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Anti-epileptic Drugs

      Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ( [email protected] ).

      Abbreviations/Key

      Ca2+
      Calcium
      CNS
      Central nervous system
      CYP
      Cytochrome P450
      D2
      Dopamine-2 receptor
      ECG
      Electrocardiogram
      EEG
      Electroencephalogram
      EFNS
      European Federation of Neurological Societies
      GABA
      Gamma-amino butyric acid
      HLA
      Human leukocyte antigen
      IASP
      International Association for the Study of Pain
      IT
      Intrathecal
      ITU
      Intensive therapy unit
      IV
      Intravenous
      K+
      Potassium
      LFT
      Liver function test
      m/r
      Modified release
      Na+
      Sodium
      NCSE
      Non-convulsive status epilepticus
      NICE
      National Institute for Health and Clinical Excellence
      NMDA
      N-Methyl-d-aspartate receptor
      NNH
      Number needed to harm
      NNT
      Number needed to treat
      RCT
      Randomized controlled trial
      SC
      Subcutaneous
      SSRI
      Serotonin specific re-uptake inhibitor
      SV2A
      Synaptic vesicle protein 2A
      TCA
      Tricyclic antidepressant
      Indications: (Licensed indications vary; see individual drug PI for details.) Epilepsy, neuropathic pain, mania, anxiety, sweats and hot flashes, refractory hiccup, terminal agitation, restless legs syndrome, spasticity, pruritus.

      Pharmacology

      Anti-epileptic drugs are structurally and functionally diverse. The relationship between clinical activity and mode of action is not fully understood. Further, clinically relevant differences exist among anti-epileptics acting in similar ways, and additional actions contribute to the beneficial and/or undesirable effects of some. Choice of drug thus remains partly empirical.
      • Perucca E.
      An introduction to antiepileptic drugs.
      Actions of anti-epileptics include:
      • membrane stabilization:
        • sodium channel blockers
      • reduced neurotransmitter release:
        • N/P/Q-type calcium channel blockers (α2δ ligands)
        • SV2A ligands
      • increased GABA-mediated inhibition:
        • GABAmimetics (Table 1 and Fig. 1).
          Table 1Mechanisms of Action of Anti-epileptics
          • Perucca E.
          An introduction to antiepileptic drugs.
          • Lynch B.A.
          • Lambeng N.
          • Nocka K.
          The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.
          • Jevtovic-Todorovic V.
          • Todorovic S.M.
          The role of peripheral T-type calcium channels in pain transmission.
          • Kochegarov A.A.
          Pharmacological modulators of voltage-gated calcium channels and their therapeutical application.
          • Shin H.S.
          T-type Ca2+ channels and absence epilepsy.
          • Loscher W.
          Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy.
          • Lee C.H.
          • Tsai T.S.
          • Liou H.H.
          Gabapentin activates ROMK1 channels by a protein kinase A (PKA)-dependent mechanism.
          • Sheets P.L.
          • Heers C.
          • Stoehr T.
          • Cummins T.R.
          Differential block of sensory neuronal voltage-gated sodium channels by lacosamide [(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide], lidocaine, and carbamazepine.
          Membrane Stabilizers Neurotransmitter ReleaseGABAmimeticsOther Actions
          Na+ Channel BlockerK+ Channel ActivatorCa2+ Channel Blocker (N, P/Q-type) Vesicle Release (SV2A) GABAA Receptor ActivationAltered GABA Re-uptake and BreakdownCa2+ Channel Blocker (T-type)NMDA-Receptor- Channel Blocker
          Benzodiazepines++
          Carbamazepine++
          Ethosuximide++
          Felbamate++
          Gabapentin+++
          Lacosamide++
          Lamotrigine++++
          Levetiracetam++
          Oxcarbazepine+++
          Phenobarbital++
          Phenytoin, fosphenytoin++
          Pregabalin++
          Tiagabine++
          Tiagabine and vigabatrin inhibit GABA reuptake and breakdown (via GABA transaminase), respectively. Valproic acid affects both synthesis and re-uptake/breakdown of GABA in selected brain regions.
          Topiramate++++
          Valproic acid+
          Although many anti-epileptics have more than one mode of action, valproic acid in particular is thought to have no predominant mode of action, helping to explain its broad spectrum of activity.
          +
          Although many anti-epileptics have more than one mode of action, valproic acid in particular is thought to have no predominant mode of action, helping to explain its broad spectrum of activity.
          +
          Although many anti-epileptics have more than one mode of action, valproic acid in particular is thought to have no predominant mode of action, helping to explain its broad spectrum of activity.
          +
          Although many anti-epileptics have more than one mode of action, valproic acid in particular is thought to have no predominant mode of action, helping to explain its broad spectrum of activity.
          Vigabatrin++
          Tiagabine and vigabatrin inhibit GABA reuptake and breakdown (via GABA transaminase), respectively. Valproic acid affects both synthesis and re-uptake/breakdown of GABA in selected brain regions.
          Zonisamide++++++
          Key: ++=predominant action, +=putative or non-predominant action.
          a Although many anti-epileptics have more than one mode of action, valproic acid in particular is thought to have no predominant mode of action, helping to explain its broad spectrum of activity.
          b Tiagabine and vigabatrin inhibit GABA reuptake and breakdown (via GABA transaminase), respectively. Valproic acid affects both synthesis and re-uptake/breakdown of GABA in selected brain regions.
          Figure thumbnail gr1
          Fig. 1Mechanisms of action of anti-epileptics and related drugs.
          • Perucca E.
          An introduction to antiepileptic drugs.
          • Lynch B.A.
          • Lambeng N.
          • Nocka K.
          The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.
          • Jevtovic-Todorovic V.
          • Todorovic S.M.
          The role of peripheral T-type calcium channels in pain transmission.
          • Kochegarov A.A.
          Pharmacological modulators of voltage-gated calcium channels and their therapeutical application.
          • Shin H.S.
          T-type Ca2+ channels and absence epilepsy.
          • Loscher W.
          Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy.
          • Lee C.H.
          • Tsai T.S.
          • Liou H.H.
          Gabapentin activates ROMK1 channels by a protein kinase A (PKA)-dependent mechanism.
          • Devulder J.
          Flupirtine in pain management: pharmacological properties and clinical use.
          Brackets indicate a contributory, but not predominant, action of the anti-epileptic.
          aAlthough many anti-epileptics have more than one mode of action, valproic acid in particular is thought to have no single predominant action.
          bT-type calcium channels are responsible for thalamic burst firing (implicated in absence seizures); they are also found in some nociceptors, where they may influence firing thresholds (see text).

      Membrane stabilizers

      Generally, membrane stabilizers reduce excitability by blocking sodium channels. However, those which do so through potassium channel activation are in development (see below).
      Sodium channels are present in high densities at sites which initiate action potentials, e.g., sensory nerve endings, and in lower densities along the remainder of the neuron to propagate the action potential. Neuronal damage can lead to the accumulation of sodium channels, e.g., through impaired transport or enhanced production, resulting in neuronal hyperexcitability and foci of ectopic action potential generation.
      • Devor M.
      Sodium channels and mechanisms of neuropathic pain.
      In conjunction with other effects of nerve injury, and depending on the site of the damage, this may contribute to the development of neuropathic pain (or seizures).
      Several classes of drugs used in neuropathic pain act as sodium channel blockers:
      • some anti-epileptics, e.g., carbamazepine, oxcarbazepine
        • Wiffen P.J.
        • Derry S.
        • Moore R.A.
        • McQuay H.J.
        Carbamazepine for acute and chronic pain in adults.
      • local anesthetics, e.g., lidocaine
        • Challapalli V.
        • Tremont-Lukats I.W.
        • McNicol E.D.
        • Lau J.
        • Carr D.B.
        Systemic administration of local anesthetic agents to relieve neuropathic pain.
      • class 1 anti-arrhythmics, e.g., flecainide.
        • von Gunten C.F.
        • Eappen S.
        • Cleary J.F.
        • et al.
        Flecainide for the treatment of chronic neuropathic pain: a Phase II trial.
      Important clinical differences exist among these drugs because of the variation in their duration of channel blockade and other effects beyond sodium channels.
      Potential future developments in membrane stabilizing drugs for pain management include:
      • subtype-selective sodium channel blockers, e.g., Nav1.7 (see Pharmacogenetics and pharmacokinetics)
      • drugs with reduced CNS penetration and thus fewer central undesirable effects
      • potassium channel activators which stabilize the membrane by hyperpolarization; this is the probable analgesic mechanism of flupirtine (not U.S. or U.K.).
        • Devulder J.
        Flupirtine in pain management: pharmacological properties and clinical use.

      Neurotransmitter release inhibitors: α2δ and SV2A ligands

      Gabapentin and pregabalin bind to the α2δ type 1 and 2 regulatory subunits of pre-synaptic (N, P/Q-type) voltage-gated calcium channels, reducing the calcium influx responsible for triggering neurotransmitter release.
      • Taylor C.P.
      Mechanisms of analgesia by gabapentin and pregabalin–calcium channel alpha2-delta [Cavalpha2-delta] ligands.
      • Bauer C.S.
      • Tran-Van-Minh A.
      • Kadurin I.
      • Dolphin A.C.
      A new look at calcium channel alpha2delta subunits.
      Calcium channel α2δ subunits in the forebrain/brainstem play a role in pain processing and descending pain inhibitory pathways
      • Bee L.A.
      • Dickenson A.H.
      Descending facilitation from the brainstem determines behavioural and neuronal hypersensitivity following nerve injury and efficacy of pregabalin.
      • Hayashida K.
      • Obata H.
      • Nakajima K.
      • Eisenach J.C.
      Gabapentin acts within the locus coeruleus to alleviate neuropathic pain.
      and are upregulated in the spinal dorsal horn by inflammation and neuropathic pain.
      • Boroujerdi A.
      • Kim H.K.
      • Lyu Y.S.
      • et al.
      Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain.
      • Lu S.G.
      • Zhang X.L.
      • Luo Z.D.
      • Gold M.S.
      Persistent inflammation alters the density and distribution of voltage activated calcium channels in subpopulations of rat cutaneous DRG neurons.
      Gabapentin and pregabalin primarily cause the redistribution of calcium channels away from the cell surface, rather than blocking them directly. Effects on sodium and potassium channels also have been shown.
      • Lee C.H.
      • Tsai T.S.
      • Liou H.H.
      Gabapentin activates ROMK1 channels by a protein kinase A (PKA)-dependent mechanism.
      • Yang R.H.
      • Wang W.T.
      • Chen J.Y.
      • Xie R.G.
      • Hu S.J.
      Gabapentin selectively reduces persistent sodium current in injured type-A dorsal root ganglion neurons.
      Despite being GABA analogues, neither gabapentin nor pregabalin is GABAmimetic.
      • Taylor C.P.
      Mechanisms of analgesia by gabapentin and pregabalin–calcium channel alpha2-delta [Cavalpha2-delta] ligands.
      They are unrelated to the L-type calcium channel blockers, nifedipine, diltiazem and verapamil.
      Levetiracetam binds to synaptic vesicle protein SV2A, and is presumed to interfere with the release of the neurotransmitter stored within the vesicle.
      • Lynch B.A.
      • Lambeng N.
      • Nocka K.
      The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.
      • Kaminskia R.M.
      • Matagnea A.
      • Leclercqa K.
      • et al.
      SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy.

      GABAmimetics

      GABAmimetic anti-epileptics either affect GABA metabolism (synthesis, re-uptake, or breakdown, e.g., vigabatrin, tiagabine, valproate) or act directly on GABAA receptors (e.g., benzodiazepines and barbiturates). In contrast to other GABAmimetics, valproic acid’s GABAmimetic effect is selective (particularly for the midbrain) and involves several mechanisms (altered synthesis, release, re-uptake, and degradation).
      • Loscher W.
      Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy.

      Other actions

      Some anti-epileptics have additional effects. For example, valproic acid, in addition to being a membrane stabilizer (sodium channel blocker) and a GABAmimetic, also blocks NMDA receptor-channels and T-type calcium channels, and impacts on dopamine and serotonin transmission.
      • Loscher W.
      Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy.
      The NMDA receptor-channel is an established analgesic target.
      T-type calcium channels may have a role in neuropathic pain,
      • Takahashi T.
      • Aoki Y.
      • Okubo K.
      • et al.
      Upregulation of Ca(v)3.2 T-type calcium channels targeted by endogenous hydrogen sulfide contributes to maintenance of neuropathic pain.
      the burst firing responsible for absence seizures
      • Perucca E.
      An introduction to antiepileptic drugs.
      and in regulating pain excitation thresholds in a “T-rich” subset of peripheral nociceptors.
      • Jevtovic-Todorovic V.
      • Todorovic S.M.
      The role of peripheral T-type calcium channels in pain transmission.

      Pharmacogenetics and pharmacokinetics

      Genetic variations in anti-epileptic targets have been identified (e.g., sodium and potassium channels, the GABAA receptor complex). Some cause inherited epilepsy, but there is no straightforward link between the affected channel/receptor and either the epilepsy type or optimal choice of anti-epileptic.
      • Mann M.W.
      • Pons G.
      Various pharmacogenetic aspects of antiepileptic drug therapy: a review.
      • Löscher W.
      • Klotz U.
      • Zimprich F.
      • Schmidt D.
      The clinical impact of pharmacogenetics on the treatment of epilepsy.
      A polymorphism in the gene (SCN1A) encoding the sodium channel α-subunit has been linked to carbamazepine-resistant epilepsy.
      • Abe T.
      • Seo T.
      • Ishitsu T.
      • et al.
      Association between SCN1A polymorphism and carbamazepine-resistant epilepsy.
      In relation to pain, inherited abnormalities of the Nav1.7 subtype sodium channel have resulted in a reduced function (e.g., congenital insensitivity to pain)
      • Cummins T.R.
      • Sheets P.L.
      • Waxman S.G.
      The roles of sodium channels in nociception: Implications for mechanisms of pain.
      or an enhanced function (e.g., primary erythromelalgia).
      • Sheets P.L.
      • Jackson 2nd, J.O.
      • Waxman S.G.
      • Dib-Hajj S.D.
      • Cummins T.R.
      A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity.
      The pharmacokinetics of anti-epileptics are summarized in Table 2. Although absorption is generally unaffected by increasing age, the volume of distribution may change (reduced albumin, total body water and lean:fat mass ratio) and elimination rates slow (altered metabolism, renal function and volume of distribution).
      • Perucca E.
      Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age.
      Table 2Pharmacokinetic Details of Selected Anti-epileptics
      • Perucca E.
      Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age.
      • Perucca E.
      The clinical pharmacokinetics of the new antiepileptic drugs.
      • Garnett W.R.
      Clinical pharmacology of topiramate: a review.
      • Perucca E.
      Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience.
      • May T.W.
      • Korn-Merker E.
      • Rambeck B.
      Clinical pharmacokinetics of oxcarbazepine.
      • Bang L.M.
      • Goa K.L.
      Spotlight on oxcarbazepine in epilepsy.
      • Kwan P.
      • Brodie M.J.
      Phenobarbital for the treatment of epilepsy in the 21st century: a critical review.
      • Patsalos P.N.
      Clinical pharmacokinetics of levetiracetam.
      DrugBioavailability PO (%)Tmax (h)Plasma Binding (%)Plasma Half-life (h)Fate
      Carbamazepine804–8758–24CYP3A4, CYP2C8
      Metabolites biologically active.
      Clonazepam≥801–480–9030–40CYP3A
      Diazepam≥801–395–9824–48CYP2C19, CYP3A4
      Metabolites biologically active.
      48–120
      Nordiazepam, active metabolite.
      Gabapentin60
      Dose or plasma concentration dependent.
      1–406Excreted unchanged
      Lacosamide≥950.5–4<1513Multiple pathways
      Metabolites biologically active.
      (40% excreted unchanged)
      Lamotrigine981–45515–30Glucuronidation
      8–20
      Metabolites biologically active.
      30–90
      With concurrent valproic acid.
      Levetiracetam≥951–2<106–8Non-hepatic hydrolysis (70% excreted unchanged)
      Oxcarbazepine
      Monohydroxycarbazepine, active metabolite of oxcarbazepine (a pro-drug).
      ≥951–3651–5Cytosolic keto-reduction to MHD,
      Monohydroxycarbazepine, active metabolite of oxcarbazepine (a pro-drug).
      which then undergoes glucuronidation
      Metabolites biologically active.
      3–8
      Monohydroxycarbazepine, active metabolite of oxcarbazepine (a pro-drug).
      40
      Monohydroxycarbazepine, active metabolite of oxcarbazepine (a pro-drug).
      7–20
      Monohydroxycarbazepine, active metabolite of oxcarbazepine (a pro-drug).
      Phenobarbital≥902–125072–144CYP2C9 (25% excreted unchanged)
      Phenytoin90–954–89010–70
      Dose or plasma concentration dependent.
      CYP2C9
      Pregabalin>90105–9
      >2 days in severe renal impairment and hemodialysis patients.
      Excreted unchanged
      Tiagabine≥901–2964–13CYP3A4
      2–5
      With concurrent enzyme-inducers.
      Topiramate≥801–41320–30Multiple pathways (>60% excreted unchanged)
      8–15
      With concurrent enzyme-inducers.
      Valproic acid951–2
      3–5h for e/c tablets, 5–10 h for m/r tablets.
      909–18Multiple pathways
      Metabolites biologically active.
      5–12
      With concurrent enzyme-inducers.
      Vigabatrin80–901–206Excreted unchanged
      Zonisamide≥501–45050–70CYP3A4 (15–30% excreted unchanged)
      25–35
      With concurrent enzyme-inducers.
      a Metabolites biologically active.
      b Nordiazepam, active metabolite.
      c Dose or plasma concentration dependent.
      d With concurrent enzyme-inducers.
      e With concurrent valproic acid.
      f Monohydroxycarbazepine, active metabolite of oxcarbazepine (a pro-drug).
      g >2 days in severe renal impairment and hemodialysis patients.
      h 3–5h for e/c tablets, 5–10 h for m/r tablets.
      A number of anti-epileptic drugs exhibit significant pharmacokinetic drug interactions through hepatic enzyme induction or inhibition (see below).
      Genetic factors affect both pharmacokinetics and the risk of undesirable effects. Two poor metabolizer CYP2C9 alleles (which occur in 10–20% of Caucasians, 10% of Japanese, and 1–5% of Asians and Africans) reduce the mean effective daily phenytoin dose by 20–40%.
      • Löscher W.
      • Klotz U.
      • Zimprich F.
      • Schmidt D.
      The clinical impact of pharmacogenetics on the treatment of epilepsy.
      Human leukocyte antigen (HLA) genes are associated with the risk of Stevens-Johnson syndrome in patients taking carbamazepine or phenytoin.
      • Chung W.H.
      • Hung S.I.
      • Hong H.S.
      • et al.
      Medical genetics: a marker for Stevens-Johnson syndrome.
      • Locharernkul C.
      • Loplumlert J.
      • Limotai C.
      • et al.
      Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B∗1502 allele in Thai population.
      The FDA recommends testing HLA B∗1502 status before carbamazepine or phenytoin is started in people of Chinese, Malaysian, Indonesian, Filipino, Taiwanese, or Thai origin.

      U.S. Food and Drug Administration. Dangerous or even fatal skin reactions - carbamazepine (marketed as Carbatrol, Equetro, Tegretol and generics). 2007. Available from http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124718.htm. Accessed October 12, 2011.

      U.S. Food and Drug Administration. Phenytoin (marketed as Dilantin, Phenytek and generics) and fosphenytoin (marketed as Cerebyx and generics). 2008. Available from http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124788.htm. Accessed October 12, 2011.

      Cautions

      Safety concerns with vigabatrin (visual field deficits) and felbamate (aplastic anemia and hepatic failure) limit their use to refractory epilepsy under specialist supervision when all other measures have failed.

      Driving

      Legislation varies between countries; both the underlying condition (e.g., seizures) and effects of the medication (e.g., drowsiness) require consideration.

      Skin rashes and cross-reactive hypersensitivity

      In relation to skin rashes, cross-reactive hypersensitivity may occur with various anti-epileptics:
      • Hirsch L.J.
      • Arif H.
      • Nahm E.A.
      Cross-sensitivity of skin rashes with antiepileptic drug use.
      • carbamazepine: increased risk of skin rash if rash has occurred with a previous anti-epileptic (particularly phenytoin, phenobarbital, or oxcarbazepine) or TCA; use alternative if possible
      • phenytoin: increased risk of skin rash if rash has occurred with a previous anti-epileptic (particularly carbamazepine or phenobarbital); use alternative if possible
      • oxcarbazepine: 25–30% risk of cross-reactivity if previous reaction to carbamazepine
      • zonisamide: avoid if hypersensitive to sulphonamides
      • lamotrigine: increased risk in children, if rash has occurred with a previous anti-epileptic, rapidly titrated and/or receiving concurrent valproic acid.

      Hepatic impairment

      With the exception of gabapentin, pregabalin, and vigabatrin, the manufacturers advise caution with all the anti-epileptics listed in Table 2 (i.e., lower initial doses, slower titration, and careful monitoring). Specific advice is given for levetiracetam (halve the dose in severe hepatic impairment because of probable concurrent renal impairment), lacosamide (usual dose with mild–moderate impairment, no data with severe impairment), lamotrigine (see PI), oxcarbazepine (usual dose with mild–moderate impairment, no data with severe impairment), phenytoin (monitor plasma concentration), tiagabine (reduce dose if mild, avoid if severe), and zonisamide (avoid if possible).
      Although previous or concurrent hepatic disease increases the risk of valproic acid and carbamazepine-related hepatic failure (see below), there is no specific information available about the risks with hepatic metastases. However, these do not generally affect the hepatic metabolism of drugs unless there is concurrent cirrhosis.
      • Morgan D.J.
      • McLean A.J.
      Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease. An update.
      • Ford-Dunn S.
      Managing patients with cancer and advanced liver disease.
      When used in this situation, careful monitoring is required.

      Renal impairment

      With the exception of phenytoin and tiagabine, the manufacturers advise caution with all the anti-epileptics listed in Table 2 (i.e., lower initial doses, slower titration and careful monitoring). Specific advice on dose adjustment is available for gabapentin (see PI), lacosamide (maximum dose 250 mg/day if creatinine clearance <30 ml/min; dose unchanged if >30 ml/min), levetiracetam (see PI), and pregabalin (see PI). There have been occasional reports of renal failure with pregabalin, which improved when it was stopped.

      Females of child-bearing age

      Enquire about oral contraceptives if using an enzyme-inducing anti-epileptic and counsel accordingly. Specialist advice should be sought, e.g., before trying to conceive because of the risk of teratogenicity and, when pregnant, in order to avoid the use of benzodiazepines or phenobarbital around the time of delivery because of the risk of floppy infant syndrome.

      Suicide

      Anti-epileptic drugs are associated with suicidal thoughts or behavior in 1/500 patients from the start of treatment onwards. Based on current evidence, it appears to be a class effect, independent of the indication for use.
      • Bagary M.
      (2011) Epilepsy, antiepileptic drugs and suicidality.
      Thus, look for underlying psychiatric comorbidities, assess suicidal risk, and advise patients to report any mood disturbance or suicidal thoughts.

      U.S. Food and Drug Administration. Safety information. Antiepileptic drugs. 2008. Available from www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm074939.htm. Accessed October 12, 2011.

      European Medicines Agency. Meeting highlights from the Committee for Medicinal Products for Human Use, 15-18 December 2008. Available from www.emea.europa.eu/pdfs/human/press/pr/67072408en.pdf. Accessed October 12, 2011.

      Additional cautions with specific anti-epileptics

      • atrioventricular block (carbamazepine, lacosamide and oxcarbazepine may cause complete block)
      • previous bone marrow suppression (carbamazepine, possible increased risk of bone marrow toxicity)
      • heart failure (oxcarbazepine and pregabalin, reported to cause fluid retention; monitor weight and plasma sodium)

      Drug Interactions

      Phenobarbital, carbamazepine and phenytoin cause numerous interactions through hepatic enzyme induction, see individual PI for details. Conversely, gabapentin, levetiracetam, and pregabalin have few clinically significant pharmacokinetic interactions.

      Undesirable Effects

      Despite their diverse actions and structures, anti-epileptics share many undesirable effects.
      • Marson A.G.
      • Al-Kharusi A.M.
      • Alwaidh M.
      • et al.
      The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.
      • Marson A.G.
      • Al-Kharusi A.M.
      • Alwaidh M.
      • et al.
      The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.
      All anti-epileptics cause psychotropic and CNS depressant effects including drowsiness, ataxia, cognitive impairment, agitation, diplopia, and dizziness. Cognitive impairment is worst with phenobarbital and least with newer anti-epileptics and valproic acid.
      • Perucca E.
      Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience.
      • Kwan P.
      • Brodie M.J.
      Neuropsychological effects of epilepsy and antiepileptic drugs.
      Anti-epileptics cause suicidal ideation in 1/500 patients (see Cautions).
      All anti-epileptics can cause personality change, behavioral disturbance, and aggression. Levetiracetam is most commonly implicated (≤15% in some RCTs).
      • Dinkelacker V.
      • Dietl T.
      • Widman G.
      • Lengler U.
      • Elger C.E.
      Aggressive behavior of epilepsy patients in the course of levetiracetam add-on therapy: report of 33 mild to severe cases.
      • Weintraub D.
      • Buchsbaum R.
      • Resor Jr., S.R.
      • Hirsch L.J.
      Psychiatric and behavioral side effects of the newer antiepileptic drugs in adults with epilepsy.
      The risk can be minimized by screening for a past history of aggression and using a cautious rate of dose titration.
      • White J.R.
      • Walczak T.S.
      • Leppik I.E.
      • et al.
      Discontinuation of levetiracetam because of behavioral side effects: a case-control study.
      Switching to an alternative anti-epileptic may be required. Pyridoxine supplementation has improved behavioral disturbance in children taking levetiracetam.
      • Major P.
      • Greenberg E.
      • Khan A.
      • Thiele E.A.
      Pyridoxine supplementation for the treatment of levetiracetam-induced behavior side effects in children: preliminary results.
      • Davis G.P.
      • McCarthy J.T.
      • Magill D.B.
      • Coffey B.
      Behavioral effects of levetiracetam mitigated by pyridoxine.
      Most cause hematological derangements. These are often asymptomatic and may not require discontinuation of the drug (see PIs for specific advice). Severe derangement (e.g., aplastic anemia and agranulocytosis) also is reported particularly with felbamate (limiting its use) and carbamazepine (where symptoms of bone marrow suppression and blood counts should be monitored), but also with many newer anti-epileptics. Folate deficiency occurs with enzyme-inducers (e.g., phenytoin).
      Biochemical derangements (particularly of LFTs) are also common but are generally asymptomatic. Rarely, hepatic failure is seen with many anti-epileptics, particularly felbamate (also limiting its use) and carbamazepine (where symptoms of hepatic disease and LFTs should be monitored). The incidence compared with newer anti-epileptics is unknown. Pancreatitis affects 1:3,000 users of valproic acid.
      • French J.A.
      First-choice drug for newly diagnosed epilepsy. [comment].
      It also occurs with many newer anti-epileptics but the incidence compared with valproic acid is unknown. Valproic acid also causes hyperammonenia (LFTs can be normal); discontinuation is not required unless symptomatic, e.g., vomiting, ataxia, drowsiness.
      Transient rashes are particularly associated with lamotrigine, carbamazepine and oxcarbazepine. Risk factors include rashes with previous anti-epileptics, higher starting doses and rapid titration (and, with lamotrigine, childhood and concurrent valproic acid). Severe rashes such as Stevens-Johnson syndrome are reported with all anti-epileptics, but most commonly with lamotrigine (affecting 1:1,000 adults). An HLA type is known to predispose specific groups to carbamazepine- and phenytoin-related Stevens-Johnson syndrome (see above).
      Undesirable effects seen with particular anti-epileptics include: urolithiasis (topiramate and zonisamide); and coarse facies, acne, hirsutism, and gingival hypertrophy (phenytoin).

      Use of Anti-epileptics in Palliative Care

      Particularly when prescribing more than one anti-epileptic, it is important to consider:
      • pharmacokinetic drug–drug interactions (see below)
      • seizure type (generalized seizures may be precipitated by carbamazepine, oxcarbazepine, gabapentin, tiagabine and vigabatrin)
        • Perucca E.
        • Gram L.
        • Avanzini G.
        • Dulac O.
        Antiepileptic drugs as a cause of worsening seizures.
      • additive cognitive impairment.

      Neuropathic pain

      Gabapentin, pregabalin, carbamazepine, and valproic acid are used for central and peripheral neuropathic pain. Their efficacy and tolerability appear comparable to each other and to alternatives (e.g., antidepressants), as judged by NNT and NNH,
      • Finnerup N.B.
      • Sindrup S.H.
      • Jensen T.S.
      The evidence for pharmaceutical treatment of neuropathic pain.
      • Saarto T.
      • Wiffen P.J.
      (2007) Antidepressants for neuropathic pain.
      • Dworkin R.H.
      • O’Connor A.B.
      • Audette J.
      • et al.
      Recommendations for the pharmacological management of neuropathic pain: an overview and literature update.
      although there have been few direct comparisons.
      Gabapentin and pregabalin are first-line options. Both are beneficial in various non-cancer neuropathic pains.
      • Dworkin R.H.
      • O’Connor A.B.
      • Audette J.
      • et al.
      Recommendations for the pharmacological management of neuropathic pain: an overview and literature update.
      • Attal N.
      • Cruccu G.
      • Baron R.
      • et al.
      EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision.
      Pregabalin’s twice daily administration is a possible advantage, although it is more expensive and is no more effective than gabapentin. Gabapentin is also effective for cancer-related neuropathic pain, although the benefit in an RCT was small.
      • Caraceni A.
      • Zecca E.
      • Bonezzi C.
      • et al.
      Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group.
      • Bennett M.I.
      Effectiveness of antiepileptic or antidepressant drugs when added to opioids for cancer pain: systematic review.
      Gabapentin appeared to act more quickly and with less sedation than carbamazepine in relation to neuropathic pain in Guillain-Barre syndrome, but neither was used optimally (dose regimens were fixed).
      • Pandey C.K.
      • Raza M.
      • Tripathi M.
      • et al.
      The comparative evaluation of gabapentin and carbamazepine for pain management in Guillain-Barre syndrome patients in the intensive care unit.
      Valproic acid is used in some centers as an alternative first choice when a smaller tablet load or once daily regimen is required, particularly if a TCA cannot be used. Benefit is reported for cancer-related neuropathic pain,
      • Hardy J.R.
      • Rees E.A.
      • Gwilliam B.
      • et al.
      A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain.
      • Snare A.J.
      Sodium valproate. Retrospective analysis of neuropathic pain control in patients with advanced cancer.
      but the results of RCTs in non-cancer pain are conflicting;
      • Kochar D.K.
      • Jain N.
      • Agarwal R.P.
      • et al.
      Sodium valproate in the management of painful neuropathy in type 2 diabetes - a randomized placebo controlled study.
      • Kochar D.K.
      • Rawat N.
      • Agrawal R.P.
      • et al.
      Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study.
      • Kochar D.K.
      • Garg P.
      • Bumb R.A.
      • et al.
      Divalproex sodium in the management of post-herpetic neuralgia: a randomized double-blind placebo-controlled study.
      • Otto M.
      • Bach F.W.
      • Jensen T.S.
      • Sindrup S.H.
      Valproic acid has no effect on pain in polyneuropathy: a randomized, controlled trial.
      thus EFNS and IASP guidelines do not recommend its use first line.
      • Dworkin R.H.
      • O’Connor A.B.
      • Audette J.
      • et al.
      Recommendations for the pharmacological management of neuropathic pain: an overview and literature update.
      • Attal N.
      • Cruccu G.
      • Baron R.
      • et al.
      EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision.
      It appears to be well tolerated in both cancer series and RCTs; rates of discontinuation because of adverse events are low (3–5%)
      • Kochar D.K.
      • Jain N.
      • Agarwal R.P.
      • et al.
      Sodium valproate in the management of painful neuropathy in type 2 diabetes - a randomized placebo controlled study.
      • Kochar D.K.
      • Rawat N.
      • Agrawal R.P.
      • et al.
      Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study.
      • Kochar D.K.
      • Garg P.
      • Bumb R.A.
      • et al.
      Divalproex sodium in the management of post-herpetic neuralgia: a randomized double-blind placebo-controlled study.
      • Otto M.
      • Bach F.W.
      • Jensen T.S.
      • Sindrup S.H.
      Valproic acid has no effect on pain in polyneuropathy: a randomized, controlled trial.
      compared with trials of gabapentin (8–19%)
      • French J.A.
      First-choice drug for newly diagnosed epilepsy. [comment].
      • Saarto T.
      • Wiffen P.J.
      (2007) Antidepressants for neuropathic pain.
      and pregabalin (8–32%)
      • Richter R.W.
      • Portenoy R.
      • Sharma U.
      • et al.
      Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial.
      • Rosenstock J.
      • Tuchman M.
      • LaMoreaux L.
      • Sharma U.
      Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial.
      • Tölle T.
      • Freynhagen R.
      • Versavel M.
      • Trostmann U.
      • Young Jr., J.P.
      Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study.
      • Freynhagen R.
      • Strojek K.
      • Griesing T.
      • Whalen E.
      • Balkenohl M.
      Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens.
      • Sabatowski R.
      • Gálvez R.
      • Cherry D.A.
      • et al.
      Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial.
      • van Seventer R.
      • Feister H.A.
      • Young Jr., J.P.
      • et al.
      Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial.
      • Dworkin R.H.
      • Corbin A.E.
      • Young Jr., J.P.
      • et al.
      (2003) Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial.
      in similar populations.
      Carbamazepine is a first-line treatment for trigeminal neuralgia. It has been used off-label for other neuropathic pains despite few supporting RCTs.
      • Wiffen P.J.
      • Derry S.
      • Moore R.A.
      • McQuay H.J.
      Carbamazepine for acute and chronic pain.
      Phenytoin is also effective, at least in the short term.
      • McCleane G.
      Intravenous infusion of phenytoin relieves neuropathic pain: a randomized, double-blinded, placebo-controlled, crossover study.
      However, both require slow titration and particular care with regard to drug interactions. Other membrane stabilizers, particularly lacosamide, lamotrigine, oxcarbazepine and topiramate also have been used, but benefit has been inconsistent or of uncertain clinical relevance. Nonetheless, they are sometimes used for patients failing to respond to more usual approaches, e.g., gabapentin or pregabalin in combination with an antidepressant and an opioid.
      • Dworkin R.H.
      • O’Connor A.B.
      • Audette J.
      • et al.
      Recommendations for the pharmacological management of neuropathic pain: an overview and literature update.
      Clonazepam is reported to improve both cancer-related and non-cancer neuropathic pain.
      • Swerdlow M.
      • Cundill J.
      Anticonvulsant drugs used in the treatment of lancinating pain: a comparison.
      • Bouckoms A.J.
      • Litman R.E.
      Clonazepam in the treatment of neuralgic pain syndrome.
      • Bartusch S.L.
      • Sanders B.J.
      • D’Alessio J.G.
      • Jernigan J.R.
      Clonazepam for the treatment of lancinating phantom limb pain.
      • Hugel H.
      • Ellershaw J.E.
      • Dickman A.
      Clonazepam as an adjuvant analgesic in patients with cancer-related neuropathic pain.
      Its concurrent anxiolytic and muscle-relaxant properties have led to its use for selected palliative care patients despite the absence of supporting RCTs.
      Alternatives to anti-epileptics include antidepressants and opioids, which are also often used in combination. The efficacy of gabapentin was similar to TCAs in two RCTs although, in one, TCAs caused more dry mouth, constipation and postural hypotension.
      • Morello C.M.
      • Leckband S.G.
      • Stoner C.P.
      • Moorhouse D.F.
      • Sahagian G.A.
      Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain.
      • Chandra K.
      • Shafiq N.
      • Pandhi P.
      • Gupta S.
      • Malhotra S.
      Gabapentin versus nortriptyline in post-herpetic neuralgia patients: a randomized, double-blind clinical trial--the GONIP Trial.
      Combined use was superior to either treatment alone.
      • Gilron I.
      • Bailey J.M.
      • Tu D.
      • et al.
      Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial.
      Morphine was as effective as TCAs,
      • Raja S.N.
      • Haythornthwaite J.A.
      • Pappagallo M.
      • et al.
      Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial.
      whereas the combination of morphine and gabapentin was superior to either treatment alone.
      • Gilron I.
      • Bailey J.M.
      • Tu D.
      • et al.
      Morphine, gabapentin, or their combination for neuropathic pain.
      An open-label trial in cancer pain with a neuropathic component also found this combination to be superior to morphine alone.
      • Keskinbora K.
      • Pekel A.F.
      • Aydinli I.
      Gabapentin and an opioid combination versus opioid alone for the management of neuropathic cancer pain: a randomized open trial.
      Combinations of ≥2 anti-epileptics are used less commonly. Undesirable effects may be increased and alternative options (e.g., antidepressants, opioids, ketamine, and nerve blocks) are often more appropriate. Where a second anti-epileptic drug is added, the first is generally withdrawn, although examples of combined use are reported. Improvements in efficacy and tolerability have been described in 11 patients with multiple sclerosis whose trigeminal neuralgia had been unsatisfactorily controlled by carbamazepine ± lamotrigine. The addition of gabapentin brought relief in 10 patients. The former were reduced to the minimal effective dose, with improved overall tolerability, but could not be withdrawn completely in any patient, suggesting that both anti-epileptics were contributing to overall relief.
      • Solaro C.
      • Messmer Uccelli M.
      • et al.
      Low-dose gabapentin combined with either lamotrigine or carbamazepine can be useful therapies for trigeminal neuralgia in multiple sclerosis.

      Epilepsy

      Overtreatment with anti-epileptic drugs is common. Seek specialist advice where the diagnosis of seizures or the dose or choice of anti-epileptic drug is in doubt.

      Initiating Treatment

      In palliative care, an anti-epileptic is generally commenced after a first seizure because the persisting underlying cause (e.g., cerebral tumor, multiple sclerosis) makes further seizures probable. In other settings, this risk is lower and an anti-epileptic is often withheld unless a second seizure occurs.
      • Miller L.C.
      • Drislane F.W.
      Treatment strategies after a single seizure: rationale for immediate versus deferred treatment.
      Focal lesions cause seizures of partial onset ± secondary generalization. Because the partial onset is not always evident, this can lead to them being incorrectly diagnosed as generalized seizures. However, true generalized convulsive seizures are generally evident within the first two decades of life.
      Choice of anti-epileptic is guided by seizure type, potential for drug interactions, co-morbidities, and the simplicity of the regimen (Box A). Because of the risk of teratogenicity with some anti-epileptics, obtain specialist advice when treating women of childbearing age. Enzyme-inducing anti-epileptics can interfere with chemotherapy, although the clinical relevance is unknown.
      • Rudà R.
      • Trevisan E.
      • Soffietti R.
      Epilepsy and brain tumors.
      Valproic acid, levetiracetam, gabapentin, carbamazepine and phenytoin are among the anti-epileptics examined in trials and case series for seizures secondary to cerebral tumors.
      • Schaller B.
      Brain tumor and seizures: pathophysiology and its implications for treatment revisited (Epilepsia 2003;44:1223–1232).
      • Vecht C.J.
      • van Breemen M.
      Optimizing therapy of seizures in patients with brain tumours.
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      • van Breemen M.S.
      • Rijsman R.M.
      • Taphoorn M.J.
      • et al.
      Efficacy of anti-epileptic drugs in patients with gliomas and seizures.
      Anti-epileptics for seizures in palliative care
      • Vecht C.J.
      • van Breemen M.
      Optimizing therapy of seizures in patients with brain tumours.
      • van Breemen M.S.
      • Wilms E.B.
      • Vecht C.J.
      Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
      • Kargiotis O.
      • Markoula S.
      • Kyritsis A.P.
      Epilepsy in the cancer patient.
      First-line alternatives
      Oxcarbazepine
      Fewer drug interactions than phenytoin and carbamazepine; effective doses achieved more quickly than with lamotrigine and carbamazepine.
      Valproic acida
      Can be titrated rapidly, IV if necessary.
      Second-line
      Switch to another first-line choice, or prescribe
      Levetiracetam
      aDespite abnormal in vitro hemostasis, valproic acid has not been shown to increase neurosurgical bleeding complications,
      • Ward M.M.
      • Barbaro N.M.
      • Laxer K.D.
      • Rampil I.J.
      Preoperative valproate administration does not increase blood loss during temporal lobectomy.
      • Anderson G.D.
      • Lin Y.X.
      • Berge C.
      • Ojemann G.A.
      Absence of bleeding complications in patients undergoing cortical surgery while receiving valproate treatment.
      but some surgeons advise caution; discuss with surgeons before starting if neurosurgery is planned.
      Anti-epileptics are better tolerated if commenced at lower than recommended doses.
      • Perucca E.
      • Kwan P.
      Overtreatment in epilepsy: how it occurs and how it can be avoided.
      Doses can be increased if seizures persist. However, the likelihood of additional benefit from a dose increment generally diminishes once higher doses are reached. In one observational study, 90% of those responding to a first-line anti-epileptic required:
      • valproic acid ≤1,500 mg/24 h
      • lamotrigine ≤300 mg/24 h
      • carbamazepine ≤800 mg/24 h.
        • Kwan P.
        • Brodie M.J.
        Effectiveness of first antiepileptic drug.
      Few patients responded to increases above these doses.
      • Kwan P.
      • Brodie M.J.
      Effectiveness of first antiepileptic drug.
      In non-responders, a change of anti-epileptic is indicated.

      Switching vs. Combining Anti-epileptics for Epilepsy

      If the first choice treatment fails, add a second anti-epileptic (Box A). When the second one is at an adequate or maximally tolerated dose, the first one is slowly withdrawn (see below).

      National Institute for Health and Clinical Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. 2004. Available from www.nice.org.uk/nicemedia/pdf/CG020fullguideline.pdf. Accessed October 12, 2011.

      Long-term combination therapy is generally avoided unless two trials of monotherapy have proved ineffective because:
      • there is an increased likelihood of drug interactions
      • toxicity may be enhanced
      • evidence of benefit compared with monotherapy is limited.
        • Perucca E.
        • Kwan P.
        Overtreatment in epilepsy: how it occurs and how it can be avoided.
        • Karceski S.
        • Morrell M.J.
        • Carpenter D.
        Treatment of epilepsy in adults: expert opinion, 2005.
      Combinations are guided by the same considerations as those for choosing first- and second-line anti-epileptics. Many successful combinations have been reported,
      • Karceski S.
      • Morrell M.J.
      • Carpenter D.
      Treatment of epilepsy in adults: expert opinion, 2005.
      • Stephen L.J.
      • Brodie M.J.
      Seizure freedom with more than one antiepileptic drug.
      but the relative benefits of such combinations have not been established. Studies of older anti-epileptics indicate probable benefit in combining GABAmimetics with sodium channel blockers or possibly with other GABAmimetics, but not in using two sodium channel blockers together.
      • Deckers C.L.
      • Czuczwar S.J.
      • Hekster Y.A.
      • et al.
      Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed.
      Despite this, combinations of sodium channel blockers are among those used by epileptologists.
      • Karceski S.
      • Morrell M.J.
      • Carpenter D.
      Treatment of epilepsy in adults: expert opinion, 2005.
      Combining valproic acid and lamotrigine increases the risk of skin reactions.
      Do not combine three or more anti-epileptics except on specialist advice; additional benefit is rare.
      • Perucca E.
      • Kwan P.
      Overtreatment in epilepsy: how it occurs and how it can be avoided.

      Prophylaxis in Patients With Cerebral Tumors

      Although about 20% of patients diagnosed with cerebral tumors will experience seizures, the risk is not reduced by prophylactic anti-epileptics. Subtherapeutic levels, a potential explanation in some trials, does not adequately account for this lack of effect. Thus, anti-epileptics should not generally be commenced in the absence of a history of seizures.
      • Miller L.C.
      • Drislane F.W.
      Treatment strategies after a single seizure: rationale for immediate versus deferred treatment.
      • Glantz M.J.
      • Cole B.F.
      • Forsyth P.A.
      • et al.
      Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology.
      Peri-neurosurgical use is an exception, but anti-epileptics should generally be slowly tapered after one week.
      • Glantz M.J.
      • Cole B.F.
      • Forsyth P.A.
      • et al.
      Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology.

      Convulsive Status Epilepticus

      Fig. 2 is modified from NICE guidance in the U.K.

      National Institute for Health and Clinical Excellence. Clinical Guideline 20. Epilepsy in adults and children: full guideline. Appendix C: Guidelines for treating status epilepticus in adults and children. 2010. Available from http://www.nice.org.uk/nicemedia/live/10954/29536/29536.pdf. Accessed October 12, 2011.

      Hypoglycemia should be excluded in all patients. If alcoholism or severely impaired nutrition is suspected, give thiamine 250 mg IV. Phenobarbital has been given preference over phenytoin because it is more likely to be immediately available in many palliative care units.
      Figure thumbnail gr2
      Fig. 2Management and IV drug treatment of status epilepticus in adults. See text for more detail.
      Lorazepam is the benzodiazepine of choice in the control of status epilepticus
      • Prasad K.
      • Al-Roomi K.
      • Krishnan P.R.
      • Sequeira R.
      Anticonvulsant therapy for status epilepticus.
      but, if unavailable, midazolam 10 mg is an alternative. If venous access cannot be obtained, give midazolam 10 mg buccally or SC (off-label routes of administration), or diazepam 10–20 mg PR.
      • Dreifuss F.E.
      • Rosman N.P.
      • Cloyd J.C.
      • et al.
      A comparison of rectal diazepam gel and placebo for acute repetitive seizures.
      Fosphenytoin is a pro-drug of phenytoin (1.5 mg of the former is equivalent to 1 mg of the latter). The dose is expressed as phenytoin sodium equivalent (PE). It can be given more rapidly than phenytoin. Ideally, heart rate, blood pressure, and respiratory function should be monitored during and for 30 min after the administration of fosphenytoin 15–20 mg(PE)/kg (50–100 mg(PE)/min). IV phenytoin sodium 15 mg/kg up to a maximum total dose of 1 g (≤50 mg/min; dilute 500 mg with 50 mL 0.9% saline) can be used instead, preferably with ECG monitoring.
      IV valproic acid is an alternative second-line treatment which carries a lower risk of cardiorespiratory depression.
      • Shorvon S.
      The treatment of status epilepticus.

      Non-convulsive Status Epilepticus (NCSE)

      NCSE is characterised by seizure activity on an EEG but without associated tonic-clonic activity. Presentations include delirium or coma.
      • Twycross R.
      • Wilcock A.
      • Stark Toller C.
      Symptom management in advanced cancer.
      In one report, NCSE was diagnosed in 5% of patients admitted to a palliative care unit; of these, half responded to treatment with anti-epileptics.
      • Lorenzl S.
      • Mayer S.
      • Feddersen B.
      • et al.
      Nonconvulsive status epilepticus in palliative care patients.
      Treatment is less urgent than for convulsive status epilepticus (Box A).

      Terminal agitation

      Phenobarbital is sometimes used in the management of intractable agitation in patients who are imminently dying.
      • Twycross R.
      • Wilcock A.
      • Stark Toller C.
      Symptom management in advanced cancer.

      Mania

      Valproic acid is generally added only when the response to an antipsychotic and a benzodiazepine is inadequate, but is an alternative first-line therapy particularly when previously effective. Carbamazepine and lamotrigine are second-line options.

      National Institute for Health and Clinical Excellence. The management of bipolar disorder in adults, children and adolescents, in primary and secondary care. Clinical guideline CG38. 2006. Available from www.nice.org.uk/CG38. Accessed October 12, 2011.

      • Yildiz A.
      • Vieta E.
      • Leucht S.
      • Baldessarini R.J.
      Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials.

      Anxiety

      Benefit is reported in various anxiety disorders,
      • Van Ameringen M.
      • Mancini C.
      • Pipe B.
      • Bennett M.
      Antiepileptic drugs in the treatment of anxiety disorders: role in therapy.
      but the best supporting evidence exists for pregabalin in generalized anxiety disorder. Efficacy is similar to lorazepam, alprazolam, and venlafaxine. Pregabalin has a faster rate of onset than venlafaxine, and causes less nausea. It has a similar rate of onset to lorazapam and alprazolam, and causes less drowsiness but more dizziness.
      • Frampton J.E.
      • Foster R.H.
      Pregabalin: in the treatment of generalised anxiety disorder.
      It is also effective for social phobia.
      • Pande A.C.
      • Feltner D.E.
      • Jefferson J.W.
      • et al.
      Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study.
      RCTs also show some benefit with gabapentin,
      • Pande A.C.
      • Davidson J.R.
      • Jefferson J.W.
      • et al.
      Treatment of social phobia with gabapentin: a placebo-controlled study.
      • Pande A.C.
      • Pollack M.H.
      • Crockatt J.
      • et al.
      Placebo-controlled study of gabapentin treatment of panic disorder.
      tiagabine,
      • Pollack M.H.
      • Roy-Byrne P.P.
      • Van Ameringen M.
      • et al.
      The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study.
      and lamotrigine.
      • Hertzberg M.A.
      • Butterfield M.I.
      • Feldman M.E.
      • et al.
      A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder.
      However, anti-epileptics are not commonly used in these settings and indirect comparison suggests that they are less effective than SSRIs.
      • Baldwin D.
      • Woods R.
      • Lawson R.
      • Taylor D.
      Efficacy of drug treatments for generalised anxiety disorder: systemic review and meta-analysis.

      Sweats and hot flashes

      Gabapentin is effective for hot flashes resulting from menopause or the treatment of breast cancer.
      • Pandya K.J.
      • Morrow G.R.
      • Roscoe J.A.
      • et al.
      (2005) Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial.
      • Nelson H.D.
      • Vesco K.K.
      • Haney E.
      • et al.
      (2006) Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis.
      Although efficacy was comparable with venlafaxine in an open-label cross-over study, twice as many patients preferred the latter.
      • Bordeleau L.
      • Pritchard K.I.
      • Loprinzi C.L.
      • et al.
      Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors.
      Benefit is also reported in idiopathic sweating in cancer.
      • Porzio G.
      • Aielli F.
      • Verna L.
      • et al.
      Gabapentin in the treatment of severe sweating experienced by advanced cancer patients.

      Refractory hiccup

      Gabapentin is reported to be effective for hiccup.
      • Alonso-Navarro H.
      • Rubio L.
      • Jiménez-Jiménez F.J.
      Refractory hiccup: successful treatment with gabapentin.
      • Jatzko A.
      • Stegmeier-Petroianu A.
      • Petroianu G.A.
      Alpha-2-delta ligands for singultus (hiccup) treatment: three case reports.
      • Moretti R.
      • Torre P.
      • Antonello R.M.
      • et al.
      (2004) Gabapentin as a drug therapy of intractable hiccup because of vascular lesion: a three-year follow up.

      Restless legs syndrome

      Anti-epileptic drugs, along with dopaminergics (D2 agonists or L-dopa) and some opioids are effective for restless legs syndrome.

      Earley CJ, Allen RP, Hening W. (2011) Restless legs syndrome and periodic leg movements in sleep. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. 2011;99:913–948.

      Benefit is reported with pregabalin, gabapentin enacarbil and gabapentin, with the latter as effective as ropinirole (a D2 agonist).
      • Bogan R.K.
      • Bornemann M.A.
      • Kushida C.A.
      • et al.
      (2010) Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study.
      • Garcia-Borreguero D.
      • Larrosa O.
      • Williams A.M.
      • et al.
      Treatment of restless legs syndrome with pregabalin: a double-blind, placebo-controlled study.
      • Allen R.
      • Chen C.
      • Soaita A.
      • et al.
      A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome.
      • Happe S.
      • Sauter C.
      • Klösch G.
      • Saletu B.
      • Zeitlhofer J.
      Gabapentin versus ropinirole in the treatment of idiopathic restless legs syndrome.
      Valproic acid and carbamazepine are possible alternatives.
      • Trenkwalder C.
      • Hening W.A.
      • Montagna P.
      • et al.
      Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice.

      Spasticity

      Although they have not been directly compared, gabapentin has been used as an alternative to baclofen.
      • Stevenson V.L.
      Rehabilitation in practice: spasticity management.

      Pruritus

      The use of gabapentin for neuropathic itch is an extrapolation from its use in neuropathic pain.
      There are reports of benefit in uremic itch
      • Manenti L.
      • Tansinda P.
      • Vaglio A.
      Uraemic pruritus: clinical characteristics, pathophysiology and treatment.
      and intractable idiopathic itch.
      • Kanitakis J.
      Brachioradial pruritus: report of a new case responding to gabapentin.
      • Yesudian P.D.
      • Wilson N.J.
      Efficacy of gabapentin in the management of pruritus of unknown origin.

      Stopping Anti-epileptics

      Withdrawal of treatment for epilepsy is a specialist area of practice best supervised by a neurologist.
      Recommendations vary regarding the rate at which it is safe to withdraw a particular anti-epileptic. For example, abrupt cessation of long-term GABAmimetics (e.g., benzodiazepines or barbiturates) should be avoided because rebound seizures may be precipitated, even when used for indications other than epilepsy. On the other hand, both gabapentin and pregabalin can be stopped progressively over one to two weeks.
      Traditionally, a gradual tapering of the dose over a period of months has been recommended (Table 3). However, few RCTs have compared gradual versus abrupt cessation
      • Ranganathan L.N.
      • Ramaratnam S.
      Rapid versus slow withdrawal of antiepileptic drugs.
      and some centers successfully withdraw anti-epileptics over shorter periods, e.g., GABAmimetics over four weeks and other anti-epileptics over ≤1 week.
      Table 3Recommended Monthly Reductions of Selected Anti-epileptics
      • Chadwick D.
      The withdrawal of antiepileptic drugs.
      Drug
      Gabapentin and pregabalin can be stopped progressively over 1–2 weeks.
      Reduction
      Carbamazepine100 mg
      Clobazam (not U.S.)10 mg
      Clonazepam0.5 mg
      Ethosuximide250 mg
      Lamotrigine25 mg
      Levetiracetam1,000 mg
      Data from PI.
      Phenobarbital15 mg
      Phenytoin50 mg
      Topiramate25 mg
      Valproic acid250 mg
      Vigabatrin500 mg
      a Gabapentin and pregabalin can be stopped progressively over 1–2 weeks.
      b Data from PI.
      In adults, the risk of relapse of pre-existing epilepsy on stopping treatment is 40–50%.
      • Hopkins A.
      • Shorvon S.
      (1995) Definitions and epidemiology of epilepsy.
      Caution also should be exercised when switching to an alternative anti-epileptic drug. The first drug should not be withdrawn until the new drug has been titrated up to an anticipated effective dose.
      For patients who are imminently dying (i.e., death expected within a few days) and who can no longer swallow medication, consider substituting SC midazolam or SC phenobarbital. However, some anti-epileptics have a long half-life (Table 2) and, in a moribund patient, might continue to be effective for 2–3 days after the last PO dose.

      References

        • Perucca E.
        An introduction to antiepileptic drugs.
        Epilepsia. 2005; 46: 31-37
        • Lynch B.A.
        • Lambeng N.
        • Nocka K.
        The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.
        Proc Natl Acad Sci U S A. 2004; 101: 9861-9866
        • Jevtovic-Todorovic V.
        • Todorovic S.M.
        The role of peripheral T-type calcium channels in pain transmission.
        Cell Calcium. 2006; 40: 197-203
        • Kochegarov A.A.
        Pharmacological modulators of voltage-gated calcium channels and their therapeutical application.
        Cell Calcium. 2003; 33: 145-162
        • Shin H.S.
        T-type Ca2+ channels and absence epilepsy.
        Cell Calcium. 2006; 40: 191-196
        • Loscher W.
        Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy.
        CNS Drugs. 2002; 16: 669-694
        • Lee C.H.
        • Tsai T.S.
        • Liou H.H.
        Gabapentin activates ROMK1 channels by a protein kinase A (PKA)-dependent mechanism.
        Br J Pharmacol. 2008; 154: 216-225
        • Sheets P.L.
        • Heers C.
        • Stoehr T.
        • Cummins T.R.
        Differential block of sensory neuronal voltage-gated sodium channels by lacosamide [(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide], lidocaine, and carbamazepine.
        J Pharmacol Exp Ther. 2008; 326: 89-99
        • Devulder J.
        Flupirtine in pain management: pharmacological properties and clinical use.
        CNS Drugs. 2010; 24: 867-881
        • Devor M.
        Sodium channels and mechanisms of neuropathic pain.
        J Pain. 2006; 7: S3-S12
        • Wiffen P.J.
        • Derry S.
        • Moore R.A.
        • McQuay H.J.
        Carbamazepine for acute and chronic pain in adults.
        Cochrane Database Syst Rev. 2011; : CD005451
        • Challapalli V.
        • Tremont-Lukats I.W.
        • McNicol E.D.
        • Lau J.
        • Carr D.B.
        Systemic administration of local anesthetic agents to relieve neuropathic pain.
        Cochrane Database Syst Rev. 2005; : CD003345
        • von Gunten C.F.
        • Eappen S.
        • Cleary J.F.
        • et al.
        Flecainide for the treatment of chronic neuropathic pain: a Phase II trial.
        Palliat Med. 2007; 21: 667-672
        • Taylor C.P.
        Mechanisms of analgesia by gabapentin and pregabalin–calcium channel alpha2-delta [Cavalpha2-delta] ligands.
        Pain. 2009; 142: 13-16
        • Bauer C.S.
        • Tran-Van-Minh A.
        • Kadurin I.
        • Dolphin A.C.
        A new look at calcium channel alpha2delta subunits.
        Curr Opin Neurobiol. 2010; 20: 563-571
        • Bee L.A.
        • Dickenson A.H.
        Descending facilitation from the brainstem determines behavioural and neuronal hypersensitivity following nerve injury and efficacy of pregabalin.
        Pain. 2008; 140: 209-223
        • Hayashida K.
        • Obata H.
        • Nakajima K.
        • Eisenach J.C.
        Gabapentin acts within the locus coeruleus to alleviate neuropathic pain.
        Anesthesiology. 2008; 109: 1077-1084
        • Boroujerdi A.
        • Kim H.K.
        • Lyu Y.S.
        • et al.
        Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain.
        Pain. 2008; 139: 358-366
        • Lu S.G.
        • Zhang X.L.
        • Luo Z.D.
        • Gold M.S.
        Persistent inflammation alters the density and distribution of voltage activated calcium channels in subpopulations of rat cutaneous DRG neurons.
        Pain. 2010; 151: 633-643
        • Yang R.H.
        • Wang W.T.
        • Chen J.Y.
        • Xie R.G.
        • Hu S.J.
        Gabapentin selectively reduces persistent sodium current in injured type-A dorsal root ganglion neurons.
        Pain. 2009; 143: 48-55
        • Kaminskia R.M.
        • Matagnea A.
        • Leclercqa K.
        • et al.
        SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy.
        Neuropharmacology. 2008; 54: 715-720
      1. Twycross R.G. Wilcock A. Hospice and palliative care formulary USA. 2nd ed. Palliativedrugs.com Ltd., Nottingham2008: 493-496
        • Takahashi T.
        • Aoki Y.
        • Okubo K.
        • et al.
        Upregulation of Ca(v)3.2 T-type calcium channels targeted by endogenous hydrogen sulfide contributes to maintenance of neuropathic pain.
        Pain. 2010; 150: 183-191
        • Mann M.W.
        • Pons G.
        Various pharmacogenetic aspects of antiepileptic drug therapy: a review.
        CNS Drugs. 2007; 21: 143-164
        • Löscher W.
        • Klotz U.
        • Zimprich F.
        • Schmidt D.
        The clinical impact of pharmacogenetics on the treatment of epilepsy.
        Epilepsia. 2009; 50: 1-23
        • Abe T.
        • Seo T.
        • Ishitsu T.
        • et al.
        Association between SCN1A polymorphism and carbamazepine-resistant epilepsy.
        Br J Clin Pharmacol. 2008; 66: 304-307
        • Cummins T.R.
        • Sheets P.L.
        • Waxman S.G.
        The roles of sodium channels in nociception: Implications for mechanisms of pain.
        Pain. 2007; 131: 243-257
        • Sheets P.L.
        • Jackson 2nd, J.O.
        • Waxman S.G.
        • Dib-Hajj S.D.
        • Cummins T.R.
        A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity.
        J Physiol. 2007; 581: 1019-1031
        • Perucca E.
        Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age.
        Clin Pharmacokinet. 2006; 45: 351-363
        • Perucca E.
        The clinical pharmacokinetics of the new antiepileptic drugs.
        Epilepsia. 1999; 40: S7-13
        • Garnett W.R.
        Clinical pharmacology of topiramate: a review.
        Epilepsia. 2000; 41: S61-S65
      2. Anderson P.O. Knoben J.E. Troutman W.G. Handbook of clinical drug data. 10th ed. McGraw Hill, New York2002
        • Perucca E.
        Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience.
        CNS Drugs. 2002; 16: 695-714
        • May T.W.
        • Korn-Merker E.
        • Rambeck B.
        Clinical pharmacokinetics of oxcarbazepine.
        Clin Pharmacokinet. 2003; 42: 1023-1042
        • Bang L.M.
        • Goa K.L.
        Spotlight on oxcarbazepine in epilepsy.
        CNS Drugs. 2004; 18: 57-61
        • Kwan P.
        • Brodie M.J.
        Phenobarbital for the treatment of epilepsy in the 21st century: a critical review.
        Epilepsia. 2004; 45: 1141-1149
        • Patsalos P.N.
        Clinical pharmacokinetics of levetiracetam.
        Clin Pharmacokinet. 2004; 43: 707-724
        • Chung W.H.
        • Hung S.I.
        • Hong H.S.
        • et al.
        Medical genetics: a marker for Stevens-Johnson syndrome.
        Nature. 2004; 428: 486
        • Locharernkul C.
        • Loplumlert J.
        • Limotai C.
        • et al.
        Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B∗1502 allele in Thai population.
        Epilepsia. 2008; 49: 2087-2091
      3. U.S. Food and Drug Administration. Dangerous or even fatal skin reactions - carbamazepine (marketed as Carbatrol, Equetro, Tegretol and generics). 2007. Available from http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124718.htm. Accessed October 12, 2011.

      4. U.S. Food and Drug Administration. Phenytoin (marketed as Dilantin, Phenytek and generics) and fosphenytoin (marketed as Cerebyx and generics). 2008. Available from http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124788.htm. Accessed October 12, 2011.

      5. Twycross R.G. Wilcock A. Palliative care formulary. 4th ed. Palliativedrugs.com Ltd., Nottingham2011: 659-663
        • Hirsch L.J.
        • Arif H.
        • Nahm E.A.
        Cross-sensitivity of skin rashes with antiepileptic drug use.
        Neurology. 2008; 71: 1527-1534
        • Morgan D.J.
        • McLean A.J.
        Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease. An update.
        Clin Pharmacokinet. 1995; 29: 370-391
        • Ford-Dunn S.
        Managing patients with cancer and advanced liver disease.
        Palliat Med. 2005; 19: 563-565
        • Bagary M.
        (2011) Epilepsy, antiepileptic drugs and suicidality.
        Curr Opin Neurol. 2011; 24: 177-182
      6. U.S. Food and Drug Administration. Safety information. Antiepileptic drugs. 2008. Available from www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm074939.htm. Accessed October 12, 2011.

      7. European Medicines Agency. Meeting highlights from the Committee for Medicinal Products for Human Use, 15-18 December 2008. Available from www.emea.europa.eu/pdfs/human/press/pr/67072408en.pdf. Accessed October 12, 2011.

        • Marson A.G.
        • Al-Kharusi A.M.
        • Alwaidh M.
        • et al.
        The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.
        Lancet. 2007; 369: 1016-1026
        • Marson A.G.
        • Al-Kharusi A.M.
        • Alwaidh M.
        • et al.
        The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial.
        Lancet. 2007; 369: 1000-1015
        • Kwan P.
        • Brodie M.J.
        Neuropsychological effects of epilepsy and antiepileptic drugs.
        Lancet. 2001; 357: 216-222
        • Dinkelacker V.
        • Dietl T.
        • Widman G.
        • Lengler U.
        • Elger C.E.
        Aggressive behavior of epilepsy patients in the course of levetiracetam add-on therapy: report of 33 mild to severe cases.
        Epilepsy Behav. 2003; 4: 537-547
        • Weintraub D.
        • Buchsbaum R.
        • Resor Jr., S.R.
        • Hirsch L.J.
        Psychiatric and behavioral side effects of the newer antiepileptic drugs in adults with epilepsy.
        Epilepsy Behav. 2007; 10: 105-110
        • White J.R.
        • Walczak T.S.
        • Leppik I.E.
        • et al.
        Discontinuation of levetiracetam because of behavioral side effects: a case-control study.
        Neurology. 2003; 61: 1218-1221
        • Major P.
        • Greenberg E.
        • Khan A.
        • Thiele E.A.
        Pyridoxine supplementation for the treatment of levetiracetam-induced behavior side effects in children: preliminary results.
        Epilepsy Behav. 2008; 13: 557-559
        • Davis G.P.
        • McCarthy J.T.
        • Magill D.B.
        • Coffey B.
        Behavioral effects of levetiracetam mitigated by pyridoxine.
        J Child Adolesc Psychopharmacol. 2009; 19: 209-211
        • French J.A.
        First-choice drug for newly diagnosed epilepsy. [comment].
        Lancet. 2007; 369: 970-971
        • Perucca E.
        • Gram L.
        • Avanzini G.
        • Dulac O.
        Antiepileptic drugs as a cause of worsening seizures.
        Epilepsia. 1998; 39: 5-17
        • Finnerup N.B.
        • Sindrup S.H.
        • Jensen T.S.
        The evidence for pharmaceutical treatment of neuropathic pain.
        Pain. 2010; 150: 573-581
        • Saarto T.
        • Wiffen P.J.
        (2007) Antidepressants for neuropathic pain.
        Cochrane Database Syst Rev. 2007 Oct 17; ([update of Cochrane Database Syst Rev 2005;(3):CD005454]): CD005454
        • Dworkin R.H.
        • O’Connor A.B.
        • Audette J.
        • et al.
        Recommendations for the pharmacological management of neuropathic pain: an overview and literature update.
        Mayo Clin Proc. 2010; 85: S3-S14
        • Attal N.
        • Cruccu G.
        • Baron R.
        • et al.
        EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision.
        Eur J Neurol. 2010; 17: e1113-e1188
        • Caraceni A.
        • Zecca E.
        • Bonezzi C.
        • et al.
        Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group.
        J Clin Oncol. 2004; 22: 2909-2917
        • Bennett M.I.
        Effectiveness of antiepileptic or antidepressant drugs when added to opioids for cancer pain: systematic review.
        Palliat Med. 2011; 25: 553-559
        • Pandey C.K.
        • Raza M.
        • Tripathi M.
        • et al.
        The comparative evaluation of gabapentin and carbamazepine for pain management in Guillain-Barre syndrome patients in the intensive care unit.
        Anesth Analg. 2005; 101: 220-225
        • Hardy J.R.
        • Rees E.A.
        • Gwilliam B.
        • et al.
        A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain.
        J Pain Symptom Manage. 2001; 21: 204-209
        • Snare A.J.
        Sodium valproate. Retrospective analysis of neuropathic pain control in patients with advanced cancer.
        J Pharm Tech. 1993; 9: 114-117
        • Kochar D.K.
        • Jain N.
        • Agarwal R.P.
        • et al.
        Sodium valproate in the management of painful neuropathy in type 2 diabetes - a randomized placebo controlled study.
        Acta Neurol Scand. 2002; 106: 248-252
        • Kochar D.K.
        • Rawat N.
        • Agrawal R.P.
        • et al.
        Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study.
        QJM. 2004; 97: 33-38
        • Kochar D.K.
        • Garg P.
        • Bumb R.A.
        • et al.
        Divalproex sodium in the management of post-herpetic neuralgia: a randomized double-blind placebo-controlled study.
        QJM. 2005; 98: 29-34
        • Otto M.
        • Bach F.W.
        • Jensen T.S.
        • Sindrup S.H.
        Valproic acid has no effect on pain in polyneuropathy: a randomized, controlled trial.
        Neurology. 2004; 62: 285-288
        • Richter R.W.
        • Portenoy R.
        • Sharma U.
        • et al.
        Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial.
        J Pain. 2005; 6: 253-260
        • Rosenstock J.
        • Tuchman M.
        • LaMoreaux L.
        • Sharma U.
        Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial.
        Pain. 2004; 110: 628-638
        • Tölle T.
        • Freynhagen R.
        • Versavel M.
        • Trostmann U.
        • Young Jr., J.P.
        Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study.
        Eur J Pain. 2008; 12: 203-213
        • Freynhagen R.
        • Strojek K.
        • Griesing T.
        • Whalen E.
        • Balkenohl M.
        Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens.
        Pain. 2005; 115: 254-263
        • Sabatowski R.
        • Gálvez R.
        • Cherry D.A.
        • et al.
        Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial.
        Pain. 2004; 109: 26-35
        • van Seventer R.
        • Feister H.A.
        • Young Jr., J.P.
        • et al.
        Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial.
        Curr Med Res Opin. 2006; 22: 375-384
        • Dworkin R.H.
        • Corbin A.E.
        • Young Jr., J.P.
        • et al.
        (2003) Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial.
        Neurology. 2003; 60: 1274-1283
        • Wiffen P.J.
        • Derry S.
        • Moore R.A.
        • McQuay H.J.
        Carbamazepine for acute and chronic pain.
        Cochrane Database Syst Rev. 2005 Jul 20; : CD005451
        • McCleane G.
        Intravenous infusion of phenytoin relieves neuropathic pain: a randomized, double-blinded, placebo-controlled, crossover study.
        Anesth Analg. 1999; 89: 985-988
        • Swerdlow M.
        • Cundill J.
        Anticonvulsant drugs used in the treatment of lancinating pain: a comparison.
        Anaesthesia. 1981; 36: 1129-1132
        • Bouckoms A.J.
        • Litman R.E.
        Clonazepam in the treatment of neuralgic pain syndrome.
        Psychosomatics. 1985; 26: 933-936
        • Bartusch S.L.
        • Sanders B.J.
        • D’Alessio J.G.
        • Jernigan J.R.
        Clonazepam for the treatment of lancinating phantom limb pain.
        Clin J Pain. 1996; 12: 59-62
        • Hugel H.
        • Ellershaw J.E.
        • Dickman A.
        Clonazepam as an adjuvant analgesic in patients with cancer-related neuropathic pain.
        J Pain Symptom Manage. 2003; 26: 1073-1074
        • Morello C.M.
        • Leckband S.G.
        • Stoner C.P.
        • Moorhouse D.F.
        • Sahagian G.A.
        Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain.
        Arch Intern Med. 1999; 159: 1931-1937
        • Chandra K.
        • Shafiq N.
        • Pandhi P.
        • Gupta S.
        • Malhotra S.
        Gabapentin versus nortriptyline in post-herpetic neuralgia patients: a randomized, double-blind clinical trial--the GONIP Trial.
        Int J Clin Pharmacol Ther. 2006; 44: 358-363
        • Gilron I.
        • Bailey J.M.
        • Tu D.
        • et al.
        Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial.
        Lancet. 2009; 374: 1252-1261
        • Raja S.N.
        • Haythornthwaite J.A.
        • Pappagallo M.
        • et al.
        Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial.
        Neurology. 2002; 59: 1015-1021
        • Gilron I.
        • Bailey J.M.
        • Tu D.
        • et al.
        Morphine, gabapentin, or their combination for neuropathic pain.
        N Engl J Med. 2005; 352: 1324-1334
        • Keskinbora K.
        • Pekel A.F.
        • Aydinli I.
        Gabapentin and an opioid combination versus opioid alone for the management of neuropathic cancer pain: a randomized open trial.
        J Pain Symptom Manage. 2007; 34: 183-189
        • Solaro C.
        • Messmer Uccelli M.
        • et al.
        Low-dose gabapentin combined with either lamotrigine or carbamazepine can be useful therapies for trigeminal neuralgia in multiple sclerosis.
        Eur Neurol. 2000; 44: 45-48
        • Miller L.C.
        • Drislane F.W.
        Treatment strategies after a single seizure: rationale for immediate versus deferred treatment.
        CNS Drugs. 2007; 21: 89-99
        • Rudà R.
        • Trevisan E.
        • Soffietti R.
        Epilepsy and brain tumors.
        Curr Opin Oncol. 2010; 22: 611-620
        • Schaller B.
        Brain tumor and seizures: pathophysiology and its implications for treatment revisited (Epilepsia 2003;44:1223–1232).
        Epilepsia. 2006; 47 (author reply 661): 661
        • Vecht C.J.
        • van Breemen M.
        Optimizing therapy of seizures in patients with brain tumours.
        Neurology. 2006; 67: S10-S13
        • van Breemen M.S.
        • Wilms E.B.
        • Vecht C.J.
        Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management.
        Lancet Neurol. 2007; 6: 421-430
        • van Breemen M.S.
        • Rijsman R.M.
        • Taphoorn M.J.
        • et al.
        Efficacy of anti-epileptic drugs in patients with gliomas and seizures.
        J Neurol. 2009; 256: 1519-1526
        • Perucca E.
        • Kwan P.
        Overtreatment in epilepsy: how it occurs and how it can be avoided.
        CNS Drugs. 2005; 19: 897-908
        • Kwan P.
        • Brodie M.J.
        Effectiveness of first antiepileptic drug.
        Epilepsia. 2001; 42: 1255-1260
        • Kargiotis O.
        • Markoula S.
        • Kyritsis A.P.
        Epilepsy in the cancer patient.
        Cancer Chemother Pharmacol. 2011; 67: 489-501
        • Ward M.M.
        • Barbaro N.M.
        • Laxer K.D.
        • Rampil I.J.
        Preoperative valproate administration does not increase blood loss during temporal lobectomy.
        Epilepsia. 1996; 37: 98-101
        • Anderson G.D.
        • Lin Y.X.
        • Berge C.
        • Ojemann G.A.
        Absence of bleeding complications in patients undergoing cortical surgery while receiving valproate treatment.
        J Neurosurg. 1997; 87: 252-256
      8. National Institute for Health and Clinical Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. 2004. Available from www.nice.org.uk/nicemedia/pdf/CG020fullguideline.pdf. Accessed October 12, 2011.

        • Karceski S.
        • Morrell M.J.
        • Carpenter D.
        Treatment of epilepsy in adults: expert opinion, 2005.
        Epilepsy Behav. 2005; 7 (quiz S65–67): S1-S64
        • Stephen L.J.
        • Brodie M.J.
        Seizure freedom with more than one antiepileptic drug.
        Seizure. 2002; 11: 349-351
        • Deckers C.L.
        • Czuczwar S.J.
        • Hekster Y.A.
        • et al.
        Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed.
        Epilepsia. 2000; 41: 1364-1374
        • Glantz M.J.
        • Cole B.F.
        • Forsyth P.A.
        • et al.
        Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology.
        Neurology. 2000; 54: 1886-1893
      9. National Institute for Health and Clinical Excellence. Clinical Guideline 20. Epilepsy in adults and children: full guideline. Appendix C: Guidelines for treating status epilepticus in adults and children. 2010. Available from http://www.nice.org.uk/nicemedia/live/10954/29536/29536.pdf. Accessed October 12, 2011.

        • Prasad K.
        • Al-Roomi K.
        • Krishnan P.R.
        • Sequeira R.
        Anticonvulsant therapy for status epilepticus.
        Cochrane Database Syst Rev. 2005; : CD003723
        • Dreifuss F.E.
        • Rosman N.P.
        • Cloyd J.C.
        • et al.
        A comparison of rectal diazepam gel and placebo for acute repetitive seizures.
        N Engl J Med. 1998; 338: 1869-1875
        • Shorvon S.
        The treatment of status epilepticus.
        Curr Opin Neurol. 2011; 24: 165-170
        • Twycross R.
        • Wilcock A.
        • Stark Toller C.
        Symptom management in advanced cancer.
        4th ed. palliativedrugs.com, Nottingham2009 (283–284)
        • Lorenzl S.
        • Mayer S.
        • Feddersen B.
        • et al.
        Nonconvulsive status epilepticus in palliative care patients.
        J Pain Symptom Manage. 2010; 40: 460-465
        • Twycross R.
        • Wilcock A.
        • Stark Toller C.
        Symptom management in advanced cancer.
        4th ed. palliativedrugs.com, Nottingham2009 (430–433)
      10. National Institute for Health and Clinical Excellence. The management of bipolar disorder in adults, children and adolescents, in primary and secondary care. Clinical guideline CG38. 2006. Available from www.nice.org.uk/CG38. Accessed October 12, 2011.

        • Yildiz A.
        • Vieta E.
        • Leucht S.
        • Baldessarini R.J.
        Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials.
        Neuropsychopharmacology. 2011; 36: 375-389
        • Van Ameringen M.
        • Mancini C.
        • Pipe B.
        • Bennett M.
        Antiepileptic drugs in the treatment of anxiety disorders: role in therapy.
        Drugs. 2004; 64: 2199-2220
        • Frampton J.E.
        • Foster R.H.
        Pregabalin: in the treatment of generalised anxiety disorder.
        CNS Drugs. 2006; 20 (discussion 694–695. [erratum appears in CNS Drugs. 2007;21(6):481]): 685-693
        • Pande A.C.
        • Feltner D.E.
        • Jefferson J.W.
        • et al.
        Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study.
        J Clin Psychopharmacol. 2004; 24: 141-149
        • Pande A.C.
        • Davidson J.R.
        • Jefferson J.W.
        • et al.
        Treatment of social phobia with gabapentin: a placebo-controlled study.
        J Clin Psychopharmacol. 1999; 19: 341-348
        • Pande A.C.
        • Pollack M.H.
        • Crockatt J.
        • et al.
        Placebo-controlled study of gabapentin treatment of panic disorder.
        J Clin Psychopharmacol. 2000; 20: 467-471
        • Pollack M.H.
        • Roy-Byrne P.P.
        • Van Ameringen M.
        • et al.
        The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study.
        J Clin Psychiatry. 2005; 66: 1401-1408
        • Hertzberg M.A.
        • Butterfield M.I.
        • Feldman M.E.
        • et al.
        A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder.
        Biol Psychiatry. 1999; 45: 1226-1229
        • Baldwin D.
        • Woods R.
        • Lawson R.
        • Taylor D.
        Efficacy of drug treatments for generalised anxiety disorder: systemic review and meta-analysis.
        BMJ. 2011; 342: 1199
        • Pandya K.J.
        • Morrow G.R.
        • Roscoe J.A.
        • et al.
        (2005) Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial.
        Lancet. 2005; 366: 818-824
        • Nelson H.D.
        • Vesco K.K.
        • Haney E.
        • et al.
        (2006) Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis.
        JAMA. 2006; 295: 2057-2071
        • Bordeleau L.
        • Pritchard K.I.
        • Loprinzi C.L.
        • et al.
        Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors.
        J Clin Oncol. 2010; 28: 5147-5152
        • Porzio G.
        • Aielli F.
        • Verna L.
        • et al.
        Gabapentin in the treatment of severe sweating experienced by advanced cancer patients.
        Support Care Cancer. 2006; 14: 389-391
        • Alonso-Navarro H.
        • Rubio L.
        • Jiménez-Jiménez F.J.
        Refractory hiccup: successful treatment with gabapentin.
        Clin Neuropharmacol. 2007; 30: 186-187
        • Jatzko A.
        • Stegmeier-Petroianu A.
        • Petroianu G.A.
        Alpha-2-delta ligands for singultus (hiccup) treatment: three case reports.
        J Pain Symptom Manage. 2007; 33: 756-760
        • Moretti R.
        • Torre P.
        • Antonello R.M.
        • et al.
        (2004) Gabapentin as a drug therapy of intractable hiccup because of vascular lesion: a three-year follow up.
        Neurologist. 2004; 10: 102-106
      11. Earley CJ, Allen RP, Hening W. (2011) Restless legs syndrome and periodic leg movements in sleep. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. 2011;99:913–948.

        • Bogan R.K.
        • Bornemann M.A.
        • Kushida C.A.
        • et al.
        (2010) Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study.
        Mayo Clin Proc. 2010; 85: 512-521
        • Garcia-Borreguero D.
        • Larrosa O.
        • Williams A.M.
        • et al.
        Treatment of restless legs syndrome with pregabalin: a double-blind, placebo-controlled study.
        Neurology. 2010; 74: 1897-1904
        • Allen R.
        • Chen C.
        • Soaita A.
        • et al.
        A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome.
        Sleep Med. 2010; 11: 512-519
        • Happe S.
        • Sauter C.
        • Klösch G.
        • Saletu B.
        • Zeitlhofer J.
        Gabapentin versus ropinirole in the treatment of idiopathic restless legs syndrome.
        Neuropsychobiology. 2003; 48: 82-86
        • Trenkwalder C.
        • Hening W.A.
        • Montagna P.
        • et al.
        Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice.
        Mov Disord. 2008; 23: 2267-2302
        • Stevenson V.L.
        Rehabilitation in practice: spasticity management.
        Clin Rehabil. 2010; 24: 293-304
      12. Zylicz Z. Twycross R. Jones E.A. Pruritus in advanced disease. Oxford University Press, Oxford2004
        • Manenti L.
        • Tansinda P.
        • Vaglio A.
        Uraemic pruritus: clinical characteristics, pathophysiology and treatment.
        Drugs. 2009; 69: 251-263
        • Kanitakis J.
        Brachioradial pruritus: report of a new case responding to gabapentin.
        Eur J Dermatol. 2006; 16: 311-312
        • Yesudian P.D.
        • Wilson N.J.
        Efficacy of gabapentin in the management of pruritus of unknown origin.
        Arch Dermatol. 2005; 141: 1507-1509
        • Ranganathan L.N.
        • Ramaratnam S.
        Rapid versus slow withdrawal of antiepileptic drugs.
        Cochrane Database Syst Rev. 2006; : CD005003
        • Chadwick D.
        The withdrawal of antiepileptic drugs.
        in: Hopkins A. Shorvon S.D. Cascino G. Epilepsy. 2nd ed. Chapman and Hall, London1995: 215-220
        • Hopkins A.
        • Shorvon S.
        (1995) Definitions and epidemiology of epilepsy.
        in: Hopkins A. Shorvon S.D. Cascino G. Epilepsy. 2nd ed. Chapman and Hall, London1995: 1-24