Gabapentin and pregabalin in dermatology

Asit Mittal, Chesta Agarwal, Manisha Balai, Ayush Taneja

 Department of Dermatology, Venereology and Leprology, R. N. T. Medical College, Udaipur, Rajasthan, India

Correspondence Address:
Asit Mittal
Department of Dermatology, Venereology and Leprology, R. N. T. Medical College, Udaipur - 313 001, Rajasthan
India

Introduction

The anticonvulsants gabapentin and pregabalin are of interest to dermatologists. The drugs have found uses in conditions that are frequently of interest to dermatologists and often primarily present to a dermatologist. These drugs are likely to find greater use in dermatology practice in future. This review is intended to familiarize dermatologists with these drugs.

History

Pregabalin was synthesized in 1990 as an anticonvulsant. It was invented by Richard Bruce Silverman at Northwestern University in Chicago, Illinois. The drug was approved in the European Union in 2004. The US received Food and Drug Administration approval for use in treating epilepsy, diabetic neuropathic pain and postherpetic neuralgia in December 2004. Gabapentin was originally approved by the U.S. Food and Drug Administration in December 1993 for use as an adjuvant medication to control partial seizures in adults; that indication was extended to children in 2000. In 2004, its use for treating postherpetic neuralgia (neuropathic pain following shingles) was approved.

Mechanism of Action

Gabapentin consists of a gamma amino butyric acid molecule covalently bound to a lipophilic cyclohexane ring (C₉H₁₇ NO₂) [Figure - 1]. It is a centrally active gamma amino butyric acid agonist, with its high lipid solubility aimed at facilitating its transfer across the blood–brain barrier. Despite their design as gamma amino butyric acid agonists, neither gabapentin nor pregabalin mimics gamma amino butyric acid when iontophoretically applied to neurons in primary culture.^[1] These compounds bind with a high affinity to a protein in cortical membrane with aminoacid sequence identical to that of calcium channel subunit α2δ-1.^[2] It has been speculated that the anticonvulsant effect of gabapentin is mediated by α2δ-1 protein, but whether and how binding of gabapentin to this protein regulate neuronal activity remains unclear.^[1] Pregabalin binding is reduced but not eliminated in mice carrying a mutation in α2δ-1 protein.^[3] It is unclear whether the anticonvulsant and analgesic effect of gabapentin and pregabalin are mediated by affecting calcium currents, and if so how.

Figure 1: Chemical structure of gabapentin

Pharmacokinetics

Gabapentin is not metabolized. It is eliminated via renal mechanism and is excreted unchanged. It does not induce hepatic enzymes. Absorption is nonlinear and dose-dependent at very high doses, but the elimination kinetics is linear. The drug is not bound to plasma protein. Drug–drug interactions are negligible. The half-life is relatively short ranging from 5.0 to 8.0 hours, hence, it is administered two or three times per day.^[4] It requires gradual adjustment of the dose. In contrast to gabapentin, pregabalin has linear and dose proportion absorption in therapeutic dose range (150 to 600 mg/d). It also has rapid onset of action and more limited dose range.^[4] Similar to gabapentin, it is also not metabolized and is almost entirely excreted unchanged in the urine. It is not bound to plasma proteins and has virtually no drug–drug interaction, again resembling the characteristics of gabapentin. Similarly, other drugs do not affect the pharmacokinetics of pregabalin. The half-life of pregabalin ranges from approximately 4.5 hour to 7.0 hours, thus, requiring more than once daily dosing in most patients.^[4]

Dosing

The initial dosage of gabapentin is 300 mg/d and can be increased up to 1200 mg three times a day.^[5],[6] It can be started at its effective dose rather than gradually titrated upwards in dosage.^[7] It should not be discontinued abruptly, but rather tapered gradually, because it can lead to withdrawal-related side-effects.^[8] It has a high toxicity ratio, minimizing the chance of adverse effects with even very high overdoses,^[9] hence, routine monitoring of clinical laboratory parameters is not required.^[5] Pregabalin is started at an initial dose of 150 mg/d and can be increased up to 600 mg/d.^[10]

Clinical Uses

Postherpetic neuralgia and other similar neuropathies

Approximately 10–15% of herpes zoster patients will develop postherpetic neuralgia, which can persist for many years. Dermatologists are often the primary care providers for postherpetic neuralgia patients. Several trials conducted previously reported statistically significant reduction in average daily pain after gabapentin and pregabalin.^{[11],[12],[13],[14],[15],[16],[17]} Gabapentin is the first oral medication approved in the USA for this condition.^[5] Reviews of controlled studies showed that patients suffering from postherpetic neuralgia experienced a statistically significant reduction in average daily pain after treatment with gabapentin. The study also showed that those receiving gabapentin experienced improvement in sleep and overall quality of life.^[11] Gabapentin is useful in the treatment of neuralgia in all areas of the body [Table - 1]. Its positive effect on neuralgia includes trigeminal neuralgia,^[18] glossopharyngeal neuralgia refractory to the usual medical treatments^[19] and facial neuritis.^[20] It is also useful in treating inflammatory pain.^[21] Gabapentin is also effective in the treatment of human immunodeficiency virus (HIV) neuropathy,^[22] painful diabetic neuropathy^[23] and diabetic neuropathic pain.^[24] Of particular interest to dermatologist is the probable usefulness of this drug in decreasing the trophic ulcerations that results from neuropathy in diseases such as HIV, leprosy and diabetes that are prone to such ulcers.^[5] Pregabalin is found to be efficacious in treating Red scrotum syndrome (poorly understood, chronic dysesthetic erythema primarily involving the anterior scrotum).^[25]

Pruritus

Generalized pruritus is a distressing symptom that can occur in several dermatologic and systemic disorders. Strong similarities exist between neural induction, transmission and processing of pruritus and pain. While itch is transmitted by a functionally distinct subset of neurons, overlap exists between the mediators and receptors involved in the pathogenesis of these sensations.^[26] In addition, it is now clear that chronic itch is influenced by a phenomenon of neural hypersensitization in a process that parallels what has been observed in chronic pain.^[27] In the wake of these discoveries, agents that target the neural system have emerged as effective antipruritic therapies.^[28] Gabapentin has been reported to be an effective antipruritic agent in uremic pruritus,^{[29],[30],[31],[32],[33],[34],[35],[36]} brachioradial pruritus,^{[9],[37],[38],[39],[40]} pruritus associated with wound healing in burns^[41] and notalgia paresthetica^[42] and pruritus of unknown origin.^[6],[43] Its effect in pruritus can be central and peripheral. It inhibits voltage-dependent calcium ion channels located in the spinal cord (with particular high density in the superficial laminae of the dorsal horn), inhibiting the release of excitatory neurotransmitters. Other mechanisms involved are increase in the synthesis of γ-aminobutyric acid from glutamate by altering the activity of glutamic acid decarboxylase in neurological tissue,^[44] inhibition of the release of calcitonin gene-related peptide, a neuropeptide, described as an itch mediator.^[45] Gabapentin also increases the threshold to experience nociception.^[46] Related drug Pregabalin, a gamma amino butyric acid analogue of gabapentin, has been used in the treatment of uremic pruritus,^{[47],[48],[49],[50]} brachioradial pruritus,^[51],[52] pruritus in prurigo nodularis^[53] and polycythemia vera-associated aquagenic pruritus.^[54] It was hypothesized that the beneficial effect of Pregabalin in chronic pruritus may result from counteracting the effects on the central sensitizing processes involved in the generation of chronic itch.^[55] It has also been reported to improve interleukin 2^[56] and cetuximab-related^[57] pruritus in cancer patients. However, at present there are insufficient data to conclude that these anticonvulsants can be an effective therapeutic alternative in the management of pruritus.

Gabapentin in various dynias

The “dynias” are a group of chronic, focal pain syndromes with a predilection for the orocervical and urogenital regions. They include glossodynia, carotidynia, scalp dysesthesia, vulvodynia, orchidynia, prostatodynia, coccygodynia and proctodynia [Table - 1].^[5] In some cases, the dynia occur secondarily, but more often, despite an exhaustive evaluation, no etiology is found, and in these cases the cause of pain remains enigmatic. Sometimes, these patients initially present to dermatologist. These dynias are found responsive to gabapentin. Allodynia is a sensation of pain to slight touch. It is another complication of postherpetic neuralgia. It can be effectively treated by gabapentin which can block both the static and dynamic components of mechanical allodynia.^[58] It also relieves cutaneous hyperalgesia after skin has been sensitized to pain.^[58] Reflex sympathetic dystrophy is a condition involving persistent pain that results from nerve injury. It has a variety of cutaneous manifestations, including atrophy, edema, erythema, bullae, and ulcers.^[59] Gabapentin has a role in the control of reflex sympathetic dystrophy-related pain in children^[60] and adults.^[61]

Other uses

Gabapentin has shown benefit in pain related to leiomyomas^[5] in patients with painful sclerodermatous changes that have affected nerve conduction,^[62] pain of the vasolabile condition and erythromelalgia.^[63],[64] Gabapentin has also shown benefits in various conditions associated with neurologic problems and skin. It is useful in the treatment of dysesthetic pain after reconstructive surgery,^[65] seizures due to acute intermittent porphyria,^[66] self-injurious behavior in Lesch-Nyhan syndrome^[67] and as a prophylaxis against steroid-induced mania.^[68] Finally, gabapentin improves pain control during wound dressing of cancer patients,^[69] suggesting that it might have a role in toxic epidermal necrolysis patients who complain of “painful skin.”^[70] In a recent article, gabapentin was also found to be effective for Vismodegib-induced muscle cramps.^[71] Pregabalin was also used for the treatment of painful hand-foot skin reaction associated with darafenib.^[72] Studies showing effect of gabapentin and pregabalin in various dermatological conditions have been described briefly in [Table - 2].

Adverse Effects

These drugs are relatively safe with very few serious adverse effects [Table - 3]. The most frequently reported adverse event is drowsiness/sedation. This is seen during the first month of treatment.^[5] This is also one of the most common cause for discontinuation of the drug.^[6] Others causes include dizziness, malaise/lassitude and ataxia.

Rarely, they can cause pancytopenia, causing fever, sore throat and ulcers in the mouth, or unusual bleeding and easy bruising, fluid retention in the legs and weight gain.^[5],[6] A few cases of allergic eruptions^[73] and Stevens–Johnson's syndrome^[74] have also been reported.

Very rarely gabapentin has induced cholestasis^[75] and hepatotoxicity.^[76] Studies conducted for its efficacy in pregnancy showed no congenital anomalies among the infants. However, the crude mortality rate was up to five times higher than in the general population.^[77] There are a few isolated reports about anorgasmia in women taking gabapentin.^[78]

Conclusion

Gabapentin and pregabalin are very promising medications in the treatment of painful conditions that often are domain of dermatologists such as postherpetic neuralgia, painful tumors, neuropathic ulcers or pain during dressing changes in conditions such as toxic epidermal necrolysis. Of great interest to a dermatologist is its use in chronic itch unresponsive to other medication. However, at present, there is insufficient data to suggest that these anticonvulsants can be an effective alternative to treat various types of skin sensitivities and pruritus. Future large randomized controlled studies are required that use behavioral methodology rather than subjective methodology. The chances of placebo effects are quite high with subjective methodologies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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