Vol 10, No 3, May/June 2002 153 Both nociceptive pain and neuropathic pain are com- monly encountered in the orthopaedic setting. In most patients, nociceptive pain (eg, acute postoperative pain or pain associated with a fracture) may be adequately controlled with nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, or a combination of these. Neuropathic pain refers to a group of disorders charac- terized by pain resulting from dysfunction or disease of the nervous system at a peripheral level, central level, or both. Frequently, NSAIDs and opioid analgesics do not provide relief, and adequate control requires medica- tions directed specifically at neuropathic pain. Medications commonly used include antispasmodics, tricyclic antidepressants, and anticonvulsant agents. Anticonvulsant drugs have been used in pain manage- ment since the 1960s, soon after they were first used in the management of epilepsy. A recent addition to this class of agents is gabapentin. Gabapentin was initially approved by the FDA for use as an adjunct in treating partial seizures with or without generalization. Its safe- ty and efficacy soon led to its use in treating a wide vari- ety of neuropathic pain conditions. It has some distinct advantages over other available medications. As a result, gabapentin has rapidly become a first-line agent for the treatment of neuropathic pain. Structure and Mechanism of Action Neuropathic pain is the result of complex pathophysio- logic changes occurring at many levels. These changes include increased neuronal excitability and ectopic firing at the site of injury and the dorsal root ganglia. In addi- tion, upregulation of sodium channels, enhanced sensi- tivity to mechanical and chemical stimuli, proliferation of adrenergic innervation, and changes involving calcium signaling affecting synaptic neurotransmitter release contribute to the pathophysiology of neuropathic pain. Gabapentin is a structural analog of gamma-amino- butyric acid (GABA), an inhibitory amino acid that exerts presynaptic control of large primary afferent fibers. The GABA receptor is a metabotropic receptor that inhibits depolarization via G protein–coupled effects on calcium or potassium currents. Gabapentin readily crosses the blood-brain barrier when given sys- temically (Fig. 1). GABA is metabolized by GABA transaminase and succinic semialdehyde dehydroge- nase (SSADH). Production of succinic acid by SSADH allows entry of the GABA carbon into the tricarboxylic acid cycle. Gabapentin does not bind to GABA receptors. It may influence the synthesis and release of GABA, but it does not influence the uptake and metabolism of endoge- nous GABA. The analgesic effect on neuropathic pain may be a stereospecific action mediated, at least in part, by the inhibition of impulse generation of ectopic afferent discharges at the site of nerve injury. A gabapentin-spe- cific binding site in the central nervous system has been identified as the α 2 δ subunit of voltage-dependent cal- cium channels. Sarantopoulos et al 1 assessed the effect of gabapentin on the membrane voltage–activated inward calcium currents in the primary afferent neurons of dorsal root ganglia in rats. They found that clinically relevant doses of gabapentin decreased neuronal peak inward cal- cium currents of midsized neurons in both control and neuropathic rats in a fast, reversible, concentration- dependent manner. They concluded that analgesia might be caused by diminished release of neurotransmitter by sensory neurons, a calcium-dependent process. 1 Although these channels have been implicated in hyper- algesia, binding to these receptors alone may not be suffi- cient to explain the effects of gabapentin on allodynia and hyperalgesia. At present, the picture remains unclear. 2 Pharmacokinetics Gabapentin displays dose-dependent absorption, with systemic bioavailability decreasing with increasing doses. This is the result of an active and saturable trans- Dr. Rosenquist is Associate Professor, Anesthesia, and Director, Pain Medicine Division, University of Iowa Hospitals and Clinics, Iowa City, IA. The author or the departments with which he is affiliated have received something of value from a commercial or other party related directly or indirectly to the subject of this article. Reprint requests: Dr. Rosenquist, 200 Hawkins Drive, Iowa City, IA 42242. Copyright 2002 by the American Academy of Orthopaedic Surgeons. J Am Acad Orthop Surg 2002;10:153-156 Gabapentin Richard W. Rosenquist, MD Advances in Therapeutics and Diagnostics port system. 3 Over the recommended dose range of 300 to 600 mg tid, the differences in bioavailability are not large, and bioavailability is approximately 60%. However, at large doses (>1,800 mg/day), changing from a tid to a qid schedule may result in greater sys- temic availability. Peak serum levels are achieved 2 to 3 hours after administration. Gabapentin has very little affinity for plasma proteins, and 97% is unbound. It is not appreciably metabolized in humans or animals and does not appear to interact pharmacokinetically with other antiepileptic medications. The elimination half- life is 5 to 7 hours. Gabapentin’s primary route of elimi- nation is renal excretion. The elimination rate constant, plasma clearance, and renal clearance are directly pro- portional to creatinine clearance. 4 Indications for Use Gabapentin is an anticonvulsant with FDA approval as an adjunctive therapy for partial seizures with and with- out secondary generalization. The established record of successful neuropathic pain treatment with anticonvul- sants and gabapentin’s improved safety profile soon led to its off-label use for treatment of neuropathic pain. Neuropathic pain is frequently a component of many conditions encountered in the practice of orthopaedics. Examples include painful diabetic neuropathy, the com- plex regional pain syndromes ([CRPSs] reflex sympa- thetic dystrophy and causalgia), radicular pain from her- niated intervertebral disk or spinal stenosis, persistent radicular pain after spinal surgery, or peripheral nerve injury. These pains are frequently described as burning, lancinating, numbing, electrical sensations that may bear no relationship to activity or intensity of stimulus. Patients who report neuropathic pain with lancinating and steady-burning qualities are more likely to respond to treatment with gabapentin compared with pain of other qualities. There have been very few large trials studying the use of gabapentin for the treatment of neuropathic pain, and future studies to obtain new FDA indications are unlikely to be completed. (The second-generation drug pregabalin is undergoing clinical trials that include not only anticonvulsant activity but also treatment of a wide variety of neuropathic pain conditions.) The majority of published reports have been case series of gabapentin use in a variety of neuropathic pain conditions. In a study of 165 patients, Backonja et al 5 reported a 60% improvement on a global scale for those on gabapentin monotherapy (up to 3.6 grams/day) after 4 weeks of treatment for diabetic neuropathy. In 80% of patients, the dose was escalated from 900 to 3,600 mg/day administered in three divided doses over a period of 2 weeks. Pain was measured using a Likert scale (0, no pain; 10, worst possible pain). Pain relief was noted during the second week of the study, when the dose reached 1,800 mg/day. Pain relief was maintained after further increases in the dose and for the remainder of the 8-week study (P < 0.05). 5 Additional, statistically significant differences favoring gabapentin treatment were observed in measures of quality of life (the Medical Outcomes Study 36-Item Short Form [P < 0.01] and the Profile of Mood States [anger/hostility, P = 0.02; vigor/activity, P = 0.01; fatigue/inertia, P = 0.01; total mood disturbance, P = 0.03]). Mellick et al 6 and Mellick and Mellick 7 reported the successful use of gabapentin as an adjuvant in reducing the symptoms of CRPS type I in two case series with a total of 15 patients. All patients were middle-aged adults (predominantly women) who had experienced symptoms of CRPS for extended periods and had received treatment with medications, physical therapy, and nerve blocks before receiving gabapentin. The authors reported successes with doses ranging from 900 to 3,600 mg/day and concluded that gabapentin might become the treatment of choice for CRPS. 6,7 Rusy et al 8 reported the successful use of gabapentin as an adjuvant in the treatment of phantom limb pain in children and young adults (aged 4 to 28 years) who had undergone lower limb amputation because of trauma or for treatment of osteosarcoma. Peak daily gabapentin doses ranged from 14 to 40 mg/kg given in three divided doses. Five of seven patients were able to wean themselves off gabapentin without recurrence of symptoms. One patient continued to take gabapentin, with improved control of her phantom limb pain. One patient used gabapentin with good control of his symptoms for 4 months until his death. The authors Gabapentin Journal of the American Academy of Orthopaedic Surgeons 154 H 2 N COOH Figure 1 Gabapentin. C 9 H 17 NO 2 1-(aminomethyl)cyclohexane- acetic acid. Molecular weight, 171.24. concluded that gabapentin may have a useful role in the management of phantom limb pain in children and young adults. 8 Persistent radicular pain or epidural fibrosis, which can occur after lumbosacral spine surgery, is frequently resistant to physiotherapy and pharmacologic treat- ment. Long-term outcome studies focusing on pharma- cologic management of pain associated with epidural fibrosis are lacking in the literature; however, Braver- man et al 9 reported the successful use of gabapentin monotherapy as an adjuvant to treat persistent pain caused by epidural fibrosis in a 36-year-old woman after microdiscectomy and in an 81-year-old woman after lumbar decompressive laminectomy. 9 Chronic neuropathic pain occurs in 77% of all patients with spinal cord injury and frequently affects quality of life. 10 This pain is difficult to treat and often requires multiple trials with different pharmacologic agents to balance side effects with benefit. Kapadia and Harden 11 reported on the use of gabapentin as an adjuvant in a 30- year-old woman with an L1 complete spinal cord injury secondary to a gunshot wound. She had a 13-year history of chronic lower extremity pain described as throbbing, aching, and stabbing and had been treated unsuccessfully with opioids, carbamazepine, and tricyclic antidepres- sants. She was initially treated with gabapentin 300 mg tid. Within 1 week, the patient’s visual analog pain score fell from 95 to 27 mm and her Short Form McGill pain score fell from 13 to 3. Her long-term treatment regimen consisted of gabapentin 600 mg tid with doxepin 100 mg nightly. 11 A recently reported series of 31 patients with traumatic spinal cord injury were treated for their pain with gabapentin. Of the 27 available for follow-up at 6 months, 14 had a favorable response. And of that group, 91% continued to have effective analgesia at 36-month follow-up. 12 Werner et al 13 examined the effects of gabapentin monotherapy in acute inflammatory pain in a double- blind, randomized, placebo-controlled crossover study. Gabapentin or placebo was given on two separate days. Three hours after drug administration, a first-degree burn injury was produced on the medial aspect of the calf. Quantitative sensory testing included pain ratings to thermal and mechanical stimuli, assessments of ther- mal and mechanical detection thresholds, and areas of secondary hyperalgesia. The burn injury produced sig- nificant primary and secondary hyperalgesia (P < 0.0001). Gabapentin diminished the decrease in mechan- ical pain threshold in the burn area (P = 0.04) and reduced secondary hyperalgesia, but not significantly (P = 0.06). Heat pain thresholds, pain during the burn, and mechanical pain in the area of secondary hyperalgesia also were not affected significantly by gabapentin (P < 0.2). The authors concluded that gabapentin has no analgesic effect on normal skin, although it may reduce primary mechanical allodynia in acute inflammation after thermal injury, suggesting a clinical potential for gabapentin in treating acute postoperative pain. 13 It has been used as an adjuvant to morphine during daily wound care in cancer patients. Drug Interactions and Adverse Effects The most common adverse effects with gabapentin are somnolence, dizziness, ataxia, fatigue, blurriness of vision, and nystagmus. 4 Other reported side effects include headache, diarrhea, confusion, nausea, short- term memory difficulty, gait instability, and slowed response time for completing tasks of daily living. 6 Occasionally, peripheral edema or a craving for sweets has been reported. In addition, gabapentin might impair patients’ cognition and ability to operate machinery. 4 Gabapentin has few drug interactions; however, ant- acids have been shown to decrease the bioavailability of gabapentin by 20%. Therefore, gabapentin should be given at least 2 hours after antacid administration. 4 Dosage and Cost The cost of gabapentin is approximately equivalent to the cost of comparable anticonvulsant drugs (Table 1). Richard W. Rosenquist, MD Vol 10, No 3, May/June 2002 155 Table 1 Cost Comparison of Gabapentin and Other Anticonvulsant Drugs Cost/ Cost/ Anticonvulsant Oral Dosage Day * Month * Gabapentin 600 mg tid $5.96 $178.69 (Neurontin) Lamotrigine 600 mg bid $4.58 $137.42 (Lamictal) Divalproex 750 mg bid $5.01 $152.05 † (Depakote) Topiramate 100 mg bid $5.74 $172.19 (Topamax) Carbamazepine 400 mg bid $2.10 $63.10 † (Tegretol) Oxcarbazepine 300 mg bid $3.46 $103.89 (Trileptal) * Cost estimates from www.drugstore.com, March 14, 2002. † These costs are undervalued relative to the cost of appropriate laboratory testing. The effective dose of gabapentin for the treatment of neuropathic pain varies but is similar to the doses effec- tive for seizure treatment, ranging from as little as 300 mg/day to over 3,600 mg/day. The effective dose for treatment of partial seizures recommended by the man- ufacturer is 900 to 1,800 mg/day in divided doses using 300- or 400-mg capsules or 600- or 800-mg tablets. Doses of up to 2,400 mg/day have been well tolerated in long- term clinical studies. Doses of up to 3,600 mg/day have been administered for a short duration with minimal side effects. The recommended starting dose is 300 mg tid. In some patients, this is poorly tolerated; an alterna- tive regimen for starting gabapentin is 100 mg tid for 1 week, 200 mg tid for 1 week, then up to 300 mg tid. In some patients, a starting dose of as little as 100 mg qhs may be required. Further dose escalation may be accom- plished more rapidly if the patient tolerates it. The maxi- mum time between doses should not exceed 12 hours. Discontinuation of gabapentin should be done grad- ually over 1 week. In addition, gabapentin should be used cautiously in the elderly and in patients with renal impairment and dosed accordingly. If creatinine clear- ance is between 30 and 60 mL/min, total daily dose should not exceed 600 mg/day given as 300 mg bid. If creatinine clearance is between 15 and 30 mL/min, total daily dose should not exceed 300 mg/day given as a single 300-mg dose. If creatinine clearance is <15 mL/min, total daily dose should not exceed 150 mg/day given as 300 mg qod. The ability to give a drug of this class without the need to perform clinical laboratory testing or blood-level monitoring simplifies its use. This is because of the ab- sence of known dose-related toxic effects such as those observed with carbamazepine or a known therapeutic blood-level range. In addition, dose modification may be readily accomplished with a phone call. If drug administration is not limited by side effects, treatment failure should not be considered until a daily dose of at least 3,600 mg is reached. Because of dose-related decreases in bioavailability, adding an additional dose rather than increasing the dose in some patients may be more effective and reduce overall cost of drug adminis- tration. There are no issues of drug dependence or abuse, and discontinuing the drug is straightforward. Summary Gabapentin is commonly used as a monotherapy or adjunctive therapy for the treatment of neuropathic pain in a wide variety of settings. Its proven safety record, lim- ited side-effect profile, wide dose-ranging capabilities, and effectiveness make it extremely valuable compared with other anticonvulsant drugs that might be considered for the control of neuropathic pain. Despite gabapentin’s relative ease of use, neuropathic pain is frequently chal- lenging to treat and may require several medications in the setting of a multidisciplinary treatment program. Gabapentin Journal of the American Academy of Orthopaedic Surgeons 156 References 1. Sarantopoulos C, McCallum B, Kwok WM, Hogan Q: Gaba- pentin decreases membrane calcium currents in injured as well as in control mammalian primary afferent neurons. Reg Anesth Pain Med 2002;27:47-57. 2. 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