Neuropathic Pain, Complex Regional Pain Syndrome, and Gabapentin Therapy
First Poster Presentation: Complex Regional Pain Syndrome & Gabapentin (Neurontin)
Benefits of Gabapentin Therapy
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)
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.|
Gary A. Mellick,
D.O. and Larry B. Mellick, M.D.
report our experience with the recently released anticonvulsant,
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
suggests that this medication is an effective medical
treatment for RSD
pain. In addition to
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.
was chosen because it has properties similar to other anticonvulsant drugs
and because previous studies have sh own
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
relief. These patients represent the first case series documenting the use
of gabapentin for
(Key Words: Pain, Reflex sympathetic dystrophy, Causalgia, Sudeck’s atrophy, Sympathetically maintained pain, Gabapentin, Neurontin, Anticonvulsant therapy, Serotonin, GABA (Gamma-aminobutyric acid)
Mellick LB. Successful
Treatment of Reflex Sympathetic
Dystrophy (RSD) with Gabapentin
(Letter) Journal of
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
(Neurol 1995, 45:A 285-6): May 1995, Platform Presentation, American
Academy of Neurology Annual Meeting
Restless Legs Syndrome:
|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)
Gary A. Mellick, D.O., DAAPM
Re: Management of Painful Peripheral Neuropathy with
Current therapy for many patients with
peripheral neuropathy does not provide satisfactory
pain relief. We report
our experience with gabapentin
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.
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
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
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.
therapy results in increased synthesis of the inhibitory neurotransmitter
gamma-aminobutyric acid (GABA) in various brain locations.5
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
facilitate sleep by both pain
reduction and SWS modulation.
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
and restless leg syndrome.12
The satisfactory control
of pain in our
patients suggests that gabapentin
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
for the management of painful peripheral neuropathy.
Gary A. Mellick,
Larry B. Mellick,
MD, FAAP, FACEP
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
Rao M.L., Clarenbach P., Vahlensieck, M., Kratzschmar, S.
whole blood serotonin in healthy young men. J. Neural Transm.
3. Jouvet, M. Biogenic amines and the states of sleep. Science. 1969; 163:32-41.
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.
Loscher W., Honack, D., Taylor, C.P.
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.
Andrew J., Chadwick, D., Bates, D., et al.
Gabapentin in partial
epilepsy. Lancet 1990; 335:1114-1117.
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.
Mellick, G., Seng, M. The
use of gabapentin
in the treatment
of reflex sympathetic dystrophy and a phobic disorder. AJPM
Mellick, G. Successful
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
|% Pain Decreased||Adverse Effects||Beneficial Effects|
|5.||Diabetes, RLS||59||F||900||10||80||None||Sleep Cramps|
|10.||Restless Legs Syndrome||69||F||300||6||85||None||Sleep RLS Control|
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.
Gary A. Mellick, a Lorain, Ohio neurology pain specialist wishes to announce
his discovery of a new drug therapy for RSDS at the:
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
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
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.
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
|What are Neurontin's Off-Label Uses: What isn't Neurontinused 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.|