Novel Targets in the Treatment of Pain



GABAPENTIN (NEURONTIN()

IN THE MANAGEMENT OF PAINFUL PERIPHERAL POLYNEUROPATHY

Gary A. Mellick, D.O., DAAPM

Larry B. Mellick, M.D., FAAP, FACEP

Novel Targets in the Treatment of PAIN

October 6 & 7, 1997

The Westin Washington D.C. City Center

Washington DC

Novel Targets in the Treatment of Pain

An open clinical trial using gabapentin (Neurontin() in the management of painful peripheral polyneuropathy.

G.A. Mellick, President, American Pain Specialists, Inc. 1100 N. Abbe Rd., Suites C & D, Elyria, OH 44035; L.B. Mellick, Chair and Professor, Department of Emergency Medicine, Medical College of Georgia, Augusta, GA 30912-6811

Aim of investigation: Current therapy for many patients with painful peripheral polyneuropathy remains frustratingly difficult. The authors report our encouraging clinical experiences using gabapentin (1-(aminomethyl) cyclohexane acetic acid; Neurontin(), a novel anticonvulsant drug with a mechanism of action apparently distinct from that of other antiepileptic agents. We describe our use of gabapentin in the treatment of refractory painful peripheral polyneuropathy in ten patients ranging from forty-eight to seventy-eight years of age.

Methods: Gabapentin therapy was initiated at 300 mg t.i.d. and titrated upwards to maximal pain relief. Each patient’s peripheral neuropathy was confirmed by a detailed neurologic examination, electromyography and nerve conduction study. Gabapentin dosage ranged from 300 to 2000 mg with an average dose of 900 mg per day.

Results: All ten patients experienced significant and sustained pain relief with only transient central nervous system adverse effects. Fortuitously, two patients also reported relief from refractory restless legs syndrome that had been unresponsive to previous multiple therapies. All patients reported improved quality of sleep. Both anxiolytic and mood enhancement properties were described by several patients.

Conclusions: Recent research has identified that gabapentin binds to the alpha 2 delta subunit of voltage-dependent calcium channels and dose-dependently inhibits the late phase of the nociceptive response in inflammatory pain models. Gabapentin effectively inhibited thermal and mechanical hyperalgesia but failed to show an antinociceptive action in transient pain models. Gabapentin likely manifests its pain relieving qualities by similar mechanisms in these patients.

GABAPENTIN (NEURONTIN()

Gabapentin (Neurontin(), Parke-Davis Morris Plains, NJ): Gabapentin is described as 1-(aminomethyl) cyclohexane acetic acid with an empirical formula of C9H17No2. Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalization in adults with epilepsy.1 The mechanism by which it prevents seizures is unknown. Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but it does not interact with GABA receptors. Radioligand binding assays showed that gabapentin does not exhibit affinity for other common receptor sites. Recent research has shown that gabapentin binds to the alpha 2 delta subunit of voltage-dependent calcium channels.2

AIM OF INVESTIGATION

Current therapy for many patients with painful peripheral polyneuropathy remains frustratingly difficult. We report the first author’s encouraging experiences using gabapentin (Neurontin(), a novel anticonvulsant drug with a mechanism of action apparently distinct from that of other antiepileptic agents.

This initial list of ten patients ranging from forty-eight to seventy-eight years of age, represents the first reported series of patients with painful peripheral neuropathy treated with gabapentin.

METHODS

Peripheral neuropathy was confirmed in each patient by a detailed neurologic examination, nerve conduction study and electromyography (EMG). Quantitative thermal sensory testing was completed on selected patients.

Gabapentin was chosen because recent reports described its effectiveness in the management of reflex sympathetic dystrophy pain3,4,5,6 and because it is well tolerated and has a benign efficacy-to-toxicity ratio. Treatment with gabapentin was begun with 300 mg per day and titrated upward to maximal pain relief.

RESULTS

The gabapentin dosage ranged from 300 to 2000-mg with an average dose of 900 mg per day. All ten patients experienced significant and sustained pain relief with only transient central nervous system adverse effects. Fortuitously, two patients reported relief from refractory restless legs syndrome that had been unresponsive to previous multiple therapies. All patients reported improved quality of sleep. Several patients described Anxiolytic and mood enhancing effects.

discussion

Other authors have described gabapentin’s value for the treatment of neuropathic pain. In 1996, Segal and Rordof described gabapentin as a novel treatment for postherpetic neuralgia7 while Schacter and Suter identified gabapentin as a useful medication for the treatment of central pain.9 Chevelle and colleagues described the use of gabapentin for radiation myelopathy8 pain. Rosner and colleagues discussed the management of a variety of neuropathic pain states.10 In this report, the authors document the use of gabapentin in a series of patients with painful peripheral polyneuropathy.

CONCLUSION

Recent research has identified that gabapentin may relieve pain by binding to the alpha 2 delta subunit of voltage-dependent calcium channels and dose-dependently by which it inhibits the late phase of the nociceptive response in inflammatory pain models. Studies showed that gabapentin effectively inhibited thermal and mechanical hyperalgesia but failed to display an antinociceptive action in transient pain models.1

Research to identify gabapentin’s novel pain relieving mechanism in these patients is ongoing.

REFERENCES

1. Field MH, Oles RJ, Lewis AS, McCleary S, Hughes J, Singh L: Gabapentin (Neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents. Br J Pharmacolog 1997 Aug;121(8):1513-1522.

2. Gabapentin package insert, Parke-Davis company, Morris Town, NJ

3. Mellick LB and Mellick GA: Successful treatment of reflex sympathetic dystrophy with gabapentin. Am J. Emerg. Med. 1995;13:96.

4. Mellick GA and Seng ML: The use of gabapentin in the treatment of reflex sympathetic dystrophy and a phobic disorder. Am J. Pain Management 1995;5:7-9.

5. Mellick GA and Mellick LB: Gabapentin in the management of reflex sympathetic dystrophy. J. Pain and Symptom Management 1995; 10:265-266

REFERENCES

6. Mellick GA and Mellick LB: Reflex sympathetic dystrophy treated with gabapentin. Arch. Phys Med Rehabil.1977;78:98-105

7. Segal AZ and Rordorf G: Gabapentin as a novel treatment for postherpetic neuralgia. Neurology 1996;1175-1176

8. Cheville A et al: Neuropathic pain in radiation myelopathy: a case report. Program book, American Pain Society (14th Annual Scientific Meeting). Abstract #95823, Page A-115.

9. Schacter S. and Suter M: Treatment of central pain with gabapentin: Case Reports. J. Epilepsy 1996;223-226.

10. Rosner H, et al: Gabapentin adjunctive therapy in neuropathic pain states. Clin J. Pain . 1996;12:56-58.

PATIENTS TAKING GABAPENTIN

|TABLE 1 |

Pt. |Underlying Condition |Age |Gender |Neurontin Dose |Treatment |% Pain

Relief |Adverse Effects |Positive Effects | |1. |Diabetes Mellitus

|48 |Male |1600 mg/day |7 Months |75% |Drowsiness |Improved Sleep Quality | |2. |Rheumatoid Arthritis |77 |Female |300-600 mg q hs |11 Months |45% |Unsteady gait |Improved Sleep Quality | |3. |Diabetes Mellitus,

Hypothyroidism |59 |Female |1200 mg/day |5 Months |75% |None |Improved Sleep Quality | |4. |Paraneoplastic Syndrome |78 |Female |600-900 mg/day |11 Months |60% |Unsteady gait |Improved Sleep Quality | |5. |Diabetes Mellitus,

Restless Legs Syndrome |59 |Female |900 mg/day |10 Months |80% |None |Reduction of Leg Cramps and Restless Legs Syndrome, Improved Sleep | |6. |Unknown, Familial |62 |Female |900 mg/day |5 Months |85% |None |Improved Sleep Quality | |7. |Diabetes Mellitus,

Hypothyroidism |59 |Female |900 mg/day |9 Months |75% |Dizziness |Improved Sleep Quality | |8. |Alcohol Abuse, Prostate Cancer |69 |Male |2000 mg/day |6 Months |60% |None |Improved Sleep Quality | |9. |Porphyria

|46 |Male |1600 mg/day |2 Months |95% |Mild Euphoria |Improved Sleep Quality, Control of Leg Cramps | |10. |Unknown, Restless Legs Syndrome |69 |Female |300 mg q hs |6 Months |85% |None |Improved Sleep Quality, Control of Restless Legs Syndrome Symptoms | |

GABAPENTIN (NEURONTIN()

IN THE MANAGEMENT OF PAINFUL

PERIPHERAL polyNEUROPATHY

Gary A. Mellick, D.O., DAAPM

PRESIDENT, AMERICAN PAIN SPECIALISTS

1100 n. abbe rd, suites c & d ( Elyria, oh 44035

LARRY B. Mellick, M.D., FAAP, FACEP

CHAIR AND PROFESSOR, DEPARTMENT OF EMERGENCY MEDICINE

MeDICAL COLLEGE OF GEORGIA ( AUGUSTA, GA 30907

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