophy, Causalgia, Sudeck’s atrophy, Sympathetically maintained pain, Gabapentin, Neurontin, Anticonvulsant therapy, Serotonin, GABA (Gamma-aminobutyric acid)

Selected Publications:

Mellick GA, Mellick LB. Successful Treatment of Reflex Sympathetic Dystrophy (RSD) with Gabapentin (Neurontin) (Letter) Journal of Pain and Symptom Management 1995;10;4:265-66

 Mellick GA, Mellick LB. Reflex sympathetic dystrophy (RSD) treated with Gabapentin (Neurontin), Archives of Physical Medicine & Rehabilitation 1997;78(1):98-105 

 Mellick GA, Mellick LB. Successful treatment of restless legs syndrome with gabapentin (Neurontin). Sleep Research 1995;24:290 

 Mellick GA, Mellick LB. Management of Restless Legs Syndrome with Gabapentin (Neurontin) Sleep  1996;19;3:224-226

Abstract: Management of Restless Legs Syndrome with Gabapentin (Neurol 1995, 45:A 285-6): May 1995, Platform Presentation, American Academy of Neurology Annual Meeting
Gary A. Mellick, D.O.
& Larry B. Mellick, M.D.
American SLEEP  Disorders Center, Lorain, OH; Department of Emergency Medicine, Loma Linda University, Loma Linda, CA

 Restless Legs Syndrome: Successful Treatment with Gabapentin
Platform & Poster Presentation: Annual APSS (Sleep Societies) meeting June 4, 1995
Gary A. Mellick, D.O., & Larry B. Mellick, M.D.
American
SLEEP  Disorders Center, Lorain, OH; Department of Emergency Medicine, Loma Linda University, Loma Linda, CA

Mellick LB, Mellick GA. Successful Treatment of Reflex Sympathetic Dystrophy with Gabapentin. American Journal of Emergency Medicine. 1995;13:96.

The First Treatment of Neuropathic Pain With Gabapentin (Neurontin)

 

American PAIN  Specialists, Inc.

Gary A. Mellick, D.O.,  DAAPM
AMERICAN SLEEP DISORDERS CENTER
 Pain Consultation & Neurodiagnostics Services 

Re:   Management of Painful Peripheral Neuropathy with Gabapentin  (Neurontin)

May 14, 1995

 Dear Editor:

Current therapy for many patients with peripheral neuropathy does not provide satisfactory pain relief.  We report our experience with gabapentin (NEURONTIN), a recently released anticonvulsant, in the treatment of refractory peripheral neuropathy pain in ten patients ranging from 46 to 78 years of age (Table 1).  Each patient had the presence of a peripheral polyneuropathy confirmed by a detailed neurologic examination and electromyography and nerve conduction studies completed by a second neurologist.  All ten patients experienced significant and sustained pain relief when treated with gabapentin.  In addition to pain relief, two patients fortuitously experienced relief from their symptoms of restless leg syndrome which had been refractory to treatment in the past.  Furthermore, most patients reported improved quality of sleep.

        Painful neuropathies occur due to many etiologies, but the most common causes are of toxic, metabolic, vascular, or mechanical origin.  Patients with polyneuropathy resulting from diabetes mellitus may experience numbness, distal sensory loss, associated with burning pain and hyperesthesia.  Alcoholic neuropathy patients may report burning and tenderness in the feet and legs.  Cancer patients as a result of the remote effects of cancer on the nervous system may develop painful subacute or chronic sensorimotor polyneuropathies.

        Neuropathies which are complicated by pain are characterized by axonal rather than demyelinating pathology.  Usually, there is an extensive loss of small fibers, or loss of large and small fibers together.  With the possible exception of postherpetic neuralgia, neuropathies in which large fibers are selectively lost are seldom painful. 

        The paresthetic and dysesthetic pain of peripheral neuropathies is characteristically described as “tingling”, “burning”, “aching” or as “numbness”.  Patients may also describe unpleasant, paroxysmal electric shock-like sensations of several seconds duration.  The electrical shock-like pain may respond to anticonvulsant drugs such as carbamazepine, phenytoin, valproic acid, clonazepam or nitrazepam.  The aching and burning pain may respond to tricyclic antidepressant compounds such as amitriptyline or to neuroleptic agents such as fluphenazine.

        The mechanism of pain relief from gabapentin is unknown; however, animal research by Xiao and Bennett1 has recently shown that gabapentin provides significant efficacy against heat-hyperalgesia and mecho-allodynia in rats and that this pain relief appears to be mediated largely or entirely by a spinal site of action. 

        Other research has shown a gabapentin induced elevation of CNS serotonin (5HT) in both humans2 and animals.3  A 5HT pain relieving mechanism may occur via the raphe-spinal descending control system which acts to impede nociception at the substantia gelatinosa of the spinal cord, an area with a high density of projections from the raphe magnus and which contains substance P terminals, opiate receptors, and serotonin terminals.    

         Reduced peripheral neuropathy pain may be solely responsible for the improved sleep in our patients.  However, in his studies on human subjects, Rao2 discovered a significant increase in slow wave sleep (SWS) without an effect on rapid eye movement (REM) sleep.  Gabapentin therapy results in increased synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in various brain locations.5  Gabapentin therapy causes increased concentrations of brain serotonin (5-HT).3  Both GABA and 5-HT are considered possible modulators of slow wave sleep (SWS).3,6,7  Drugs that enhance levels of GABA , or act on GABA receptors increase SWS.6  Jouvet et al7 have proposed that 5-HT may not directly induce sleep, but instead act as a sleep modulator through its effects on other hypnogenic factors in the anterior hypothalamus and suprachiasmatic nuclei.  Even though the mechanism is presently unknown, we believe that gabapentin may facilitate sleep by both pain reduction and SWS modulation.

        Gabapentin was selected for the treatment of peripheral polyneuropathy in these patients because it is well tolerated with a benign efficacy-to-toxicity ratio,8,9 and in our experience, it has been effective in the management of reflex sympathetic dystrophy pain10,11 and restless leg syndrome.12

        The satisfactory control of pain in our patients suggests that gabapentin (NEURONTIN) is a well tolerated, and effective treatment for the pain of peripheral neuropathy.  The mechanism of pain relief in these patients is only beginning to be understood and further research concerning the use of this drug is indicated.  Nevertheless, this initial series of patients represents the first documented use of gabapentin (NEURONTIN) for the management of painful peripheral neuropathy.

Gary A. Mellick, DO, DAAPM
American Pain  Specialists, Inc.
Lorain, OH, 44053                     

Larry B. Mellick, MD, FAAP, FACEP
Loma Linda University Medical Center
Loma Linda, CA 92354        

References:

 1.    Xiao, W.H., Bennett, G.L. Gabapentin relieves abnormal pains in a rat model of painful peripheral neuropathy. Soc. Neuosci Abstr., 21 (1995) in press

2.    Rao M.L., Clarenbach P., Vahlensieck, M., Kratzschmar, S. Gabapentin augments whole blood serotonin in healthy young men. J. Neural Transm. 1988;73(2):129-34

3.    Jouvet, M. Biogenic amines and the states of sleep. Science. 1969; 163:32-41.

4.    Besson, J.M.R:, Supraspinal modulation of the supraspinal transmission of pain, in Kosterlitz, H.W., Terenius, L.Y. (eds.): Pain and Society. Weinheim, Germany, Verlag Chemie, 1980, pp. 161-182.

5.    Loscher W., Honack, D., Taylor, C.P. Gabapentin increases aminooxyacetic acid-induced GABA accumulation in several regions in rat brain. Neurosci Lett 1991;128:150-154.

6.    Scherschlicht, R. Role for GABA in the control of the sleep-wakefulness cycle, In: Sleep Neurotransmitters and Neuromodulators, Waquier, A., Gaillard, J.M., Monti, J.M., Radulovacki, M., (Eds.) New York: Raven Press, 1985; 237-249.

7.     Jouvet, M., Denoyer, M., Kitahama, K., Sallanon, M. Slow wave sleep and indolamines: a hypothalamic target, In: Slow Wave Sleep: Physiological, Pathophysiological and Functional Aspects, Wauquier, A., Dugovic, C., Radulovacki, M. (Eds.) New York: Raven Press, 1989; 91-108.

8.    Andrew J., Chadwick, D., Bates, D., et al. Gabapentin in partial epilepsy. Lancet 1990; 335:1114-1117.

9.    Ojemann L.M., Wilensky, A.J., Temkin, N.R., Chmelir .T., Ricker, B.A., Wallace, J. Long-term treatment for partial epilepsy. Epilepsy Res. 1992;13:159-165.

10. Mellick, G., Seng, M. The use of gabapentin in the treatment of reflex sympathetic dystrophy and a phobic disorder. AJPM 1995;5:7-9.

11. Mellick, L., Mellick, G. Successful treatment of reflex sympathetic dystrophy with gabapentin. AJEM 1995;13(1):96

12. Mellick, G., Mellick, L. Successful treatment of restless legs syndrome with gabapentin (Neurontin) Neurol 1995;45:A 285-6  

PATIENTS TAKING GABAPENTIN (NEURONTIN) TO CONTROL PERIPHERAL NEUROPATHY PAIN
 

Pt. Illness Age Gender Dose Mg

Duration Months

% Pain Decreased  Adverse Effects Beneficial Effects
1. Diabetes 48 M 1600 7 75 Drowsy Sleep
2. Rheumatoid Arthritis 77 F 600 11 45 Gait Sleep
3. Diabetes Hypothyroid 59 F 1200 5 75 None Sleep
4. Unknown 78 F 900 11 60 Gait Sleep
5. Diabetes, RLS 59 F 900 10 80 None Sleep Cramps
6. Unknown 62 F 900 5 85 None Sleep
7. Diabetes Hypothyroid 59 F 900 9 75 Dizzy Sleep
8. Alcoholism 69 M 2000 6 60 None Sleep
9. Porphyria 46 M 1600 2 95 Euphoria Sleep Cramps
10. Restless Legs Syndrome 69 F 300 6 85 None Sleep RLS Control

 


A RECENT DISCOVERY!

  Since the beginning of time, mankind has suffered from reflex sympathetic dystrophy syndrome (RSDS).  Most treatments have been ineffective, painful, and risky.  The toll of human suffering because of the disability and pain has been staggering. 

Dr. Gary A. Mellick, a Lorain, Ohio neurology pain specialist wishes to announce his discovery of a new drug therapy for RSDS at the:

INDIANA CHAPTER RSDS

SYMPOSIUM

SATURDAY, AUGUST 13, 1994

9:15 A.M. To 5:00 P.M.

®®®®®

ST. JOSEPH MEDICAL CENTER

EDUCATIONAL CENTER

LASALLE STREET

SOUTH BEND, INDIANA

This new medication is proving to be a remarkably safe and effective treatment for RSDS.  Thus far, the treatment has been highly effective for all aspects of the syndrome. Severity and duration of the RSDS does not seem to effect therapeutic outcome.

Highlights Of New Drug Therapy

·         Pain relief may be immediate and dramatic.

·         Normalization of skin color and temperature.

·         Markedly reduced skin sensitivity and decreased joint stiffness.

·         Improved tolerance of physical or occupational therapy with gradual return of strength.

·         Few serious adverse effects (noted so far).

·         Less depression in some patients.

·         New “sense of well-being” in some patients (Relief of suffering as well as pain).

·         Medication is not a controlled substance.

Notice: This addendum to the Indiana Chapter RSDS Symposium is distributed solely for the purpose of informing patients, relatives, and their caretakers about a new drug with effectiveness in RSDS patients.

  The presentation of this new drug is for informational purposes only and it is not intended as a broad recommendation for the use of this or any other drug for purposes other than those of original research and production. 

Additionally, all medications have adverse effects or allergic responses in some patients and treatment with a medication may not be beneficial to all patients.

As you know, most medications that are approved by the FDA frequently find new uses that were not intended when originally released. The FDA and the pharmaceutical company typically do not recommend alternative uses for any drug other than what it originally was intended for.

Since the stated release of this medication is for other medical conditions, the decision to use the drug will be solely between you and your local RSDS specialist.  If you and your doctor utilize this drug as a therapeutic option, it is of utmost importance that your clinician and pharmacist review adverse effects associated with this drug prior to its use for RSDS management.

If interested in the Indiana symposium, return this registration form with payment to: Shirley Farkas 68137 Lawndale St. Edwardsburg, MI 49112.  Make check payable to: INDIANA CHAPTER RSDS SUPPORT GROUP.   ( Phone inquiries  

INDIANA CHAPTER RSDS SYMPOSIUM

 

HOPE TO SEE YOU THERE.

What are Neurontin's Off-Label Uses: What isn't Neurontin used for? It's the late-20th century's most successful medication for off label uses.  Monotherapy Treatment for Epilepsy (used all by its lonesome).  Bipolar Disorder - basically useful only if bad anxiety or substance abuse is also present, or nothing else has worked. And then usually only as an add-on med.  Migraines Neuropathic pain Depression PTSD.  Alcoholism (one study has it working well on mild-to-moderate alcohol withdrawal, another showed it to be insignificant for acute withdrawal). Anxiety (including panic, social phobia, and public speaking).  Sleep Disorders Restless Leg Syndrome/PLMS, MS, Chronic Fatigue.  Menopausal Symptoms Treating HIV/AIDS-related Neuropathy.   Phantom Limb Pain.   Cocaine Abuse.   Sometimes it's quite useful in these applications, sometimes it's prescribed first just because it's an anticonvulsant with a very low side effect profile.