Anticonvulsants and the Relief of Chronic Pain: Pregabalin and Gabapentin As Α2δ Ligands at Voltage-Gated Calcium Channels

B R A I N S T O R M S Clinical Neuroscience Update

Anticonvulsants and the Relief of Chronic Pain: Pregabalin and Gabapentin as α2δ Ligands at Voltage-Gated Calcium Channels

Stephen M. Stahl, M.D., Ph.D.

α δ Issue: Anticonvulsants that act as ligands at 2 subunits of voltage-gated calcium channels are proving to be novel treatments for chronic pain.

ecent BRAINSTORMS features 2 chronic pain conditions for which of reducing neurotransmission by sev- R have highlighted the fact there are, as yet, no approved treat- eral distinct mechanisms,1,8 they have that anticonvulsants have ments, namely diabetic peripheral neu- been investigated as potential treat- several different mechanisms of ac- ropathy and fibromyalgia.4Ð6 ments for chronic pain. Those that tion1 and that some of these mecha- reduce neurotransmission by blocking nisms may also have therapeutic NEUROTRANSMISSION voltage-gated sodium channels include applications in anxiety disorders.2,3 AND CHRONIC PAIN lidocaine, carbamazepine, and lamotri- Last month we specifically reviewed a gine,1,8,9 but only topical application of novel class of anticonvulsants with ac- Acute pain and its neuroanatomic lidocaine is specifically recommended α δ 10 tions as ligands at the 2 subunit of basis are well characterized, but the for the treatment of neuropathic pain. voltage-gated calcium channels.3 A pathophysiology of chronic pain is less Presumably, blocking sodium channels new entrant to this class, pregabalin, is well understood. One notion is that could interfere with the propagation of not only an effective anticonvulsant, pain circuits become modified over nerve impulses throughout the pain presumably due to its ability to reduce time in a process called “central sensi- pathway and thereby relieve pain.8,9 neurotransmitter release from acti- tization” so that neurons in the pain vated epileptic neurons, but is also a pathway become chronically acti- α 2δ LIGANDS AS NOVEL promising new anxiolytic, hypotheti- vated, transmitting painful sensations TREATMENTS FOR CHRONIC PAIN cally due to its ability to reduce neuro- in an ongoing manner.7 This continual transmitter release from activated activation may be occurring in some of Other anticonvulsants, namely pre- neurons in fear circuits.3 Here we dis- the most difficult-to-manage chronic gabalin and gabapentin, reduce neuro- α δ cuss how 2 ligands may also be ef- pain conditions, including diabetic transmission in activated neurons by fective treatments for chronic pain peripheral neuropathy, fibromyalgia, blocking voltage-gated presynaptic N conditions. In fact, new studies suggest post-herpetic neuralgia, and trigeminal and P/Q calcium channels.3,11Ð13 N- and that pregabalin is a novel treatment for neuralgia. P/Q-type calcium channels regulate the release of neurotransmitters during BRAINSTORMS is a monthly section of SODIUM CHANNEL synaptic neurotransmission; when cal- The Journal of Clinical Psychiatry aimed at BLOCKING ANTICONVULSANTS cium flows through these presynaptic providing updates of novel concepts emerging FOR CHRONIC PAIN from the neurosciences that have relevance to the channels, neurotransmitter is released. practicing psychiatrist. Pregabalin and gabapentin bind with From the Neuroscience Education Institute in One hypothetical means of reduc- high affinity to a specific subunit Carlsbad, Calif., and the Department of Psychiatry at the University of California San Diego. ing chronic pain in such conditions of these presynaptic calcium chan- Reprint requests to: Stephen M. Stahl, M.D., may be to reduce neurotransmission in 3,11Ð13 α δ nels. This subunit is called the 2 Ph.D., Editor, BRAINSTORMS, Neuroscience activated neurons within the pain path- Education Institute, 5857 Owens Street, Ste. 102, subunit, and these anticonvulsants are way. Since anticonvulsants are capable α δ Carlsbad, CA 92009. therefore called 2 ligands. When

pregabalin and gabapentin bind to the Take-Home Points 3. Stahl SM. Anticonvulsants as anxiolytics, pt 2: α δ α δ pregabalin and gabapentin as 2 ligands at 2 subunit, they decrease calcium ◆ Continuous activation of voltage-gated calcium channels [BRAINSTORMS]. flow through the channel and there- neurotransmitter release J Clin Psychiatry 2004;65:460Ð461 fore decrease neurotransmitter release 4. Dworkin RH, Corbin AE, Young JP, et al. in pain pathways may from the presynaptic neuron, which Pregabalin for the treatment of postherpetic hypothetically underlie neuralgia: a randomized placebo controlled presumably leads not only to anticon- painful symptoms in diabetic trial. Neurology 2003;60:1274Ð1283 vulsant actions but to anxiolytic and 5. Sharma U, LaMoreaux L, Corbin A, et al. peripheral neuropathy, antineuralgic (chronic painÐreducing) Pregabalin relieves pain and reduces pain inter- post-herpetic neuralgia, ference with sleep in patients with diabetic actions.3,11Ð13 fibromyalgia, and other neuropathy. Presented at the 12th annual meet- Presynaptic N and P/Q calcium ing of the European Neurological Society; June chronic pain syndromes. channels are not to be confused with 25, 2002; Berlin, Germany ◆ 6.Crofford L, Russell IJ, Mease P, et al. another subtype of voltage-gated cal- The anticonvulsants Pregabalin improves pain associated with cium channel known as the L channel, pregabalin and gabapentin fibromyalgia syndrome in a multicenter, ran- α δ domized, placebo-controlled monotherapy which resides in membranes of vascu- target the 2 subunit of trial. Presented at the 66th annual meeting of lar smooth muscle and is blocked by voltage-gated calcium the American College of Rheumatology; Octo- antihypertensives commonly known channels and reduce ber 25Ð29, 2002; New Orleans, La. Abstract as “calcium channel blockers.”3,14 neurotransmission in 02-A0-1572-ACR 7. Stahl SM. Here today and gone tomorrow: Such drugs lower blood pressure but activated neuronal circuits the curse of chronic pain and other central sen- have no anticonvulsant, anxiolytic, or by reducing the release of sitization syndromes [BRAINSTORMS]. J Clin antineuralgic actions. Presynaptic N numerous neurotransmitters. Psychiatry 2003;64:863Ð864 8.Beydoun A, Backonja M-M. Mechanistic and P/Q calcium channels are also not ◆ Decreasing neurotransmission stratification of antineuralgic agents. J Pain to be confused with ligand-gated cal- in pain pathways could Symptom Manage 2003;25:S18ÐS30 cium channels such as the NMDA 9. Tanelian DK, Brose WG. Neuropathic pain can hypothetically reduce painful be relieved by drugs that are use-dependent (N-methyl-D-aspartate) glutamate re- symptoms in a wide variety sodium channel blockers: lidocaine, carba- ceptor, one of the key mediators of of chronic pain syndromes. mazepine and mexiletine. Anesthesiology excitatory postsynaptic neurotrans- 1991;74:949Ð951 10. Dworkin RH, Backonja M, Rowbotham MC, et mission, which is loosely bound by al. Advances in neuropathic pain: diagnosis, the novel drug for the treatment of mechanisms, and treatment recommendations. Alzheimer’s disease, memantine, and view by the FDA for the treatment of Arch Neurol 2003;60:1524Ð1534 11.Fink K, Dooley DJ, Meder WP, et al. Inhibition tightly bound by the hallucinogen chronic pain as well as epilepsy and of neuronal Ca2+ influx by gabapentin and pre- α δ phencyclidine, neither of which acts at anxiety. Thus, 2 ligands may have a gabalin in the human neocortex. Neuropharma- N or P/Q calcium channels.3 novel mechanism of action with im- cology 2002;64:229Ð236 12. Gee NS, Brown JP, Dissanayake VUK, et al. Preclinical studies have established plications for potentially broad thera- The novel anticonvulsant drug gabapentin α δ the pain-relieving actions of the 2 peutic actions, i.e., the therapeutic (Neurontin) binds to the alpha 2 delta subunit ligands pregabalin and gabapentin.15,16 potential of diminishing neurotrans- of a calcium channel. J Biol Chem 1996;271: 5768Ð5776 Gabapentin is FDA approved for post- mission in activated neurons not only 13. Dooley DJ, Donovan CM, Meder WP, et al. herpetic neuralgia and is specifically in the pain pathway of chronic pain Preferential action of gabapentin and pregabalin at P/Q-type voltage-sensitive calcium recommended for the treatment of conditions but also in the fear path- + 10 channels: inhibition of K -evoked [3H]-norepi- neuropathic pain. Pregabalin is a way of anxiety disorders and in epi- nephrine release from rat neocortical slices. higher-potency analog of gabapentin leptic neurons. ◆ Synapse 2002;45:171Ð190 with better bioavailability and poten- 14. McDonough SI, ed. Calcium Channel Pharma- cology. New York, NY: Kluwer Academic/Ple- tially more consistent clinical effects. REFERENCES num Publishers; 2004 Numerous recent controlled clinical 15. Field MK, Oles RJ, Lewis AS, et al. Gabapen- studies demonstrate efficacy in a vari- 1. Stahl SM. Psychopharmacology of anticonvul- tin (Neurontin) and S-(+)-3-isobutyl GABA 4Ð6 sants: do all anticonvulsants have the same represent a novel class of selective anti- ety of chronic pain conditions, mechanism of action? [BRAINSTORMS] J Clin hyperalgesic agents. Br J Pharmacol 1997;121: including 2 for which there is no cur- Psychiatry 2004;65:149Ð150 1513Ð1522 rently approved treatment, namely 2. Stahl SM. Anticonvulsants as anxiolytics, pt 1: 16. Field MJ, Holloman EF, McCleary S, et al. 5 tiagabine and other anticonvulsants with ac- Evaluation of gabapentin and S-(+)-3-isobutyl diabetic peripheral neuropathy and tions on GABA [BRAINSTORMS]. J Clin Psychi- GABA in a rat model of postoperative pain. fibromyalgia.6 Pregabalin is under re- atry 2004;65:291Ð292 J Pharmacol Exp Ther 1997;282:1242Ð1246