Leiomyoma 

Updated: May 23, 2018
Author: Fnu Nutan, MD, FACP; Chief Editor: William D James, MD 

Overview

Practice Essentials

Cutaneous leiomyomas are benign soft-tissue neoplasms that arise from smooth muscle (arrector pili). The arrector pili muscle contracts in response to cold, most commonly, or to fear or pleasure, causing what is commonly known as goose bumps. Cutaneous leiomyomas can develop wherever smooth muscles are present, but malignant transformation probably does not occur.

The importance of correct diagnosis of cutaneous leiomyoma lies is the association of multiple cutaneous leiomyomas with uterine fibroids and papillary renal cell carcinoma in what is known as Reed syndrome, or hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant disorder. This syndrome mandates regular follow up and screening as detailed in the Consultations section. More about the pathogenesis, genetics, penetrance, and treatment have been outlined in the corresponding sections of this article.

Signs and symptoms

The most common feature in patients with multiple piloleiomyomas (cutaneous leiomyomas) is pain, which can be spontaneous or induced by cold or tactile (eg, pressure) stimuli. The pain or tenderness also may be secondary to pressure on nerve fibers within the tumor; however, some authors believe it may be solely due to contraction of muscle fibers.[1] Symptoms are also reported to occur with menses or pregnancy. See the image below.

These multiple hyperpigmented nodules are piloleio These multiple hyperpigmented nodules are piloleiomyomas on an upper extremity.

Many solitary piloleiomyomas are similarly symptomatic. However, genital leiomyomas are usually asymptomatic solitary lesions arising from the dartoic, vulvar, or mammillary muscles in the genital region or on the nipple.[2]

Multiple piloleiomyomas can occur on the face, trunk, or extremities. Various distribution patterns are reported, including bilaterally symmetric, grouped, dermatomal and linear patterns.

Features of angioleiomyomas (vascular leiomyomas) include the following:

  • Most commonly present as solitary skin-colored nodules

  • Usually well-defined, fairly deep dermal nodules that are smaller than 4 cm

  • Often, pain to palpation

  • Occur predominantly on the lower extremities, less commonly on the head or trunk, and rarely on the hands or in the mouth[3, 4, 5]

Leiomyomas of the vulva or scrotum may be larger than those already described above. Leiomyomas of the nipple and piloleiomyomas are generally similar in size.

See Clinical Presentation for more detail.

Diagnosis

Features of individual piloleiomyomas include the following:

  • Smooth, firm papules or nodules

  • SIze range from 0.2-2 cm in diameter

  • Pink or reddish brown in color

  • Usually tender to palpation

  • Usually found on a lower extremity

  • Fixed in the skin but can be easily moved over the deeper subcutaneous tissues

Testing

Laboratory testing is generally not necessary for evaluation of leiomyomas unless there is abnormal vaginal bleeding or to rule out other conditions. The measurement of hemoglobin and/or hematocrit levels might be considered in patients with multiple leiomyomas, because erythrocytosis is reported in rare cases.

Imaging studies

Imaging studies are not routinely performed for leiomyomas; however, angioleiomyomas do have characteristic findings on ultrasonographic (including color Doppler) and magnetic resonance images. Uterine leiomyomas (also called fibroids) may be assessed by Doppler ultrasonography assessment before uterine artery embolization.[6]

Procedures

Tissue examination is necessary to establish the diagnosis. Therefore, a partial or excisional biopsy is indicated.

See Workup for more detail.

Management

All leiomyomas are tumors; therefore medical management has a limited role in the resolution or destruction of these lesions. However, pharmacologic intervention may alleviate associated pain.

Pharmacotherapy

The following medications are used in women with leiomyomas, primarily for analgesia:

  • Alpha-adrenergic blocking agents (eg, phenoxybenzamine)

  • Calcium channel blockers (eg, nifedipine)

  • Anticonvulsants (eg, gabapentin)

Surgical option

Surgical excision or ablation of leiomyomas may be helpful for some symptomatic women.

See Treatment and Medication for more detail.

Background

Leiomyomas are benign soft tissue neoplasms that arise from smooth muscle; they were first described by Virchow[7] in 1854 as "tuberculum dolorosum". The hereditary form, which causes, multiple leiomyomas, was originally noted by Kloepfer et al[8] in 1958. They can develop wherever smooth muscle is present. Malignant transformation probably does not occur. A 2006 report[9] of a cutaneous leiomyosarcoma with myxoid alteration in a scar of a piloleiomyoma that had been excised 3 years previously probably does not represent a case of malignant transformation.

Hereditary leiomyomatosis and renal cell cancer (HLRCC), also called Reed syndrome, is the primary tumor predisposition syndrome associated with inherited cutaneous leiomyomas with significant mortality. This autosomal dominant disorder with variable penetrance is caused by a defect in fumarate hydratase secondary to a missense mutation. Fumarate hydratase is an enzyme in the tricarboxylic acid (Krebs) cycle that acts as a tumor suppressor, and it has a cytoplasmic and a mitochondrial form. The presentation is variable, with patients presenting with early-onset recurrent uterine fibroids. They also have piloleiomyomas, which are multiple and may be symptomatic. Patients with HLRCC should be screened for renal cell carcinoma at regular intervals; however, there is no consensus on the screening guidelines. An MRI of the abdomen performed yearly is the most sensitive with the least radiation exposure to patients. The family also needs to be counselled, and genetic counselling should be offered.

Also see Esophageal Leiomyoma, Iris Leiomyoma, and Uterine Leiomyoma (Fibroid) Imaging.

Pathophysiology

Three fairly distinct types of cutaneous leiomyomas exist: piloleiomyomas, angioleiomyomas, and genital leiomyomas with distinct clinical and histological characteristics. This classification reflects the origin of the smooth muscle tumor and corresponds to the histologic or anatomic site where the leiomyomas are found. Piloleiomyomas are believed to arise from the arrector pili muscle of the pilosebaceous unit, whereas angioleiomyomas originate from smooth muscle (ie, tunica media) within the walls of arteries and veins. Leiomyomas derived from the dartos muscle of the scrotum and the labia majora, as well as those derived from the erectile muscle of the nipple, are classified as genital leiomyomas.

The pathogenesis of leiomyomas remains obscure. Angioleiomyomas and genital leiomyomas usually occur as solitary lesions, whereas piloleiomyomas may be either solitary or multiple, at times numbering in the thousands. The arrector pili muscle, from which piloleiomyomas originate, attaches proximally to the hair follicle and distally to multiple attachment points within the papillary and reticular dermis, as well as to the basement membrane. Piloleiomyomas can plausibly emerge from each of these various points of insertion and occur as multiple tumors. Multiple lesions can be inherited as an autosomal-dominant trait with variable penetrance, or they can occur sporadically.

The pathogenesis of pain associated with these lesions is not known. Some authors have suggested that pain could result from local pressure by the tumor on cutaneous nerves. However, the histologic findings do not show that prominent nerve fibers are associated with these tumors. Others have theorized that specific infiltrating cells may play a role; one study of 24 angioleiomyomas revealed that painful tumors had fewer mast cells than asymptomatic ones. Yet others have suggested that muscle contraction may be pivotal in the induction of pain.

The excitation of the arrector pili muscle occurs via the sympathetic nervous system. Norepinephrine, secreted by postganglionic nerve fibers, activates the alpha-receptors of the muscle. Muscle contraction ensues; this is triggered by the influx of ions, most specifically calcium. Understanding this basic physiologic process may be relevant to the medical treatment of symptomatic leiomyomas.

Leiomyomas may be categorized into the following four types:

  • Multiple piloleiomyomas

  • Solitary piloleiomyoma

  • Angioleiomyoma (solitary)

  • Genital leiomyoma (solitary)

Etiology

As yet, no mutations have been discovered in association with sporadic piloleiomyomas; however, associated mutations have been discovered for sporadic genital and angioleiomyomas. According to a study in which comparative genomic hybridization was performed in 33 angioleiomyomas,[10] the most recurrent loss of chromosome for angioleiomyoma is found in 22q11.2.

Genital leiomyoma are associated with the following mutations[11, 12] :

  • OCM gene - Codes for a calcium-binding oncoprotein
  • MOS gene - Codes for a proto-oncogene serine/threonine protein kinase
  • RB1CC1 gene - Codes for a key regulator of the tumor suppressor gene RB1, with inv(12) (p12q13–q14), with a rearranged and consequently active HMGA2 gene

Research has revealed the location of the gene for transmission of dominantly inherited, multiple cutaneous piloleiomyomas associated with uterine leiomyomas in female family members. The gene was linked to band 1q42.3-q43. Haplotype construction and recombination analysis narrowed the locus to an approximately 14-centromere interval located between D1S517 on the centromeric side and D1S2842 on the telomeric side. As reported by Alam et al,[13] the locus is termed MCUL1 for multiple cutaneous and uterine leiomyomata (MCUL)‒1.

Studies of an extended family narrowed the locus further to a region of the 4.55-7.17 centromere on chromosome 1. This gene encodes for fumarate hydratase (FH gene), an enzyme of the tricarboxylic acid cycle that acts as a tumor suppressor. In families with multiple cutaneous and uterine leiomyomata (MCUL) and hereditary leiomyomatosis and renal cell cancer (HLRCC), FH missense mutations often occur in fully conserved residues and in residues functioning in the substrate binding A-site, substrate-binding B-site, or subunit-interacting region. All missense mutations in these families are associated with decreased enzyme activity, suggesting that the tumor suppressor role of fumarate hydratase is related to its enzymatic activity.[14]

A study of 108 affected individuals, including 46 probands and 62 affected relatives, revealed that highly penetrant FH mutations underlie MCUL. Of women with FH mutations, 69% had both skin and uterine leiomyomas, 15% had only skin leiomyomas, and 7% had only uterine leiomyomas.[15] Uterine leiomyomas not associated with skin leiomyomas were associated with the G354R FH mutation. Wei et al[16] have so far identified 31 different germline FH mutations in 56 families with HLRCC. Six additional FH mutations have been described among Dutch and Spanish families with MCUL.[17]

Epidemiology

Frequency

Leiomyomas are uncommon. Piloleiomyomas are the most common, while genital leiomyomas tend to be the least common of the three types.[18]

Race

A racial predilection is not described, except in regard to oral angioleiomyomas, for which the white-to-black ratio has been reported to be 3:1.[3]

Sex

The incidences of piloleiomyomas in men and women appear to be about equal. Women who have multiple cutaneous piloleiomyomas may also have uterine leiomyomas (also known as fibroids). If the latter are present, the patient most likely has a familial condition called familial leiomyomatosis cutis et uteri, or Reed syndrome. Reed syndrome is thought to be inherited as an autosomal dominant trait with incomplete penetrance. Mutations in the Krebs cycle enzyme fumarate hydratase are associated with Hereditary leiomyomatosis and renal cell cancer (HLRCC). Reed syndrome is associated with renal cell carcinoma.[19] As such, not all women in a family are affected, with some having only cutaneous, only uterine, or both cutaneous and uterine leiomyomas.[20, 21]

Angioleiomyomas are more common in women than in men, with a ratio of 2:1 overall; however, the solid subtype occurs more commonly in females (3:1), the venous subtype occurs more commonly in males, and the least common of the three, the cavernous subtype, is four times more common in males.[1, 22]

Because genital leiomyomas are rare, data to determine whether a sexual predilection exists are inadequate.

Age

Cutaneous leiomyomas are more likely to occur in adults than in children. However, isolated reports of cutaneous leiomyomas in children exist, including one involving a nonspecified type of solitary cutaneous leiomyoma on the heel of a neonate at birth.

Multiple piloleiomyomas generally occur in those aged 10-30 years. When solitary, piloleiomyomas usually appear later. For example, in a series of 28 solitary cutaneous leiomyomas, the mean patient age at presentation was 53 years.

Angioleiomyomas most often occur in those aged 20-60 years, although some investigators report a narrower window of increased incidence in those aged 20-40 years. In a retrospective clinicopathologic analysis of 562 angioleiomyomas, the mean age of the patients was 47 years; their overall age range was 12-84 years.

Leiomyomas typified as genital leiomyomas are rare enough that an age predilection is not generally described.

Prognosis

The prognosis for a solitary lesion is excellent, especially if it is surgically excised. Multiple piloleiomyomas gradually increase in size and number.

Because cutaneous leiomyomas are benign tumors, they do not directly affect mortality, unless the patient has hereditary leiomyomatosis and renal cell cancer (HLRCC). However, one case report[9] involves an angioleiomyoma that occurred in association with a leiomyosarcoma. The relevance of this association is unknown.

Associated morbidity may be from spontaneous lesional pain, as well as pain evoked by cold and/or tactile hypersensitivity. Additionally, multiple piloleiomyomas have the potential to be cosmetically disfiguring.

Around 180 families have been diagnosed with HLRCC, with most cases originating from Eastern Europe.[23]

 

Presentation

History

The most common feature in patients with multiple piloleiomyomas is pain. Pain can be spontaneous or induced by cold or tactile (eg, pressure) stimuli. The pain or tenderness may be secondary to pressure on nerve fibers within the tumor; however, some authors believe it may be solely due to contraction of muscle fibers.[1]

Many solitary piloleiomyomas are similarly symptomatic.

About 60% of angioleiomyomas are symptomatic.[22] Pain in angioleiomyomas may be due to nerve fibers in the stroma or wall of the tumors or perhaps due to the contraction of blood vessels with local ischemia.[1]

In addition to the previously described trigger factors (ie, temperature and pressure), symptoms are also reported to occur with menses or pregnancy.

Genital leiomyomas are usually asymptomatic solitary lesions arising from the dartoic, vulvar, or mammillary muscles in the genital region or on the nipple.[2]

Physical Examination

Individual piloleiomyomas are smooth, firm papules or nodules, usually smaller than 2 cm in diameter, and reddish brown. Many are tender to palpation. Multiple piloleiomyomas can occur on the face, trunk, or extremities. Various distribution patterns are reported, including bilaterally symmetric, grouped, dermatomal, and linear patterns.[24]  A solitary piloleiomyoma is usually found on a lower extremity. Because piloleiomyomas develop in the superficial dermis, they are fixed in the skin. However, they can be easily moved over the deeper subcutaneous tissues.

These multiple hyperpigmented nodules are piloleio These multiple hyperpigmented nodules are piloleiomyomas on an upper extremity.
Upon closer inspection, one can appreciate that th Upon closer inspection, one can appreciate that these piloleiomyomas are superficial dermal nodules.

Angioleiomyomas are usually well-defined, fairly deep dermal nodules that are smaller than 4 cm. Pain to palpation is not uncommon. Angioleiomyomas are generally solitary and occur predominantly on the lower extremities, less commonly on the head or trunk, and rarely on the hands or in the mouth.[3, 4, 5]  The most common clinical presentation of an angioleiomyoma is that of a solitary skin-colored nodule.

Leiomyomas of the vulva or scrotum may be larger than those already described above. Leiomyomas of the nipple and piloleiomyomas are generally similar in size.

Complications

Cosmetic disfigurement can occur in association with the presence of multiple piloleiomyomas.

Pain is present in most cases.

 

DDx

Diagnostic Considerations

Also consider the following:

  • Angiolipoma
  • Adnexal tumor
  • Cylindroma
  • Dermal nevi
  • Dermatofibroma/dermatomyofibroma
  • Neuroma
  • Giant cell tumor
  • Glomus tumor
  • Hamartoma
  • Keloids
  • Eccrine spiradenoma
  • Fibrosed epidermoid inclusion cyst
  • Breast carcinoma (differential diagnosis of leiomyoma involving areola or nipple)
  • Lipoma
  • Poroma
  • Trichoepithelioma
  • Plasmacytoma
  • Neurofibroma
  • Nevus

Multiple cutaneous and uterine leiomyomatosis (ie, MCUL or Reed syndrome) is present in women with multiple cutaneous piloleiomyomas and uterine leiomyomas. Pain can be problematic in these patients, who are frequently not surgical candidates because of the location and enormous number of tumors. Polycythemia may be associated with multiple leiomyomas in rare cases. This phenomenon may be due to tumor production of an erythropoietinlike substance.

Differential Diagnoses

 

Workup

Laboratory Studies

The measurement of hemoglobin and/or hematocrit levels might be considered in patients with multiple leiomyomas because erythrocytosis is reported in rare cases.

Imaging Studies

Imaging studies are not routinely performed for leiomyomas; however, angioleiomyomas do have characteristic findings on ultrasound and magnetic resonance images.

On ultrasound images, angioleiomyomas show well-defined margins and a homogeneous structure suggestive of their benign nature. On color Doppler, they show high resistance in intratumor arteries, suggesting the presence of muscular arteries.[22]  Doppler is useful in patient assessment before uterine artery embolization for uterine leiomyoma.[6]

MRI cannot differentiate between the different histological subtypes of angioleiomyomas; however, images show mixed hyperintense and isointense areas compared with skeletal muscle, with a hypointense rim corresponding to a fibrous capsule on T2-weighed images.[22, 25]

Procedures

Tissue examination is necessary to establish the diagnosis. Therefore, a partial or excisional biopsy is indicated.

Other Tests

Fumarate hydratase testing plays an important role in the diagnosis of patient with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Its absence causes increased expression of ferritin 38. The gene whose heterozygous expression causes HLRCC is located on chromosome one and its activity can be tested with immunohistochemistry or the gene mutation itself can be tested. However, new reports have emerged in which the sensitivity of immunohistochemistry testing was seen to be low 39% and new novel mutations were found near the hot spot of the originally tested mutation.[26]

Histologic Findings

Leiomyomas are smooth muscle tumors that are generally well differentiated. The characteristic smooth muscle nuclei are elongated with blunt ends, and they are often described as cigar or eel shaped. When these fibers are cut in cross-section, perinuclear vacuolization may be appreciated. With electron microscopy, the smooth muscle cells of a leiomyoma appear normal.

Piloleiomyomas occur mainly in the reticular dermis and are not encapsulated. The smooth muscle bundles of these tumors are interlaced with variable amounts of collagen. The rate of mitotic activity, if present, is low.

Genital leiomyomas are similar to piloleiomyomas in their histologic appearance.

In contrast, angioleiomyomas contain many dilated vascular spaces amidst smooth muscle bundles arranged in a more concentric fashion. These vascular spaces are lined by an endothelium. For further distinction, angioleiomyomas are well circumscribed or encapsulated and contain minimal collagen. In addition, larger angioleiomyomas frequently have areas of mucinous alteration.

Three histologic subtypes of angioleiomyomas are based on differences in the vascular channels: solid or capillary, cavernous, and venous. The solid or capillary type contains many small vascular spaces. Cavernous tumors have dilated vascular spaces with only small amounts of smooth muscle. The venous subtype contains veins with thick muscular walls.

Special stains can be used to distinguish smooth muscle from collagen, both of which are pink-red with hematoxylin-eosin stain. The Masson trichrome stain highlights smooth muscle as dark red and collagen as blue-green. With aniline blue stains, smooth muscle appears red and collagen appears blue. A van Gieson stain results in yellow smooth muscle contrasted against red collagen. With phosphotungstic acid–hematoxylin (PTAH) stain, myofibrils are purple. Immunohistochemical staining for desmin and actin, markers of smooth muscle differentiation, can be performed to detect these markers in leiomyomas. Interestingly, the stromal cells within an angiomyoma lack the human progenitor cell antigen CD34.[27, 28]

 

Treatment

Medical Care

Because all leiomyomas are tumors, medical management has a limited role in the resolution or destruction of these lesions. However, pharmacologic intervention may alleviate associated pain.

Several investigators report that calcium channel blockers, particularly nifedipine, relieves pain associated with many cases of piloleiomyomas. As the name implies, drugs in this class inhibit the movement of extracellular calcium ions across the cell membrane into the smooth muscle cell, thereby inhibiting muscular contraction. These data support the theory that muscle contraction is somehow responsible for pain in at least some tumors.

Phenoxybenzamine, an alpha-adrenoceptor blocker, is also reported to be helpful in alleviating pain,[29] including cold-induced pain, in some cases.

Gabapentin has also shown promise in alleviating pain from piloleiomyomas; however, larger randomized trials have not yet been conducted.[30, 31]

Two case reports describe botulinum toxin therapy for relief of pain associated with leiomyoma, although one suggested a possible placebo effect.[32, 33]

Antineoplastic drugs for use in hereditary leiomyomatosis and renal cell cancer (HLRCC)

A phase II study of bevacizumab with erlotinib specifically for use in HLRCC papillary renal cell carcinomas (NCT01130519) is underway. Metformin is another drug that has been suggested, given the association with decreasing cancer incidence in diabetic individuals. It induces oxidative damage and, hence, is proapoptotic and antineoplastic. Fumarate hydratase‒cancer-specific treatments such as heme oxygenase, Englerin A or those geared towards particular fumarate hydratase transcriptional targets, are possible future therapies.[34]

Surgical Care

Surgical excision or ablation may be helpful for some symptomatic individuals. If left alone, most of the cutaneous leiomyomas tend to grow over time. Excision is frequently effective with a solitary leiomyoma, especially when followed by skin graft.

Excision of multiple piloleiomyomas is more cosmetically problematic and less effective than excision of solitary leiomyomas. The recurrence of lesions is more common with multiple piloleiomyomas than with single lesions. After excision, subsequent recurrences have been reported to occur from 6 weeks to more than 15 years.[1] One case report described total excision of multiple leiomyomas followed by immediate artificial skin graft, with successful results.[35]

One report revealed promising results for pain relief with carbon dioxide laser ablation of several symptomatic leiomyomas over a follow-up of as long as 3-9 months. Only local anesthesia was required for this procedure.

Consultations

There are no guidelines for the management or screening of hereditary leiomyomatosis and renal cell cancer (HLRCC) . Female patients with multiple leiomyomas and a history of a family member with multiple leiomyomas should be referred to a gynecologist for evaluation at least once a year and have a full skin examination biannually. They also need consultation with a urologist once renal involvement is suspected based on a simple urinalysis.[36]

The radiological investigation of choice for surveillance still has not been established. CT scanning of the abdomen is not recommended, owing to radiation exposure. MRI and ultrasonography are indicated, but ultrasonography is not sensitive for isoechoic renal lesions. Some experts suggest wide excision for all tumors that are found.[37]

Women who have multiple cutaneous piloleiomyomas may also have uterine leiomyomas. If the latter are present, the patient most likely has a familial condition termed multiple cutaneous and uterine leiomyomata (MCUL).[14] This is also known as leiomyomatosis cutis et uteri, or Reed syndrome.

A disease variant involving aggressive renal cancer can also occur and is termed HLRCC.[14] Two family kindreds in Finland with uterine leiomyomas had the unusual association of unilateral papillary renal cell carcinoma. Interestingly, seven members of one family had cutaneous nodules. Two of them underwent skin biopsy, which showed multiple cutaneous piloleiomyomas.

Reed syndrome is thought to be inherited as an autosomal dominant trait with incomplete penetrance. As such, not all women in a family are affected, and those who are affected may have only cutaneous, only uterine, or both cutaneous and uterine leiomyomas.

Prevention

In a study of 1036 randomly selected premenopausal women (age range, 35-49 y), adequate plasma levels of vitamin D (>20 ng/mL) were associated with a reduced risk of uterine leiomyomas. Only 10% of the 620 black women and 50% of the 416 white women in the study had sufficient levels of vitamin D. Compared with women with vitamin D insufficiency, those with sufficient vitamin D had about 32% lower odds of uterine leiomyomas. This relationship was similar for black and white women. There was also an association between daily sun exposure for 1 hour or more and a reduced risk of developing uterine leiomyomas.[38]

 

Medication

Medication Summary

In the management of multiple leiomyomas, drugs are used mainly for the control of associated pain. Calcium channel blockers and phenoxybenzamine are both reported to be effective.

Alpha-adrenergic blocking agents

Class Summary

Phenoxybenzamine may alleviate pain, including cold-induced pain.

Phenoxybenzamine (Dibenzyline)

Phenoxybenzamine decreases smooth muscle contractions through long-lasting noncompetitive alpha-adrenergic blockade of postganglionic synapses at smooth muscles.

Calcium channel blockers

Class Summary

These drugs inhibit the movement of calcium ions across the cell membrane and into smooth muscle cells. They also depress both impulse formation and conduction velocity.

Nifedipine (Adalat, Procardia)

Nifedipine may relax smooth muscles. Its effects in reducing pain are not understood.

Anticonvulsants

Class Summary

Gabapentin is indicated for the treatment of partial seizures in adults and for the management of postherpetic neuralgia. It has also been used for a range of neuropathic pain conditions. The exact mechanism of action is unknown; however, it appears to interact with a high-affinity binding site in brain membranes (an auxiliary subunit of voltage-sensitive Ca2+ channels.

Gabapentin (Neurontin)

Gabapentin is a membrane stabilizer, a structural analogue of the inhibitory neurotransmitter GABA, which paradoxically is thought not to exert effects on GABA receptors. It appears to exert action via the alpha(2)delta1 and alpha(2)delta2 auxiliary subunits of voltage-gaited calcium channels. Gabapentin is used to manage pain and provide sedation in neuropathic pain.