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Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics

Targeting Voltage-Gated Channels for Neuropathic

Danielle Perret*‡ and Z. David Luo*†

*Department of Anesthesiology & Perioperative Care, †Department of , and ‡Department of Physical & Rehabilitation, School of Medicine, University of California Irvine, Irvine, California 92697

Summary: Voltage-gated calcium channels (VGCC) play lief is limited in some patients, and their long-term use is obligatory roles in diverse physiological functions. Pathologi- limited by their side-effect profiles. Certainly, there is room cal conditions leading to changes in their biophysical properties for improvement in developing more subtype-specific and expression levels may cause malfunctions of VGCC-me- VGCC blockers or modulators for chronic pain conditions. diated activities, resulting in disease states. It is believed that In this review, we summarized the most recent preclinical changes in VGCC properties under pain-inducing conditions and clinical studies related to chronic pain act- may play a causal role in the development of chronic pain, ing on the VGCC. We also included clinical trials aiming to including nerve injury-induced pain or . For expand the application of approved VGCC to different the past several decades, preclinical and clinical research in pain states derived from various pathological conditions, as developing VGCC blockers or modulators for chronic pain well as combination therapies trying to improve the management has been fruitful, leading to some U.S. Food and efficacies and side-effect profiles of current pain medica- Drug Administration-approved drugs currently available for tions. Key Words: Chronic, neuropathic pain, voltage-gated chronic pain management. However, their efficacy in pain re- calcium channels, .

INTRODUCTION derive from different pathological conditions that each mediate chronic pain states by unique mechanisms. A recent survey has indicated that at least 50 million 1 Thus, directing our treatment toward a limited number of people in the United States suffer from chronic pain. It is predicted that this number will increase dramatically targets by medications in our current toolbox could ren- due to advances in health care that will continue to der partial pain relief in some patients only. Combina- prolong the lifespan of patients. In addition to adversely tional treatment is an option to improve efficacy and affecting quality of life, inadequate management of reduce side effects. Unfortunately, most of the currently chronic pain also has profound social, economical, and available medications act through targets that psychological consequences. Current pain medications, are not only important in pain processing, but also crit- both and nonopioid, at best, cause partial pain ical in mediating normal physiological functions, which relief in some, but not all, patients. In addition, long-term therefore lead to intolerable side effects, especially after usage of these medications is often associated with in- long-term usage. Individualized pain management based tolerable side effects, some of which can be life-threat- on pain-inducing pathological conditions would have the ening. Therefore, there is an urgent need for safer and least interference with normal physiological functions, more specific analgesic medications for chronic pain and is therefore an ideal approach in chronic pain man- management. agement. Even though different etiologies of chronic pain may Voltage-gated calcium channels (VGCC) or their sub- have similar clinical manifestations, chronic pain can units are considered one family of molecules with ther- apeutic potentials in chronic pain management. The VGCC are assembled through interactions of different Address correspondence and reprint requests to: Z. David Luo, M.D., 2 ␣ ␣ ␤ ␤ ␣ ␦ ␣ ␦ subunits, namely 1 (CaV 1), (CaV ) 2 (CaV 2 ) Ph.D., Department of Anesthesiology & Perioperative Care, University ␥ ␥ ␣ of California, Irvine Medical Center, Bldg 53, Room 227, 101 The City and (CaV ). So far, 10 channel-forming CaV sub- Dr. South, Orange, CA 92868. E-mail: [email protected]. units, encoded by distinct genes, have been identified.2

Vol. 6, 679–692, October 2009 © The American Society for Experimental NeuroTherapeutics, Inc. 679 680 PERRET AND LUO

␣ These CaV subunits consist of four homologous trans- pain management, especially neuropathic pain manage- membrane regions, and each is composed of six trans- ment. For more generalized reviews about the biophysical membrane domains linked by intracellular loops and properties, and plasticity of VGCC on other disease states, amino and carboxy termini. The diversified physiological the readers are referred to other recent reviews.46,47 and pharmacological properties of VGCC are mainly ␣ derived from the existence of these CaV subunits. Four ␤ DRUGS FOR CaV subunits have been identified so far. They all have 3 ␤ PAIN MANAGEMENT alternative splicing variants. The CaV subunits are en- tirely intracellular, phosphorylated by multiple protein The diversities in biophysical properties and tissue- kinases, including protein kinase C and cAMP-depen- specific expression of VGCC thus become an important dent protein kinase, and they play a critical role in cell issue in drug specificity and safety in developing anal- surface expression and modulating the gating properties gesic drugs for pain management. Data from preclinical ␣ 4 ␣ ␦ of the CaV subunit. Four distinctive CaV 2 genes, studies have indicated that most , including sen- ␣ ␦ ␣ ␦ ␣ ␦ ␣ ␦ 48 49–51 Cav 2 1,Cav 2 2,Cav 2 3, and Cav 2 4 have been sory neurons and spinal dorsal horn neurons, ex- 5,6 identified. Their products and splice variants have spe- press multiple types of VGCC. Several types of VGCC 6–9 ␣ ␦ cific tissue distribution patterns. The CaV 2 subunit are considered potential targets for analgesics based on ␣ ␦ consists of two disulfide-linked ( 2 and ) that their distribution, biophysical/pathological roles, and 10,11 are encoded by the same gene. It is highly glycosy- plasticity under pain-inducing conditions.52 We aim lated and mainly extracellular, with a single transmem- here to highlight both preclinical and clinical advances brane domain and five intracellular carboxyl terminal in VGCC drug use, including combinational therapies, 12-14 amino acids. Data from in vitro studies have shown in pain medicine. A summary of the current VGCC ␣ ␦ that co-expression of CaV 2 with other calcium channel medications that are commonly used for pain manage- 13,15-20 subunits increases and stabilizes current amplitude, ment is available in Table 1. The U.S. Food and Drug channel binding sites, and binding affinity for N-type Administration (FDA)-approved indications for each 19,21 VGCC ligands. Three-dimensional structural analy- are noted. A summary of ongoing clinical trials, as sis of the L-type VGCC by electron cryo-microscopy has listed on clinicaltrials.gov, is available in Table 2, ␣ indicated that the extracellular CaV 2 subunit protrudes which provides the reader with information regarding from the membrane in close proximity to the channel studies using these common VGCC drugs to treat non- ␣ 22 forming CaV subunit. Recent findings have indicated FDA-approved pain etiologies and indications. ␣ ␦ that the CaV 2 subunit is also involved in cellular traf- ficking of the calcium channel complex.23,24 These find- N-type VGCC blockers ␣ ␦ ings suggest that the CaV 2 subunit is likely involved in N-type VGCC are highly expressed in dorsal root gan- ␣ VGCC assembly and stabilization, modulation of CaV glion (DRG) cell bodies and at the presynaptic termi- ␥ subunit functions, and binding. The CaV 1 sub- nals where afferent sensory fibers form with unit is a structural component for the postsynaptic dorsal horn neurons,47,53–55 implying an im- L-type calcium channels.25–27 Whether other identified portant role of these calcium channels in mediating nor- ␥ ␥ CaV or CaV -like subunits associate with other types of mal sensory excitability and re- VGCC remained to be confirmed.28–32 The functional lease. Changes in the biophysical properties and enhanced ␥ role of the CaV subunit is not well understood. expression of these VGCC under pain-inducing patho- Based on their physiological and pharmacological prop- logical conditions would likely enhance synaptic vesicle erties, VGCC can be subdivided into low voltage-activated release of pain-inducing transmitters, such as glutamate,

T-type (Cav3.1, Cav3.2, and Cav3.3), and high voltage- substance P, and calcitonin gene-related on stim- activated L- (Cav1.1 through Cav1.4), N-(Cav2.2), P/Q- ulation that could activate interneurons and projection (Cav2.1), and R-(Cav2.3) types, depending on the channel- neurons, altering sensory excitability and leading to pain ␣ 2,33 forming CaV subunits. All of these five subclasses of sensations. In addition, N-type VGCC are unique in that calcium channels are found in the central and peripheral they are a target for descending activation of adrenergic nervous systems.33 Regulation of intracellular calcium pathways by norepinephrine56 and for inhibition by opi- through activation of these VGCC plays obligatory roles oid pathways.57,58 A role for N-type VGCC in neuro- in: 1) neurotransmitter release, 2) membrane depolariza- pathic pain is solidified by findings indicating that spi- tion and hyperpolarization, 3) enzyme activation and nally delivered N-type calcium channel antagonist can inactivation, and 4) gene regulation.34–40 A large body block nerve injury-induced tactile allodynia,59 and dorsal of data has clearly indicated that VGCC are implicated in horn neuronal responses.50 Evidently, blocking the N- mediating various disease states,38,41 including pain pro- type VGCC at the levels of spinal cord and sensory cessing.40,42–45 This review focuses on recent preclinical neurons results in inhibition of stimulus-evoked release and clinical studies regarding VGCC as targets for chronic of pain-inducing peptides, such as substance P, calcito-

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Table 1. Summary of Current Calcium-Channel Drugs in Common Clinical Use for Pain Management

Drug FDA Indications Adverse Reactions Reference

Gabapentin 2002: Postherpetic ; , , , http://www.accessdata.fda.gov/ 1994: (partial nausea, dyspepsia, increased appetite, drugsatfda_docs/label/2009/ seizures), pediatric partial 020235s041,020882s028, seizures 021129s027lbl.pdf 2004: Neuropathic pain Dizziness, somnolence, dry mouth, http://www.accessdata.fda.gov/ associated with diabetic edema, blurred vision, weight gain, drugsatfda_docs/label/2009/ ; abnormal thinking (difficulty with 021446s013s014lbl.pdf ; concentration/attention) adjunctive therapy for adult patients with partial onset seizures; fibromyalgia 2004: Management of severe Vertigo, vision blurred, asthenia, http://www.accessdata.fda.gov/ chronic pain in patients for abnormal gait, pyrexia, rigors, sinusitis, drugsatfda_docs/label/2007/ whom intrathecal therapy is anorexia, muscle spasms, pain in limb, 021060s003lbl.pdf warranted, and who are amnesia, , dizziness, dysarthria, intolerant or refractory to other dysgeusia, headache, memory treatment, such as systemic impairment, nausea, , analgesics, adjunctive somnolence, , anxiety, confusion, therapies, or IT , , pruritus, increased sweating

FDA ϭ U.S. Food and Drug Administration; IT ϭ intrathecal.

nin gene-related peptide, and excitatory neurotransmit- VGCC by this toxin leads to diminished neurotransmitter ter, glutamate.43,60–62 Nerve or tissue injury-induced tac- release in the spinal cord,73 and diminished postopera- tile allodynia and thermal , but not acute tive, inflammatory, and neuropathic pain states in animal pain states, are suppressed in mice lacking the N-type models.59,74–76 The analgesic effect of intrathecal zi- ␣ 63–65 calcium channel-forming CaV subunit. This im- conotide is more potent and longer lasting than intrathe- plies that the N-type VGCC are more directly involved in cal morphine without tolerance or cross-tolerance to chronic, rather than acute, nociception. This is consistent morphine analgesia.74,75 with data from direct blockade of N-type VGCC by cone Clinical trials of intrathecal application of this peptide snail peptides ␻-conotonix-GVIA and ␻-conotonix- drug result in significant pain relief for patients with MVIIA (ziconotide or Prialt) that leads to inhibition of severe chronic pain (Table 2), including neuropathic pain neuropathic and inflammatory pain, but not acute pain, in and pain secondary to or AIDS. Several reviews 52 animal models. Interestingly, splicing variants of the summarizing the details of some early clinical trials were N-type VGCC have been identified in sensory neu- 77–79 66–68 recently published. Briefly, the first randomized, rons. With validation of their functional contribu- double-blind, placebo-controlled pilot study for pain re- tion to pain processing, these subtypes of N-type VGCC lief with intrathecal ziconotide was in patients undergo- could be potential targets for specific analgesic drugs. ing surgery.80 Patients received either a placebo or one of ␮ ␮ Peptide N-type VGCC blockers two intrathecal ziconotide doses (0.7 g/h and 7.0 g/h) The FDA approval of ziconotide, or the synthetic ver- postoperatively during the following 48 h. The mean sion of ␻-conotonix-MVIIA (also called SNX-111, or daily morphine consumption from patient-controlled ad- Prialt (Elan Pharmaceuticals, Inc., San Diego, CA), for ministration in the 24- to 48-h period was significantly the treatment of chronic severe pain refractory to other lower in patients receiving ziconotide than in placebo- current pain medications in December 2004 in the United controlled patients. Pain scores in both ziconotide groups States and in Europe69 (Table 1) marked the first clinical were lower than in the placebo group. Adverse events application of N-type VGCC peptide blockers in chronic were more frequent on the higher ziconotide dose. In an pain management. ␻-conotonix-MVIIA is a 25-amino open-label clinical study,81 31 male patients with chronic acid peptide isolated from the marine fish-hunting cone pain who had failed opioid management received con- snail, Conus magus.70 Due to the peptidergic nature of tinuous intrathecal ziconotide infusions. The average this drug, it is only approved for intrathecal application. pain reduction was 43% in 19 out of 24 patients who Ziconotide can block N-type VGCC currents with high completed the study. The concomitant use of was potency, but in a reversible manner.71,72 Data from pre- reduced by at least 50% in 15 patients. Two multicenter, clinical studies have indicated that blocking N-type randomized, double-blind, placebo-controlled trials in

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Table 2. Summary of Clinical Trials by Pain Etiology*

Study Drug Study Indication

Ziconotide, , pregabalin AIDS/HIV Pregabalin Anxiety, preoperative Ziconotide, , , pregabalin Cancer Amlodopine, gabapentin, ziconotide, , Chronic pain syndromes (pelvic, chronic prostatitis, abdominal, pregabalin, chronic pain secondary to trauma, chronic , chronic pancreatitis, vulvodynia) Pregabalin Complex regional pain syndrome Pregabalin Lamotrigine, pregabalin Facial pain (excluding postherpetic neuralgia) Gabapentin, pregabalin Hemorrhoidectomy Gabapentin, pregabalin Gabapentin, gabapentin XR, pregabalin, lamotrigine Peripheral neuropathy (, radiation, , diabetic, vascular, idiopathic) Gabapentin pain Gabapentin, gabapentin XR, lamotrigine, pregabalin Postherpetic neuralgia Gabapentin, pregabalin Postoperative pain (sternotomy, thoracotomy, hip surgery, replacement, cesarean section, tonsillectomy, keratectomy, inguinal hernia repair, spinal fusion, knee arthroscopy, scoliosis surgery, CABG, hysterectomy, cholecystectomy, mastectomy, axillary node dissection, bunionectomy) Pregabalin Post-traumatic pain Pregabalin Radiculopathy Pregabalin Spinal cord injury Pregabalin Spinal stenosis Pregabalin Stroke Gabapentin Stump pain Gabapentin Lamotrigine

*Source: clinicaltrials.gov. patients with chronic cancer or AIDS-associated pain and severity of adverse effects were observed in patients (“malignant pain”)82 or with nonmalignant pain83 were with low initial doses and gradual titration to achieve conducted. In the “malignant,” chronic cancer/AIDS-re- analgesia. In a randomized, double-blind, placebo-con- lated pain trial,82 ziconotide improved the mean visual trolled study,85 slower titration of intrathecal ziconotide analog scale of pain intensity (VASPI) scores by 53%. In to a lower maximum dose was associated with a signif- addition, 53% patients in the ziconotide group had pain icant improvement in pain relief and was better tolerated relief classified as moderate to complete compared with compared with faster titrations and higher maximum 18% patients in the placebo group. Five patients in the mean dose reported in two earlier placebo-controlled ziconotide group had achieved “complete” pain relief. In trials. It was suggested that administration of intrathecal the “nonmalignant” pain trial,83 240 patients were ran- ziconotide at a low starting (maximum) dose of 0.5 ␮g/ domized to ziconotide versus a placebo. Ziconotide re- day and a limitation of dose escalations to no more than duced the mean VASPI scores by 31% (compared with 0.5 ␮g/day may limit adverse effects.86 6% for the placebo group). In addition, more than 43% of A recent case report highlighted the use of ziconotide patients in the ziconotide group had moderate-to-com- in a patient with recalcitrant pain post-spinal cord injury, plete analgesia, compared with 17% in the placebo with both at-level and below-the-neurological-level of group. neuropathic pain syndromes. When intrathecal hydro- Several additional studies published in 2006 assessed morphone was used as a treatment modality, the patient’s the ideal effective dose and tolerability of ziconotide. In at-level, but not the below-level, pain was reduced. Con- three well-designed trials with up to 21-day durations,84 versely, when intrathecal ziconotide was administered, titration of ziconotide resulted in significant improve- analgesia was positive for the below-level, but only min- ment in the VASPI scores for chronic malignant or non- imally for the at-level, pain. When combination therapy malignant pain compared with a placebo. The analgesic with intrathecal and ziconotide was effects of ziconotide remained for up to 12 months in used, analgesia was sufficient for both pain components. long-term, open-label trials. In addition, lower incidence This study implies that central pain due to spinal cord

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injury may be an indication for intrathecal ziconotide, Nevertheless, searching for safer analgesic peptide an- particularly in combination with intrathecal opioids.87 tagonists against the N-type VGCC continues. It has The usage of this peptide drug is limited by the route been reported that ␻-conotonix-GVIA, a 27- of administration and undesirable side effects, including peptide isolated from the cone snail, Conus geographus, sedation, dizziness, nausea, emesis, somnolence, head- also exhibits analgesic properties in animal models.52 In ache, confusion, memory impairment, slurred speech, contrast to ziconotide, ␻-conotonix-GVIA is an irrevers- nystagmus, double or blurry vision, urinary retention, ible inhibitor of N-type VGCC,96 which precludes its , elevated creatine kinase levels, and gait clinical application due to potential severe side effects. abnormality.78,88–90 It is believed that the serious side However, recent studies have indicated that binding of effects of ziconotide are derived from complete blockade this toxin peptide to the N-type VGCC can also modulate of the N-type VGCC that would affect the normal bio- (inhibit) N-type VGCC gating properties so that approx- physical functions of widely distributed N-type VGCC.91 imately 50%, instead of a complete blockade, of the However, it is argued that more convincing data are calcium influx during an is inhibited,91 in needed to make definitive conclusions because similar ad- addition to the primary pore blocking mechanism. This verse effects are not detectable in N-type VGCC knockout would provide a means to normalize elevated (activated) mice, which have no detectable evidence of developmental N-type VGCC activities in a disease condition, such as compensation from other types of VGCC.89 It is possible chronic pain, but preserve the biophysical functions of that some of these adverse effects may be secondary to N-type VGCC in maintaining normal physiological func- effects at other receptors besides the N-type VGCC. tions, and thus reduce adverse side effects. High- Most adverse events occur during the first week of treat- throughput screening using a scintillation proximity as- ment. After 6 months of treatment, the incidence of say has been used to search for small molecules that can ␻ adverse events is noted to be 0 to 35% of that reported in displace -conotonix-GVIA binding to the N-type VGCC the first month of treatment.84 Potential contamination of in an attempt to find N-type VGCC modulators with high affinity to the ␻-conotonix-GVIA binding sites on the intrathecal pump devices used to administer ziconotide 97 (or any other intrathecal agent) may increase the risk of N-type VGCC. ␻ meningitis.77 The neurological side effects of ziconotide Another 27-amino acid peptide -conotonix-CVID, also Conus catus dictate that the drug should be used with caution and called AM336, from the cone snail, , is perhaps the most selective of all N-type VGCC peptide blockers careful dose titration. Particular symptoms may correlate with greater than 24 hours of analgesia observed in rats with the rate of infusion.90 Because and toler- from subnanomolar intrathecal doses.73,98,99 Intrathe- ance are not detectable with the analgesic effects of cal administration of this peptide drug into rat pain ziconotide,88 but are often observed with the use of opi- models results in inhibition of spinal release of pain- oid analgesics, intrathecal ziconotide could be an option inducing peptides and potent dose-dependent anti-no- for replacing intrathecal morphine for chronic severe ciception.73,98 In addition, AM336 showed a greater ratio pain relief. However, the combination of opioid with- of analgesic efficacy to behavioral than zi- drawal symptoms and the cognitive/psychiatric adverse conotide,73,98 probably due to its greater selectivity for effects of ziconotide could make the conversion chal- N-type in comparison with P/Q type VGCC.71 This pep- lenging. Successful treatment with ziconotide mono- tide drug was assessed in a phase I in on- therapy has been suggested to include and cology patients with severe pain100 and its efficacy was psychological supports to decrease possible adverse psy- 92 established in a small phase IIa clinical trial for patients chological and physiological complications. with severe cancer pain.40 Unfortunately, the side effects Overall, although pain relief by ziconotide is accom- were undesirable and dose limiting. The adverse effect panied with some adverse effects, use of this analgesic profile is surprising given the 106-fold binding selectivity has several benefits. Ziconotide is less mood-altering of this peptide for N-type in comparison with P/Q-type than morphine for comparable analgesia and has the VGCC,71 and it may be secondary to supraspinal effects. advantage of lacking addiction, opioid-induced hyperal- gesia, and other systematic effects commonly observed Small molecule N-type VGCC blockers with opioids.93 For these reasons, the Polyanalgesic Con- The potency of ziconotide in chronic pain relief, and sensus Conference of 2007 puts ziconotide in the first its association with an undesirable administration route line of intrathecal therapy management, along with mor- and an undesirable side-effect profile, has prompted a phine and hydromorphone, in its recommended algo- race in searching for small molecules that would be rithm for nociceptive, mixed, and neuropathic pain.94 As orally active and have an acceptable therapeutic window summarized in a recent review, the evidence for short- for chronic pain management. Using a high-throughput

term improvement of -related pain or neuro- fluorescence-based in vitro assay to compare IC50 values pathic pain with intrathecal ziconotide is also strong.95 of blocking both N-type and L-type VGCC in a human

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neuroblastoma cell line for identifying specific N-type Peptide T-type VGCC blockers VGCC blockers from its corporate compound library, Low-voltage T-type VGCC are found in DRG primary scientists in Ionix Pharmaceuticals Ltd. have developed a afferent cell bodies and in free nerve endings. They series of new N-type VGCC blockers derived from struc- contribute to the initiation of the action potential in these tural modifications of “hit” structures.101 After structural locations by lowering the required threshold for activa- and activity relationship analysis, compounds with up to tion.108 By promoting burst activity and synaptic excita- 30-fold of N-type/L-type VGCC selectivity and up to 0.2 tion, enhanced T-type VGCC activity favors the devel- ␮ opment of pain.51,109 T-type VGCC density has been MinIC50 values are identified. Unfortunately, analge- sic efficacies in chronic pain models were not included in increased in rat neuropathic pain models of diabetic neu- 110,111 the study. Further investigations for the analgesic effi- ropathy and chronic constriction nerve injury. The cacy and toxicity in animal pain models may prove the facts that T-type VGCC knockout animals have hypo- usefulness of these compounds for further development sensitivity to pain and that intrathecal injection with T- as therapeutic agents for chronic pain management. type VGCC blockers or antisense oligonucleotides re- sults in reduced excitability of the primary afferents and Indirect inhibitors of N-type channels therefore reduced nociceptive responses all attest to their established role in the processing of pain, especially N-type VGCC can be modulated by morphine, an im- 51,112–118 portant analgesic. Binding of morphine to ␮-opioid re- neuropathic pain. However, the exact mecha- nisms underlying the role of T-type VGCC in nocicep- ceptors activates G␤␥ which translocates to the mem- tion still remain elusive. Several regulatory mechanisms brane and binds to the N-type VGCC. A massive of T-type VGCC in pain processing have been proposed. G-protein-dependent inhibition of calcium currents re- These include redox modulation of T-type VGCC in rat sults in an inhibition of neurotransmitter release,2,45,102 peripheral nociceptors,119 and the selective enhancement and reduces the ability of the DRG sensory neurons to of T-type VGCC in nociceptive DRG neurons by reduc- propagate pain signals. This process is at least partially ing agents, such as L-cysteine, synthetic, and endoge- responsible for morphine’s analgesic effect, but can also nous chelators of zinc.119 The latter is supported by the contribute to tolerance development. Combination of zi- findings that peripherally injected reducing agents pro- ␮ conotide with -opioids shows synergistic analgesia duce thermal hyperalgesia in wild-type but not Cav3.2 74,98,103 when administered intrathecally. This combina- knockout mice, indicating that T-type VGCC may have a tion therapy may help to reduce opioid tolerance, a poor special role in peripheral sensitization.119 Currently, side-effect profile, and the potential for opioid-induced is the only T-type VGCC blocker approved hyperalgesia, all of which limit the long-term usefulness for human use.120 of ␮-opioid in pain medicine. Spinal noradrenaline can reduce VGCC-mediated transmission L-type VGCC blockers by presynaptic and postsynaptic inhibition, and by ␣1- Evidence from recent clinical studies shows that L- adrenoceptor-mediated activation of inhibitory interneu- type VGCC blockers, such as , are efficacious rons.40 These may explain the effectiveness of ␣2-adren- for neuropathic pain management, and leads to the sug- ergic agonists (such as ) and nonselective small gestion that this should be a third-line agent 121 molecule norepinephrine transporter (NET) inhibitors for neuropathic pain treatment. In one study, topira- (such as ) in pain relief. However, these med- mate has been shown to cause statistically significant 104 reduction in pain intensity compared to a placebo, as ications also have limiting side-effect profiles. Highly measured on a 100-mm visual analog scale, for up to 12 selective NET inhibitors, ␹-conopeptides, have been iso- weeks in diabetic peripheral neuropathy patients.122 lated from the cone snail, Conus marmoreus.105 It was However, three other randomized, double-blind, place- demonstrated that the ␹-conopeptide NET-binding site bo-controlled trials with more than 1,200 diabetic neu- partially overlaps the tricyclic NET-bind- 106 ropathy patients failed to show statistically significant ing site. Based on studies in rat neuropathic pain mod- reductions in pain intensity after 18 to 22 weeks of ␹ els, the -conopeptide compound MrIA (Xen2174) was treatment. In addition, these three studies also resulted in found to produce strong anti-allodynic effects without topiramate drop out rates ranging from 16% to 31% 107 significant side effects after intrathecal administration. compared with 8% for a placebo. The most commonly A phase I/IIa clinical trial involving intrathecal evalua- reported adverse events were , , nau- tion of Xen2174 in cancer patients with sea, somnolence, and diminished appetite.123 Another shows initial promising results.40 This line of compounds study evaluated the efficacy of topiramate for pain in may represent an important option in the search to iden- patients associated with chronic lumbar radiculopathy tify a potentially different therapeutic approach in target- and found modest pain relief in the topiramate-treated ing VGCC for chronic pain management. group, but with a 24% drop out rate.124 At least one

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␣ ␦ recent case report has suggested that topiramate may be cleotides against the Cav 2 1 subunit can block nerve ␣ ␦ a useful pharmacologic modality for pain relief in pa- injury-induced Cav 2 1 upregulation and prevent the on- tients with postherpetic neuralgia who have failed other set of allodynia152 and reserve established allodynia.136 agents.125 It has been reported that topiramate has other Both gabapentin and pregabalin are structural deriva- pharmacologic actions including blockage of voltage- tives of the inhibitory neurotransmitter GABA although gated sodium channels in a dose-dependent manner,125 they do not bind to GABAA, GABAB, or potentiation of GABA inhibition, and AMPA receptor receptors, or alter GABA regulation in animal blockade,122–124,126 which may contribute to both its an- preparations.153 Binding of gabapentin and pregabalin to ␣ ␦ algesic potential and its adverse side effects. the Cav 2 1 subunit of VGCC results in a reduction in the calcium-dependent release of multiple neurotransmit- Other types of VGCC blockers ters,121,154 leading to efficacy and tolerability for neuro- Contribution of other types of VGCC to pain process- pathic pain management.121 ing have been suggested in some preclinical studies. Missense mutations in the Cav2.1 P/Q-type calcium Gabapentin channels lead to familial hemiplegic , an inher- Gabapentin is approved by the FDA for postherpetic 127–129 ited form of migraine with aura and hemiparesis. neuralgia, neuropathic pain, and partial seizures155–157 In addition, R-type VGCC have been implicated in the (Table 1). Several studies also suggest a clinical role for 130 processing of neuropathic pain and other pain states. restless leg syndrome,158 general anxiety,159 and general However, few clinical researches evaluating the effica- neuropathic pain.141 In common practice, gabapentin is cies of specific blockers to these VGCC in pain relief are used as a first-line agent to treat neuropathic pain from available; thus, these are not covered in this review. central origin (such as stroke or spinal cord injury) or from peripheral origin (such as peripheral neuropathy or radiculopathy). Despite its role and ubiquity, several CALCIUM CHANNEL ␣2␦1 LIGANDS FOR controlled trials demonstrate a low responder rate of PAIN MANAGEMENT approximately 32%.155 ␣ ␦ The unique features of the Cav 2 subunit and a large Gabapentin has inherent pharmacokinetic limitations; ␣ ␦ body of recent findings have suggested that the Cav 2 1 the half-life of gabapentin is short, and therefore admin- subunit may play an important role in neuropathic pain istration must be frequent. In addition, gabapentin is development. Biochemical data have indicated a significant absorbed actively via absorption pumps located in the ␣ ␦ ␣ ␦ Cav 2 1, but not Cav 2 2, subunit upregulation in the spi- upper . Therefore, conventional sus- nal dorsal horn, and DRG after nerve injury23,131–135 that tained-release formulations, where drug release is pro- correlates with neuropathic pain development.131,132,136 longed and occurs throughout the gastrointestinal tract, In addition, blocking axonal transport of injury-induced would simply decrease the of the drug.160 ␣ ␦ DRG Cav 2 1 subunit to the central presynaptic termi- Therapeutic doses and responses vary among patients nals diminishes tactile allodynia in nerve injured ani- and prediction of the ultimate desired doses is exceed- ␣ ␦ mals, suggesting that elevated DRG Cav 2 1 subunit ingly difficult. Furthermore, most gabapentin absorption contributes to neuropathic allodynia, even though a is nonlinear (i.e., as the dose is increased, the bioavail- postsynaptic mechanism can not be completely ruled ability decreases).160–162 23,24,136 ␣ ␦ out. Interestingly, the Cav 2 1 subunit (and the The FDA has approved gabapentin at a dose of up to ␣ ␦ ␣ ␦ ␣ ␦ Cav 2 2, but not Cav 2 3 and Cav 2 4, subunits) is the 1,800 mg/day. This drug is frequently used off-label for binding site for gabapentin,6,7,137 which has anti-allo- the treatment of other neuropathic pain conditions, in- dynic/hyperalgesic properties in patients and animal cluding painful diabetic peripheral neuropathy and radic- models with unknown mechanisms.131,132,138–143 Be- ulopathy, at higher doses up to 3,600 mg/day.141,163,164 It ␣ ␦ cause injury-induced Cav 2 1 expression correlates with has been suggested that gabapentin may be effective for neuropathic pain development and maintenance, and var- the treatment of chronic pain of any etiology, including ious calcium channels are known to contribute to spinal musculoskeletal headache, cervical pain, neuropathic synaptic neurotransmission50,144–149 and DRG neuron pain, lumbar pain, or multiple pains, such as fibromyal- 66,149–151 ␣ ␦ 165,166 excitability, injury-induced Cav 2 1 subunit up- gia (Table 2). Although gabapentin is well toler- regulation may contribute to the initiation and mainte- ated in studies, a statistically significant incidence of nance of neuropathic pain by altering the properties sedation, lightheadedness, and dizziness is noted when and/or distribution of VGCC in the subpopulation of compared to control patients.166 DRG neurons and their central terminals, therefore mod- Combinational treatment of gabapentin with other pain ulating excitability and/or synaptic neuroplasticity in the medications for pain management has been tested in dorsal horn. This is supported by findings from preclin- numerous clinical trials. Combination treatment of gaba- ical studies indicating that intrathecal antisense oligonu- pentin and morphine in an animal model of neuropathic

Neurotherapeutics, Vol. 6, No. 4, 2009 686 PERRET AND LUO pain results in a significant increase in the inhibitory twice-daily group (28.8%) was comparable with that re- effect of morphine on the dorsal horn neural response ported in the immediate-release gabapentin studies to peripheral stimulation,167 providing preclinical evi- (32.2%)156 and in the pregabalin studies (150 mg/day, dences to support that combination therapies with gaba- three times a day [26%], or 300 mg/day three times a day pentin may have clinical benefits in chronic pain man- [28%]).172 The incidence of adverse events was not sta- agement. A crossover study involving 57 patients with tistically different between the placebo group and either neuropathic pain demonstrated improved clinical out- of the gabapentin ER groups (once- or twice-daily), and comes when patients received a combination of mor- it did not appear to be dose-dependent.173 phine and gabapentin versus monotherapy.168 A larger study with 338 patients demonstrated that co-administra- XP13512: tion of gabapentin and prolonged-release of A novel pro-drug of gabapentin, XP13512/GSK has a clinically meaningful effect in patients with painful 1838262 ((Ϯ)-1-([(␣-isobutanoyloxyethoxy)carbonyl]- (diabetic) neuropathy.169 aminomethyl)-1-cyclohexane acetic acid) was recently developed. This drug has enhanced absorption in the Gabapentin extended-release large intestine, allowing an extended-release formula- A gabapentin extended-release (ER) has been devel- tion.174 Four clinical studies (two immediate-release [IR] oped. Gabapentin ER was constructed using polymer- formulation studies and two extended-release [XR] for- based AcuForm technology (Depomed, Inc., Menlo mulation studies) have evaluated the bioavailability of Park, CA). When taken with a meal, the tablet is retained the drug. In the first IR study, XP13512 was adminis- in the stomach for up to 8 h and the drug is gradually tered to healthy adults. Five groups of 10 subjects were released over 10 h to the , its optimal site randomized to receive the pro-drug or placebo in a dou- of absorption.162,170 This prolonged release was designed ble-blind fashion with five ascending pro-drug/placebo to provide similar or improved systemic exposure as doses (200, 400, 800, 1,200, and 1,400 mg). Maximum compared with the immediate release formulation. gabapentin concentrations were noted at 2.5 h In an exploratory study, the daily exposure provided postadministration. Bioavailability was consistently high by less frequent gabapentin extended-release dosing (Ͼ67%) across all doses. In the second IR study, twice (once- and twice-daily) was found not to be statistically daily dosing (350 mg–2,100 mg) was given. Steady state different from that provided by gabapentin immediate- concentrations of XP13512 were found proportional to release, administered more frequently (three times a day the oral dose range. In addition, the bioavailability [TID]). Gabapentin ER once-daily dosing was found to of gabapentin from XP13512 was consistently high produce higher maximum plasma concentrations com- (Ͼ72%) across the dose range. Blood concentrations of pared with the TID gabapentin immediate-release regi- the intact pro-drug after oral dosing were low. In the first men and twice-daily gabapentin ER dosing was found to XR study, plasma exposure to gabapentin was higher result in less fluctuation in plasma concentrations.171 post-XR treatment than after an equimolar dose of oral A recent randomized, double-blinded, placebo-con- gabapentin. The time to maximum concentration (T- trolled study evaluated gastric-retentive gabapentin in max) of gabapentin was substantially greater in the sub- 158 individuals who had chronic pain from post-herpetic jects given XP13512 than in subjects given oral gabap- neuralgia for at least 3 months. Patients were given 1,800 entin. In another XR study, plasma gabapentin was mg gabapentin ER once daily in the afternoon or 600 mg proportional to the XP13512 dose over the range studied in the morning with 1,200 mg in the afternoon (twice- (300 mg–1200 mg); bioavailability was increased in the daily dosing) or placebo. Efficacy outcomes included presence of food. Sustained delivery was noted at all changes from baseline on the pain intensity numeric dose levels. Overall, both IR and XR formulations of rating scale (average daily pain) and average daily sleep XP13512 were well tolerated without serious adverse interference score. The authors found statistically signif- events. Minor adverse events reported included dizzi- icant reductions in pain scores at all time points and as ness, headache, and sedation. Minor event reporting was early as week 1 post-treatment in the gabapentin ER similar for oral gabapentin, except for increased dizzi- twice-daily group compared with the placebo group. But ness in the IR formulation of XP13512, perhaps due to there was no significant reduction in pain scores in the rapid absorption. The XR formulation, although with once-daily gabapentin ER group compared with the pla- higher peak gabapentin concentrations than oral gabap- cebo control, although a trend was noted. It was con- entin, actually had similar adverse events compared with cluded that although ideal, once-daily gabapentin ER oral gabapentin.174 dosing may result in plasma levels that fall below the Given its increased absorption and more predictable therapeutic range before the end of the 24-hour dosing gabapentin exposure, its reduced inter-patient variability, period. Overall, the proportion of responders with at least and its reduced-dosing frequency, XP13512 may become a 50% reduction in pain score in the gabapentin ER an important option in our toolbox of upcoming neuro-

Neurotherapeutics, Vol. 6, No. 4, 2009 CALCIUM CHANNEL DRUGS IN TREATING CHRONIC PAIN 687 pathic agents. This novel extended-release pro-drug was approved by the FDA in 2007 as the first drug for the would be ideal for patients requiring prolonged clinical treatment of fibromyalgia181 (Table 1). exposure, such as patients with restless leg syndrome, Pregabalin is well tolerated, has predictable absorption using a single daily dose. Use of the XR formulation may across the gastrointestinal tract, and has minimal drug- dramatically improve treatment compliance. drug interactions.182 Clinical trials have been conducted GlaxoSmithKline announced results from a phase II to examine the efficacy of pregabalin in other chronic clinical trial of XP13512 for painful diabetic neurop- pain conditions (Table 2). At least seven published pro- athy in adults in April 2009 (Phase II Results for spective, randomized clinical trials have documented its GSK1838262 [XP13512] Reported for Neuropathic Pain efficacy in postherpetic neuralgia and painful diabetic Associated with Diabetic Peripheral Neuropathy; Medi- peripheral neuropathy with improvements in pain inten- cal News Today; article date, 4/29/2009; http://www. sity scores, decreased sleep interference, and secondary 182 medicalnewstoday.com/articles/148026.php). There were outcome improvements. The effects of pregabalin on 421 patients who were enrolled in a 14-week, double- patients with fibromyalgia are a current focus. These 183 blind, placebo-controlled study and were randomized to were first published in 2005 in an 8-week multicenter receive either 1,200 mg/day, 2,400 mg/day, or 3,600 efficacy and safety clinical trial. Pain intensity, sleep, mg/day of XP13512 in divided doses twice-daily; 300 fatigue, and quality of life were measured outcomes. mg/day pregabalin as an active control in divided doses Pregabalin (at 450 mg/day) significantly reduced pain three times daily, or a placebo. The primary endpoint intensity ona0to10point scale as compared with a placebo (p Յ 0.001). Pregabalin (at doses of 300 mg/day was a change from baseline on the Pain Intensity-Nu- and 450 mg/day) was reported to statistically improve merical Rating Scale (PI-NRS). Both the pregabalin ac- sleep, fatigue, and global measures of change. At 450 tive control and XP13512 failed to show a statistically mg/day, pregabalin also improved other secondary out- significant benefit when compared with a placebo. These comes associated with health-related quality of life as results may be due to an unusually high placebo re- measured in the Short Form-36 (SF-36) Health Survey. sponse. Therefore, efficacy conclusions are difficult to Adverse events were mostly mild, and the most fre- draw. XP13512, at all doses, was well tolerated in the quently reported adverse events were dizziness and som- study. Dizziness and somnolence were the most common nolence, although weight gain and peripheral edema reported adverse events. were also reported.183 The efficacy of XP13512 was also recently tested in a Pregabalin was also studied in combination therapy for randomized, double-blind, placebo-controlled study in a pain management. It was used in a combinational treat- population of patients with moderate-to-severe primary 184 175 ment of fibromyalgia in an open-label, 12-week study restless leg syndrome. There were 222 patients who in 19 female patients already receiving therapy with were randomized to 1,200 mg/day of XP13512 once- (76 mg/day). At the dose range from 75 mg/ daily or a placebo, and 192 patients completed the study. day to 300 mg/day, depending on the patient’s tolerabil- At week 12, there was a greater improvement in inter- ity, pregabalin was found to statistically improve the national restless leg syndrome scores. Significant treat- physical component of the SF-12 Health Survey, as well ment effects were noted as early as 1 week, the earliest as the pain and tiredness in the awakening subscales of time point measured, in the treatment group. More pa- the fibromyalgia impact questionnaire. Six of 19 patients tients treated with XP13512 (76%) were responders withdrew from the study, including 3 of them due to side compared with placebo (39%) (p Ͻ 0.0001). The medi- effects.184 cation was generally well tolerated; mild-to-moderate A multicenter study involving more than 700 patients side effects, including somnolence and dizziness were evaluated the efficacy and safety of pregabalin in patients reported.175 with fibromyalgia.185 Patients were given 300, 450, or 600 mg/day in twice-daily dosing schedules for 13 Pregabalin weeks. All patients treated with pregabalin had statisti- Pregabalin, S-enantiomer of racemic 3-isobutyl GABA, cally improved pain scores and patient global impression is a second-generation and structurally of change scores as compared with placebo treatments. similar to gabapentin. The binding affinity of pregabalin Statistically significant improvements in secondary out- ␣ ␦ for the Cav 2 1 subunit, however, is 6 times greater than comes measuring sleep were also reported. Side effects that of gabapentin, which makes pregabalin more clini- were mild to moderate and the most frequently reported cally effective at lower doses.176 Pregabalin is approved side effects were dizziness, somnolence, headache, infec- in the United States and Europe for the treatment of tion, and weight gain. This efficacy and safety was similarly neuropathic pain associated with diabetic peripheral neu- documented in another recently published trial.186 A recent ropathy and postherpetic neuralgia, and epilepsy as an long-term multicenter double-blind, placebo-controlled ran- add-on agent177–180 (Table 1). In addition, pregabalin domized discontinuation trial (FREEDOM) in the fibro-

Neurotherapeutics, Vol. 6, No. 4, 2009 688 PERRET AND LUO myalgia population demonstrated the durability (mainte- 13. Gurnett CA, De Waard M, Campbell KP. Dual function of the ϩ nance of response with pregabalin treatment relative to voltage-dependent Ca2 channel alpha 2 delta subunit in current 187 stimulation and subunit interaction. Neuron 1996;16:431–440. placebo) of pregabalin for this indication. In this trial, 14. Wiser O, Trus M, Tobi D, Halevi S, Giladi E, Atlas D. The alpha individually-determined optimal pregabalin doses were 2/delta subunit of voltage sensitive Ca2ϩ channels is a single determined with the hypothesis that the therapeutic re- transmembrane extracellular protein which is involved in regu- lated secretion. Febs Letters 1996;379:15–20. sponse would persist longer. The trial included a 6-week, 15. Mikami A, Imoto K, Tanabe T, et al. 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