Neuropathy in the Cancer Patient: Causes and ... - Dr. Jeffrey Fudin

EDUCATIONAL REVIEWImage courtesy of the National Cancer Institute/Linda Bartlett (Photographer)Neuropathy in the Cancer Patient:Causes and CuresIdentifying the causes of neuropathy in cancer patients can be difficult. This review looks atthe common causes of neuropathy in cancer patients, as well as effective therapies—and evenpreventions.Josephine Sasu-Tenkoramaa, PharmDPGY1 Pharmacy Practice ResidentStratton VA Medical CenterAlbany, New YorkJeffrey Fudin, BS, PharmD, RPh, DAAPM, FCCPAdjunct Associate Professor of Pharmacy PracticeAlbany College of Pharmacy and Health ServicesAlbany, New YorkNeuropathic pain is often defined as paincaused by a lesion or disease of the somatosensorynervous system. Peripheral neuropathiesarise from disorders associatedspecifically outside the central nervoussystem (CNS) and within the peripheralnervous system. 1 Symptoms of peripheralneuropathy include numbness, tingling, paresthesia (pinsand needles sensations), sensitivity to touch, or muscleweakness. In patients with extreme symptoms, they maypresent with burning pain, muscle wasting, paralysis, ororgan dysfunction. 1There are multiple causes of peripheral neuropathy,and in the cancer patient, identifying the culprit may becomplicated by a plethora of etiologies. This review willfocus on potential origins of neuropathic pain in the cancerpatient, including both disease- and drug-inducedperipheral neuropathy; current treatment modalities ofcancer-induced peripheral neuropathy (CIPN); and howto prevent the development of peripheral neuropathy incancer patients. According to the American Cancer Society,about 11.9 million Americans suffer from cancer pain, butit remains unclear what portion of that pain is specificallyneuropathic versus somatic, visceral, or a combination. ItApril 2013 | Practical Pain Management53

Neuropathy in the Cancer Patient: Causes and CuresTable 1. Most Common CancersCausing Peripheral Neuropathy••Breast cancer••Bone marrow transplantation a••Lung cancer••Lymphoma (non-Hodgkin’s)••Multiple myeloma••Waldenström’smacroglobulinemiaaBone marrow transplantation is a treatment ofcertain cancers that may cause neuropathy.also is equally unclear what percentageof these cases is due to disease,treatments, or both. 2Cancer-induced PeripheralNeuropathyBy virtue of the nature of the disease,cancer alone can cause neuropathy.Certain neuropathies can develop dueto remote or paraneoplastic effect;invasion of the cancer or compressionof the nerves; or as a side effectsecondary to treatment. 3 The cancerscommonly associated with neuropathiesare listed in Table 1. This sectionfocuses on the role of CIPN in thecancer patient.PEN/SNParaneoplastic encephalomyelitis/sensoryneuronopathy (PEN/SN) is a type ofneuropathy most commonly associatedwith lung cancer, typically smallcelllung cancer. Unlike other typesof pain syndromes, PEN/SN is notdue to the effects of the tumor itself,metastasis, treatment, infection, ormetabolic abnormalities. Rather, itis thought to be a result of “remoteeffects” of the cancer that lead to theproduction of antibodies or inflammatorycells against any neural antigensthat the tumor may express. 4 Thesymptoms can be acute or progressive.Patients typically present withnumbness and parasthesias in thedistal extremities, usually unilaterally.Eventually, this type of neuropathymay result in loss of proprioceptionand sensory ataxia. Oftentimes, thesepatients develop confusion, memoryloss, depression, hallucinations,seizures, and/or cerebellar ataxia.Treating the underlying cancer doesnot always affect the clinical courseof PEN/SN. Some patients mayoccasionally improve after the tumorhas been treated. Other treatmentssuch as plasmapheresis, intravenousimmunoglobulin, and immunosuppressiveagents have not shown anygreater benefit. 3,4Tumor InfiltrationPeripheral neuropathy may developsecondary to tumor infiltration.Leukemia and lymphoma cells caninfiltrate the cranial and peripheralnerves; the result can be mononeuropathy,mononeuropathy multiplex,polyradiculopathy, or plexopathyas a complication. This neuropathyis generally painful and may be anindication of newly diagnosed cancerand/or disease progression. Thesymptoms can be managed by treatingthe underlying hematologicalmalignancy or by initiating glucocorticoidsif not contraindicated. 3LymphomaLymphoma most often causes neuropathyeither by infiltration or directcompression of nerves, or by a paraneoplasticprocess. 3 Most peripheralcomplications are due to non-Hodgkin’slymphoma (NHL). 5 Hodgkin’slymphoma, on the other hand, rarelycauses neuropathy; it generally causesimmunological disorders of theperipheral nervous system such asinflammatory plexopathy or Guillain-Barré syndrome. 5 Although the NHLneuropathy may manifest as a sensoryor motor symptom, it is commonlyseen as a sensorimotor neuropathy.The course of the neuropathy maybe acute, gradually progressive, orrelapsing and remitting. The neuropathymay respond to the treatment ofthe underlying lymphoma. 5Multiple MyelomaMultiple myeloma (MM) is a commonhematologic malignancy associatedwith monoclonal gammapathy.About 40% of patients with MMdevelop some type of peripheral neuropathy.Patients may develop painfulparesthesia and loss of differentiatingbetween pinprick and temperaturesensations. The mechanism ofthe neuropathy is primarily due toamyloidosis with infiltration of thenerves. It is also thought to be dueto the metabolic or toxic effects ofthe systemic consequences of renalfailure. 3,5A myeloma cell (abnormal plasma cell) making Mproteins. M proteins are antibodies created by amyeloma cell.Waldenström’s MacroglobulinemiaWaldenström’s macroglobulinemiais a cancer of the B lymphocytes. Itis caused by a malignant proliferationof lymphoplasmacytoid cells,which produces an overabundanceof immunoglobulin M monoclonalproteins with a κ light chain—causingthe blood to become hyperviscous.The mechanism of neuropathyImage courtesy of the National Cancer Institute/Lydia Kibiuk(Illustrator)54Practical Pain Management | April 2013

Neuropathy in the Cancer Patient: Causes and Curesis unknown, but it’s thought to berelated to myelin-associated glycoproteinantibodies. However, a causal relationshiphas not been confirmed. 6Solid TumorsThe most common solid tumorsassociated with peripheral neuropathyinclude breast cancer and lungcancer as reported in case reports andin a prospective, multicenter studyin radiotherapy oncology units. 7,8Bone Marrow TransplantationAlthough not a neoplasm, bonemarrow transplantation (BMT) isa treatment for certain malignancies,which may cause neuropathy.Peripheral neuropathy associatedwith BMT usually occurs concurrentlywith chronic graft-versus-hostdisease (GVHD). Chronic GVHDis a clinical syndrome that occursin approximately 60% to 80% oflong-term survivors of allogeneichematopoietic stem cell transplantation.3 Chronic GVHD is defined asan autoimmune disorder that occurs100 days after the allogeneic transplant.Symptoms of chronic GVHDusually include oral ulcerations;keratoconjunctivitis; xerophthalmia;hepatic failure; obstructive lung disease;involvement of the skin andsoft tissues; and involvement of theneuromuscular system, CNS, andthe gastrointestinal tract. 9 Thesefeatures are shared with a variety ofautoimmune disorders, and it is possiblethat the etiology of this peripheralneuropathy is an immunemediatedresponse directed againstthe peripheral nerves. Patients maydevelop cranial neuropathies, sensorimotorpolyneuropathies, multiplemononeuropathies, and severegeneralized neuropathies. Symptomsmay improve when the intensity ofthe immunosuppressive therapy forGVHD is increased. 3Table 2. Non-cytotoxic Medications That Cause Peripheral NeuropathyCategoryAntimicrobial AgentsCardiovascular MedicationsAntirheumatic MedicationsAnticonvulsantsOthersNon–cytotoxic-inducedPeripheral NeuropathyWhen identifying medicationinducedperipheral neuropathy in acancer patient, it is important to firstidentify which of the patient’s noncytotoxicmedications could causeor contribute to their painful neuropathy.All iatrogenic causes must beconsidered in order to delineate thevarious possibilities and capitalize onopportunities for successful preventionand treatment. Table 2 outlinessome of the common agents that causeperipheral neuropathy. It excludes theantiretrovirals that are well-known tocause peripheral neuropathy.Antimicrobial AgentsSome antimicrobial agents havebeen shown to induce peripheralneuropathy. Among antituberculosisagents, isoniazid and ethambutol(Myambutol) are well known forinducing peripheral neuropathy. 10Isoniazid induces a mixed sensorimotorperipheral neuropathy. This neuropathycan be prevented by administeringvitamin B 6or pyridoxine.Drug (Brand)Dapsone (Aczone, generic),Ethambutol (Myambutol)Isoniazid (Nydrazid, generic)Nitrofurantoin (Macrobid, generic)Metronidazole (Flagyl, generic)Amiodarone (Cordarone, generic)Disopyramide (Norpace, generic)Hydralazine (Apresoline, generic)Propranolol (Inderal, generic)Chloroquine (Aralen)Hydroxychloroquine (Plaquenil, generic)Phenytoin (Dilantin, generic)Colchicine (Colcrys)Indomethacin (Indocin, generic)Long-term use of isoniazid can causedepletion of pyridoxine by two mechanisms.First, isoniazid metabolitescan bind to and inactivate pyridoxine.Second, isoniazid inhibits theenzyme pyridoxine phosphokinase,which is necessary to activate pyridoxineto pyridoxal-5’-phosphate, theactive cofactor in many reactions thatinvolve pyridoxine. 11 Ethambutol canalso cause peripheral neuropathy ofthe extremities, which is manifestedby numbness and tingling, 12 but it ismuch less neurotoxic than isoniazid.Nitrofurantoin, an antibacterial,has also been reported to cause mixedsensorimotor neuropathy. The symptomsmay develop during or aftertreatment with nitrofurantoin. 13 It ismore prevalent in patients with renalimpairment; however, it has also beenreported in patients with normalrenal function. 14Peripheral neuropathy has alsobeen reported in patients treated withthe antibiotic metronidazole (Flagyl)at conventional doses for 6 to 24weeks. 15 Dapsone, used in the treatmentof bacterial skin infections, hasApril 2013 | Practical Pain Management55

Neuropathy in the Cancer Patient: Causes and CuresTable 3. Medications Used to Treat Chemotherapy-induced PeripheralNeuropathyDrug (Brand)Bortezomib (Velcade)Cytarabine/Cytosine arabinoside/Ara-C (Cytosar-U)Etoposide (VePesid, generic)Ifosfamide (Ifex, generic)Platinum-based agents:• Cisplatin (Platinol, generic)• Oxaliplatin (Eloxatin, generic)Taxanes:• Paclitaxel (Taxol, generic)• Docetaxel (Taxotere, generic)Thalidomide (Thalomid)Vinca alkaloids:• Vincristine (generic)• Vinorelbine (Navelbine, generic)• Vinblastine (Velban, generic)been linked to peripheral neuropathy.In a case reported by Koller et al, thepatient experienced significant motordeficit and loss of vibration senseshortly after initiation of low-dosedapsone. This reaction was reversibleafter cessation of the therapy.This patient was a slow metabolizerof isoniazid (slow acetylator), thus alsowas most likely a slow acetylator ofdapsone. 16Cardiovascular AgentsFor the cancer patient with cardiovascularcomorbidities, it is important toproperly evaluate all their medications,as some cardiovascular drugs can causeperipheral neuropathy. Propranolol isa commonly prescribed non-cardioselectiveß blocker used in the treatmentof hypertension, angina, secondaryMechanism of Peripheral NeuropathyToxicityUnknownNot well understood, potentially due toinhibition of proteins necessary in myelinsynthesis or axonal transportUnknown; potential neurotoxicity effectssecondary to inhibiting microtubule functionUnknownBinding to DNA may inhibit the transcription ofimportant proteins and impair axonal transportToxic effect to the neuronal cell body, axon, orbothUnknownInference with axonal microtubule assembly,impairment of axonal transport. Vinblastine isincluded for completeness but incidence ofneuropathy is lower than others listedprevention of myocardial infarction,arrhythmia, migraine headaches, andtremor. It is also used in the managementof hyperthyroidism and thyrotoxiccrisis. There have been severaldocumented episodes of peripheralneuropathy associated with the use ofpropranolol—for example, paresthesiasof the hands, peripheral neuropathy,and myotonia have been reportedwith the use of propranolol. 17Hydralazine, a vasodilator used inthe treatment of hypertension and asan adjunct following heart failure, maycause a subclinical peripheral neuropathyin about 15% of patients. 18The development of peripheral neuropathyis linked to an antipyridoxineeffect, since hydralazine is structurallysimilar to isoniazid. Peripheral neuropathyhas also been linked to theuse of amiodarone and disopyramide(Norpace). 19-21 Studies have shownthat long-term use of high-dose amiodaronetherapy induces peripheralneuropathy. 22 The agent is thought tocause demyelinating neuropathy. 22Other AgentsChloroquine (Aralen) is a quinolonederivative with several indicationssuch as malaria, sarcoidosis, systemiclupus erythematosus, scleroderma, andrheumatoid arthritis. Chloroquine isan amphiphilic drug with both hydrophilicand lipophilic properties; thus, itinteracts with the anionic phospholipidsof cell membranes. The drug–lipidcomplexes are resistant to lysosomaldestructions so the result is formationof vacuoles filled with myeloid debris. 6Peripheral neuropathy ensues secondaryto severe vacuolar myopathy, whichhas been supported by histologicalstudies showing both axonal degenerationand damage to Schwann cells.Hydroxychloroquine shares structuralsimilarity with chloroquine andit also causes neuropathy. Patients takinghydroxychloroquine do not havesevere abnormalities as they wouldwith chloroquine-induced peripheralneuropathy. 6Phenytoin is an anticonvulsant,which, when given long term, couldcause predominantly sensory polyneuropathy.This type of neuropathy couldbe bothersome, but is usually mild andrarely symptomatic. 10Colchicine (Colcrys) inhibits thepolymerization of tubulin into microtubules.It is used to treat patients withgout. The proposed mechanism ofneuropathy lies in the disruption ofthe microtubules that lead to defectiveintracellular movement or lysosomes,which accumulate in autophagic vacuolesin muscle and nerve fibers. 6 Thismechanism of iatrogenic neuropathycorrelates closely with that caused bythe vinca alkaloids as outlined below.56Practical Pain Management | April 2013

Neuropathy in the Cancer Patient: Causes and CuresAlthough rare, indomethacin hasalso been associated with the developmentof mostly motor peripheralneuropathy. 23Chemotherapy-inducedPeripheral Neuropathy (CIPN)Peripheral neuropathy is a well-documentedadverse reaction to severalcancer chemotherapeutic agents(Table 3). These agents include theplatinum-based salts (eg, cisplatin, carboplatin,oxaliplatin), vinca alkaloids(eg, vinblastine, vincristine), and thetaxanes (eg, paclitaxel, docetaxel). Theincidence of the neuropathy varies,and the incidence rates can increaseto about 38% when agents are combined.24 However, newer anti-cancerformulations have also proven to causeneuropathies.Bortezomib (Velcade), a proteasomeinhibitor, is one such agent.It is a reversible inhibitor of thechymotrypsin-like activity of the26S proteasome in mammalian cellsindicated for the treatment of multiplemyeloma, and as a second-linetherapy in patients with mantle celllymphoma. 25 It is increasingly beingrecognized that bortezomib-inducedperipheral neuropathy may be a proteasomeinhibitor class effect, producingprimarily a small fiber and painful,axonal, sensory distal neuropathy. 26The mechanism of bortezomibinducedperipheral neuropathy is currentlyunknown. When bortezomib isadministered, metabolic changes areobserved secondary to accumulationof the drug in the dorsal root gangliacells; mitochondrial-mediated dysregulationof calcium (Ca 2+ ) homeostasisand dysregulation of neurotrophinsmay be responsible for this adverseevent. 26 There is no neuroprotectivetreatment effective to reduce bortezomib-inducedperipheral neuropathy;however, a dose modification algorithmis available as a guideline.Cytosine arabinoside, also knownas cytarabine or Ara-C (Cytosar-U),is an antimetabolite used in the managementof leukemia and lymphoma.Peripheral neuropathy has beenreported in patients at cumulativedoses of 36 to 60 g/m 2 . 27 The mechanismof toxicity is not well understood.It has been hypothesized thatthe antimetabolite action of cytarabineinhibits proteins that are importantin the production of myelin or inaxonal transport. These neuropathiesmay start within hours or weeks aftertreatment. 28Platinum-based AgentsPlatinum-based agents exert theirantineoplastic effects by formingcovalent bonds and creating a crosslinkwith DNA, preferentially to guanine.Cisplatin is a platinum agentused widely in the treatment of avariety of malignancies such as ovarian,testicular, and bladder cancer. Itproduces mainly a sensory neuronopathyat cumulative does of 225 to501 mg/m 2 . The proposed mechanismof this neuropathy is due to potentialinhibition of transcription ofimportant proteins and impairmentof axonal transport secondary to cisplatin’sbinding to DNA. 3 Oxaliplatinadministration also has been linked tothe development of peripheral neuropathy.29 The neuropathy is mostlysensory and it occurs in two forms—acute and chronic. Acute oxaliplatininducedneuropathy is the most commonform (>90%), develops shortlyafter infusion, and is transient.Patients will develop dysthesias thatare exacerbated by cold and sometimesmuscle contractions and weakness.For chronic oxaliplatin-inducedperipheral neuropathy, dose intensityplays a significant role (cumulativedoses ≥540 mg/m 2 ). 29 It is usuallyobserved after a long treatment durationand resembles cisplatin-inducedCisplatin crystals, a platinum-based salt, isknown to cause neuropathy.neuropathy. 30 This neuropathy can bemitigated by administering intravenouscalcium and magnesium priorto and post-oxaliplatin infusions. 31TaxanesTaxanes are a class of medicationsthat disrupt microtubule function.Paclitaxel is utilized in chemotherapyregimens for the treatment of ovariancancer, breast cancer, lung cancer,bladder cancer, head and neck cancer,and lymphoma. It has shown toproduce dose-dependent neuropathy,predominantly sensory neuropathy. 7Up to 85% of patients exposed topaclitaxel after 3 to 7 cycles at a doseof 135 to 200 mg/m 2 develop mild,subclinical peripheral neuropathy. 32For doses between 250 to 350 mg/m 2 ,neuropathy can develop within thefirst or second cycle. 33-35 Docetaxel isa semisynthetic analog of paclitaxelthat also produces a dose-dependentsensory neuropathy with an incidencerate of 17% to 50%. 36,37 The taxanesinduce the peripheral neuropathy secondaryto toxic effect to the neuronalcell body, axon, or both. 3Vinca AlkaloidsVinca alkaloids inhibit microtubuleformation by binding to α- andβ-tubulin. Vincristine produces asensorimotor and autonomic neuropathy.The earliest symptomspresented include paresthesias andnumbness that occur in the fingersImage courtesy of the National CancerInstitute/Larry Ostby (Photographer)April 2013 | Practical Pain Management57

Neuropathy in the Cancer Patient: Causes and Curesprior to the toes. Symptoms can occurwithin 14 days of a single 2 mg/m 2dose. 7,38 Vinorelbine, another vincaalkaloid, used in a variety of differentcancers, has a much lower incidenceof neurotoxicity compared to vincristine.7,39 In a study of vinorelbine,dose-related peripheral neuropathyhas been observed in 20% to 50% ofexposed patients, with severe neuropathyreported only in 1% of patients. 40Impairment of the microtubules interfereswith axon transport, which subsequentlycauses cytoskeletal disarray anddegeneration.Other AgentsEtoposide is a semisynthetic derivativeof podophyllotoxin used in lymphoma,leukemia, small cell lung cancer,and testicular cancer. Four percentof patients treated with etoposidedevelop moderate to severe distal,axonal, and mostly sensory polyneuropathy.The potential mechanismfor this neurotoxicity is inhibition ofmicrotubule function. 41Ifosfamide is an analogue of cyclophosphamidewith neuropathy as aside effect at a total dose of at least14 g/m 2 . 42 Patients often experiencenumbness and painful paresthesiasthat begin in both hands and feetwithin 10 to 14 days after treatment. 42Thalidomide (Thalomid) is an antiangiogenicdrug used in patients withrefractory MM. Greater than twothirdsof patients exposed to thalidomidefor at least 6 months experiencesome form of peripheral neuropathy.Mostly motor, sensory, and autonomicdysfunctions are observed. 43Management of NeuropathicPainThe World Health Organization’sanalgesic ladder for cancer pain reliefrecommends a stepwise approach,starting with non-opioids then movingup the ladder to opioid therapy,as needed. 44 Several factors have beenidentified that impede appropriatepain control in cancer patients. 45Often, when multiple agents areadministered at the same time, it isdifficult to assess which of the agentsare efficacious and which causeadverse events. Proper managementof neuropathic cancer pain (NCP) iscomplex because of the heterogeneityof etiologies, variable symptoms, andthe underlying neurogenic pathophysiology.These properties contributeto patients’ poor responses to conventionalpain management therapy.An additional consideration is thatmost of the agents used in the managementof neuropathic pain aregrouped according to their pharmacologicalclass or original therapeuticcategory—such as antidepressants andanticonvulsants. Confusion occurswhen healthcare professionals unfamiliarwith neuropathic pain assumethat all anticonvulsants or antidepressantsmay be efficacious in the managementof neuropathic pain. A painmedication that was efficacious for agroup of patients with similar mechanismsof neuropathic pain may nottranslate to equal response in a differentpatient population or varyingneuropathy types. 45Lastly, it has been noted that opioidtherapy has limited utility intreating neuropathy. 46 However, it isimportant to note that certain opioidsseem to have more usefulness thanothers for neuropathic pain disorders;these include methadone, levorphanol,tapentadol (Nucynta), andtramadol. 47 Often, higher doses ofopioids are required to manage neuropathicpain. However, increasedopioid doses usually translate intoincreased risk of toxicity, whichoften leads to discontinuation of thetherapy. When managing patientswith NCP, it is important to initiatepharmacotherapy one medication at atime, with a slow titration to matchthe patient’s response and tolerability.48 Thus, the recommendation is totailor each patient’s pain managementtherapy to suit the individual.Table 4 highlights treatments forNCP. As noted, addition of adjuvantanalgesics to schedule II and III opioidsare the mainstay of neuropathymanagement in a cancer patient;however, non-opioid analgesicsthat combine multiple mechanismsacross two or more agents are oftenmore useful than adding or continuingan opioid. A list of recommendedadjuvants include antiepileptic drugs(AEDs), antidepressants (eg, tricyclicantidepressants, duloxetine [Cymbalta],and venlafaxine), corticosteroids,bisphosphonates, -methyl-D-aspartate(NMDA) antagonists, and other substances.Selection of the right agentdepends on side-effect profile, and thefinal choice should be based on identifyingthe type of painful neuropathyand perhaps comorbid non-neuropathicpain issues. If, for example, thepatient does in fact require an opioidother than for neuropathy, it makessense to select an agent that is particularlyuseful for both pain types.Adjuvant AnalgesicsAntidepressantsTricyclic antidepressants (TCAs)inhibit norepinephrine and serotoninreuptake by blocking the serotoninand norepinephrine transporters. Thisaction results in an increased synapticconcentration of serotonin and norepinephrineto enhance neurotransmission.TCAs also modulate peripheralsodium channels and antagonizeNMDA to a small degree. As a result,they are known to enhance dorsal rootinhibition and reduce peripheral sensitization.49 Since it was first reportedby Paoli et al in 1960, 50 TCAs havebeen shown to exhibit an effect inmanaging chronic pain. In addition,58Practical Pain Management | April 2013

Neuropathy in the Cancer Patient: Causes and CuresTable 4. Treatments for Neuropathic Cancer Pain aDrug (Brand) Mechanism of Action Common Adverse Reactions Special ConsiderationsTCAsAmitriptyline(generic)Desipramine(Norpramin, generic)Doxepin(Silenor, generic)Inhibits the reuptake of NE.All but desipramine andnortriptyline also block reuptakeof 5-HTSomnolence (drowsiness),confusion, orthostatichypotension, xerostomia(dry mouth), constipation,urinary retention, weight gain,arrhythmiaAmitryptyline most likely to producedrowsinessAll TCAs require dose adjustments incases of hepatic impairment exceptamitriptylineImipramine(Tofranil, generic)Nortriptyline(Pamelor, generic)Trimipramine(Surmontil, generic)Trimipramine also blocks reuptake ofdopamineSNRIsDuloxetine(Cymbalta)Inhibits the reuptake of NE and5-HTSedation, nausea, constipation,ataxia, xerostomiaContraindicated in patients withglaucomaMilnacipran(Savella)Nausea, insomnia, hypertension,seizures, dizziness, hot flashesContraindicated in closed-angleglaucomaVenlafaxine(Effexor, generic)Nausea, dizziness, somnolence,hyperhidrosis, hypertension,constipationDosage adjustments required in renalfailureAntiepilepticsGabapentin(Neurontin, Gralise,generic)Pregabalin(Lyrica)Binds to α 2δ subunit onvoltage-gated calcium channelsto reduce neuronal calciumcurrentsLethargy, peripheral edema, backpain, weight gain, somnolence,dyspepsiaSomnolence, xerostomiaDosage adjustments required if renalimpairment (CrCl

Neuropathy in the Cancer Patient: Causes and CuresTable 4. Treatments for Neuropathic Cancer Pain a (continued)Drug (Brand) Mechanism of Action Common Adverse Reactions Special ConsiderationsTapentadolµ-opioid receptor agonist,inhibits reuptake of NEDizziness, vertigoPhase II glucuronidation toO-glucuronide; CYP2C9/2C19 mediatedmethylation to N-desmethyl-tapentadol.Listed risk of serotonin syndrome is notsupported by mechanism of actionTramadol(Ryzolt, Ultram, generic)µ-opioid receptor agonist,inhibits reuptake of NE and5-HTDizziness, vertigo, constipation,vomitingSubstrate of CYP2D6, CYP3A4, andCYP2B6. Increased risk of serotoninsyndrome when administered withserotoninergicsGeneral AnestheticKetamine(Ketalar, generic)NMDA-receptor antagonistHypertension, diplopia,nystagmus, hallucinationsContraindicated in patients with headtrauma, hypertension, intracranialbleeding, intracranial mass, myocardialinfarction, strokeTopical AnestheticLidocaine 5% patch(Lipoderm)Blocks initiation and conductionof nerve impulses by decreasingnerve membrane permeabilityto sodium to reduce rate ofmembrane depolarizationLocal rash and erythemaContraindicated in patients with amidelocal anesthetic hypersensitivity, sepsis.Used for local neuropathies only and notintended for transdermal absorptionaOnly includes selected medications mentioned in text; table not inclusive.5-HT, serotonin; CrCl, creatinine clearance; CYP, cytochrome; NE, norepinephrine; NMDA, N-methyl-D-aspartate; SNRIs, serotonin norepinephrine reuptakeinhibitors; TCAs, tricyclic antidepressantsclinical reports have also demonstratedtheir effectiveness in treatingneuropathic pain and HIV sensoryneuropathy. The effectiveness of amitriptylinein relieving neuropathicpain following breast cancer wasreported by Kalso et al in a randomized,placebo-controlled study witha 2-week washout period. 51 Fifteenpatients participated in the study, andeach started at a dose of 25 mg, whichwas escalated to 100 mg daily over 4weeks. At the end of the study, 53%of the patients were classified as goodresponders (50% decrease in painintensity) with a median dose of 50mg amitriptyline. The patients whowere poor responders reported moreadverse effects with amitriptyline andplacebo.Despite efficacy in treating neuropathicpain related to breast cancer,the adverse effects prevent manypatients from regularly using themedication. Tertiary amines suchas amitriptyline, imipramine, anddoxepin produce a greater anticholinergicactivity than the secondaryamines: nortriptyline and desipramine.Anticholinergic side effectsinclude dry mouth, impaired diaphoresis,increased thirst, tachycardia andpupillary dilation. Patients may alsoexperience urinary retention, agitation,cognitive impairment, seizures,cardiac arrhythmias, and heart block.The anticholinergic side effects all canadd to problematic side effects thatare common with opioids.TCAs should be started at the lowesteffective dose possible and shouldbe given at bedtime. The dose canbe titrated upward slowly every 3to 7 days usually until 150 mg oruntil adverse events make themintolerable .45Serotonin norepinephrine reuptakeinhibitors (SNRIs) have a differentchemical structure comparedto TCAs. They exert their antidepressanteffects by inhibiting norepinephrineand serotonin reuptake.Venlafaxine is an SNRI with someefficacy for neuropathic pain. Datasupporting its use in this patient populationreported a number neededto treat (NNT) of 3.6. In a randomized,crossover trial of venlafaxine(220 mg/d) and imipramine (150mg/d) in patients with polyneuropathy,both antidepressants providedsuperior relief compared to placebo. 52However, there were no differencesin efficacy between those two groups.Venlafaxine was effective at a dose>150 mg/day in diabetic neuropathy,60Practical Pain Management | April 2013

Neuropathy in the Cancer Patient: Causes and Cureswhereas 75 mg daily was ineffective.The side effects of venlafaxine includehypertension, which limits its use inpatients with pre-existing or uncontrolledhypertension. 53 The efficacyof venlafaxine in cancer patients wasdemonstrated in a study by Tasmuthet al. 54 In the randomized, doubleblind,crossover study, patients givenvenlafaxine over a 10-week periodshowed superior pain relief for painfulpolyneuropathy and neuropathicpain following treatment with venlafaxinecompared with placebo. 53Duloxetine is an SNRI that is FDAapproved for the treatment of diabeticneuropathy. Recently, it was reportedin a randomized, placebo-controlledphase III trial to be effective in reducingpainful chemotherapy-inducedperipheral neuropathy. 55 The studyshowed that duloxetine 60 mg dailywas efficacious and well tolerated forthe treatment of either taxane- orplatinum-related painful chemotherapy-inducedperipheral neuropathy.Milnicipran (Savella) is also anSNRI, which is FDA approved forthe management of fibromyalgia, butnot depression. 56 There have beenno comprehensive studies involvingmilnacipran in cancer patients withperipheral neuropathy. However,since it has similar mechanisms asother medications in this class, it isprobable that this drug may have utilityin some patients.AntiepilepticsGabapentin is an analogue of the neurotransmitterγ-aminobutyric acid(GABA). The agent binds to theα 2δ subunit of calcium-dependentvoltage-gated channels in the nervoussystem. Gabapentin is an anticonvulsantmedication that currently has thebroadest evidence for efficacy in themanagement of neuropathic pain 57-59It exerts its action on the brainstem viaits glutamate-dependent mechanism.It has also been shown to have antimallodyniceffects through alterationof the microglial cell function.In one study, 75 patients with CIPNand neuropathic pain were given afixed low dose of gabapentin (800mg/d). 60 These patients were comparedto 35 patients in the controlgroup (same symptoms and historyof similar treatment who refusedgabapentin) who were given fixeddosenaproxen (250 mg bid) andcodeine/acetaminophen (30/500mg tid). The authors noted that outcomeswere based on four stages ofanalgesic response: complete, partial,minor, and no response. In thegabapentin arm, the treatment led to25.3% complete response, 44% partialresponse, 25.3% minor response,and 5.3% no response. In the controlgroup, none of the patients experiencedcomplete response; percentagefor partial, minor, and no responsewere 5.7%, 45.7%, and 48.6%,respectively. 60In another study evaluating gabapentinin cancer patients previouslytreated with opioids with minimalanalgesia response, 121 patients weregiven gabapentin at a dose of 600 to1,800 mg daily. The study found asignificant difference of average painintensity between gabapentin (painscore, 4.6) and placebo group (painscore, 5.4; =0.0250). Among secondaryoutcome measures, dysesthesiascore showed a statistically significantdifference (=0.0077) This studydemonstrated that patients who wereunsuccessfully managed on opioidscan transition to gabapentin andobtain pain relief. 61In addition, gabapentin has beenshown to be helpful in patientswith burning pain, shooting pain,and allodynia when pain does notrespond to opioids. Results from astudy looking at a combination ofgabapentin with morphine showedimprovement in sleep, daily activity,mood, and quality of life incancer-related pain conditions. 61,62Gabapentin also is a useful medicationfor patients with malignanciesof the upper abdomen such aspancreatic cancer; for reducing painassociated with procedures in cancer;and for decreasing myoclonic movementsthat are associated with highdoses of opioids in cancer pain. 61,62Effective doses of gabapentin forneuropathic pain in adults rangefrom 1,800 to 3,600 mg daily, individed doses, based on a metaanalysisdouble-blind placebocontrolled,randomized trials in2003. 63 Effective counseling pointsfor patients include knowing thatthe drug can induce somnolence,dizziness, and some mild peripheraledema.Pregabalin’s (Lyrica) mechanism ofaction is similar to gabapentin: bothbind to the α 2δ subunit of voltagegatedcalcium channels of the nervoussystem. Pregabalin also minimizesthe release of the neurotransmittersglutamate, norepinephrine,substance P, and calcitonin generelatedpeptide. It does not binddirectly to GABA receptors.Pregabalin has been approved forpostherpetic neuropathy and peripheraldiabetic neuropathy, but notNCP. The efficacy of pregabalin toprovide significant pain relief anddecrease the need for higher opioiddoses in cancer patients battlingneuropathic pain was assessed in aprospective, open-label study. 64 Inthe study, 66 cancer patients withneuropathic pain resistant to a combinationof acetaminophen, codeine,non-steroidal anti-inflammatorydrugs, and methylprednisolonewere randomly divided into twogroups. Group one received pregabalinadded to their pain regimen.Pregabalin was titrated up to 600 mgApril 2013 | Practical Pain Management61

Neuropathy in the Cancer Patient: Causes and Curesdaily until pain relief was observed orpatients experienced intolerable sideeffects. The second group receivedfentanyl 25 mcg per hour, whichwas escalated by 25 mcg per hourevery 72 hours—up to a maximumof 125 mcg per hour—until thepatient experienced adequate painrelief or intolerable toxicities. Theauthors discovered that pregabalinwas effective in providing significantpain relief (69% decrease in a visualanalogue scale [VAS] pain score—from 7.8 to 2.4) and both minimizedthe use of opioids and opioidinducedside effects. Pregabalin wasalso found to be efficacious in anopen-label study of pediatric cancerpatients on a daily dose of 150 to300 mg for 8 weeks. 65 The investigatorsreported significant andlong-lasting pain relief in 86% ofthe children, and the median VASscore decreased by 59%. Adverseeffects were infrequent and transient.According to pharmacokinetic studies,pregabalin is more potent thangabapentin because its binding affinityfor the α 2δ subunit is six timesgreater than that of gabapentin, ithas faster absorption (does not bindto plasma proteins), and has greaterbioavailability (>90%). 66Other AEDs have shown efficacy inother types of neuropathic pain butnot in neuropathic pain associatedwith cancer. For instance, lamotrigineis effective in treating HIV sensoryneuropathy, painful diabeticneuropathy, central poststroke pain,and pain from spinal cord injury. 67-70There has been wide application ofanticonvulsants in neuropathic painmanagement; however, only a fewtrials have shown efficacy in cancerpatients. We must be especially cognizantthat drugs such as lamotriginemay carry a higher risk of hepatotoxicityin patients receiving hepatotoxicantineoplatics. A huge advantage ofgabapentin is that it’s not metabolizedin humans, has very limitedeffect on the liver, and has relativelyno drug interactions for this reason.71 It should be noted, however,that the dose of gabapentin mustbe adjusted for renal insufficienciesbeginning with a creatinine clearance250 mgdaily. Due to its low abuse potentialand minimal chance of developingtolerance and dependence duringlong-term use, tramadol serves as agood alternative for cancer patientswith disease-induced neuropathicpain. The most common side effectsassociated with tramadol include dizziness,nausea, constipation, somnolence,and orthostatic hypotension.It is possible for patients to developseizures when tramadol is used concomitantlywith selective serotoninreuptake inhibitors or monoamineoxidase inhibitors.Methadone is an opioid that blocksNMDA receptors and inhibits reuptakeof norepinephrine—both activitiescontributing to its efficacy in themanagement of neuropathic pain andNCP. Cancer patients who might beideal candidates for a trial of methadoneinclude patients with poor paincontrol, those who have received anadequate trial of other schedule IIor III opioids, patients with severeor multiple toxicities to other strongopioids, and those receiving opioidswho have difficulty swallowing. 74Methadone is associated with lifethreateningadverse effects that areattributable to elevated serum levelsfrom drug interactions. Drugs thatinhibit P-glycoprotein and cytochromeP450 isoenzymes CYP2C19,CYP3A4, and CYP2B6 could significantlyincrease serum levels ofmethadone and induce methadonetoxicity. 75Ketamine is a general anesthetic thatrecently has been studied as a postoperativepain medication. Ketamine isan NMDA-receptor antagonist. TheNMDA receptors within the spinalcord have been shown to play a significantrole in the pathophysiologyof chronic neuropathic pain. At subanestheticdoses, ketamine has beenshown to reduce hypersensitivityin the dorsal horn. 76 There has beensome suggestion that ketamine mayreduce opioid-resistant NCP. Whencombined with morphine, ketamineprovided superior pain relief and opioid-sparingability. 76 There are multiplecase reports of ketamine’s use,either orally or intravenously, as anadjuvant for cancer-induced neuropathicpain management. What limitsthe use of ketamine are the potentialdevelopments of dissociative reactionsand hallucinations after a patient isexposed to it. Ketamine has been usedas a recreational drug due to its rapidonset, short duration of action, andpsychotropic effects. 7762Practical Pain Management | April 2013

Neuropathy in the Cancer Patient: Causes and CuresTopical TherapyThe only topical antineuralgic agentshown to have efficacy in NCP isthe lidocaine 5% patch (Lidoderm).It is most effective with pain associatedwith allodynia, a pain due tostimulus that does not normally provokepain. 78 It has also been used incentral neuropathic pain syndromein patients with metastatic lesions ofthe spinal cord. 79 Despite some statedefficacy, lidocaine patches did not significantlyreduce pain intensity ratingsor related secondary endpointsin cancer patients with persistent painassociated with incisions. 80Thus far, no single pharmacotherapyhas an FDA indication forCIPN. Only pregabalin, tapentadol,and duloxetine are approved for diabeticperipheral neuropathic pain,with pregabalin having an addedindication for neuropathic painassociated with spinal cord injury.Carbamazepine has the indication fortrigeminal neuralgia.Preventing CIPNinfusions have been shown to reducethe incidence of CIPN. Several studieshave shown that calcium-magnesiuminfusions reduce the incidence ofneurotoxicity and subsequent peripheralneuropathy in cancer patientsundergoing chemotherapy. 81,82 Theantitumor efficacy of these chemotherapyagents was not affected; however,patients who received the infusionsstayed on therapy longer thanthe control group.was studied in an open-labeltrial in patients receiving oxaliplatin.There was significantly lessgrade 1-2 and grade 3-4 CIPN after4 to 6 cycles in patients who weregiven glutamine compared to thecontrol arm. 83 While there was alower need for oxaliplatin dose reductionin the glutamine group, a largerrandomized placebo-controlled trialis needed before this can be used in alarger practice.has been shown to prevent theaccumulation of platinum agents inthe dorsal root ganglia. Two smalltrials looked at the effectiveness ofglutathione in preventing CIPN inpatients receiving either cisplatin oroxaliplatin. There was significantlyless peripheral neuropathy of anygrade in patients receiving either 4or 8 cycles of oxaliplatin in the glutathione-treatedgroup, comparedwith the placebo-controlled group. 84Moreover, there was no differencein chemotherapy response rates. Asimilar result was obtained in patientsgiven glutathione while undergoingtreatment with cisplatin. 85is an antioxidant that increasesthe body’s concentration of glutathione.In a study where 14 patientswere receiving oxaliplatin, oralN-acetylcysteine reduced the incidenceof CIPN in these colon cancerpatients. 86 Additional, larger studiesare needed prior to recommendationfor widespread use.There have been some data tosuggest that vitamin E has somerole to play in decreasing the riskof CIPN. In an open-label study,patients were given vitamin E300 mg daily during cisplatin therapyand for 3 months after treatmentcompletion. CIPN was observed in31% of patients who received vitaminE compared to 86% of the controlarm (

Neuropathy in the Cancer Patient: Causes and CuresWhat Options Are Available to Treat ThisPatient’s Pain?• Since the patient is actively receiving chemotherapy,non-steroidal anti-inflammatory drugs(NSAIDs) are not recommended; they offer minimalif any efficacy for neuropathic pain and thereis an increased risk of thrombocytopenia. Otherrisks include elevated blood pressure and diabeticnephropathy considering the already elevatedserum creatinine. Due to hepatic impairment,his international normalized ratio is also elevated,which presents another risk for NSAIDs.• Tricyclic antidepressants (TCAs) should beavoided, as they can significantly add to lethargyassociated with the disease, anemia, and treatments.Furthermore, titration of TCAs for extended usemost likely will eventually become problematicshould the need for opioid therapy arise consideringthe significant constipating effects when combiningthese therapies.• Tramadol (25 mg po qid) titrated weekly could beused for management of back pain and neuropathy,but it is not an option in this patient due touncontrolled hypertension.• When considering opioids, combination withacetaminophen should be avoided in this patientbecause of his liver issues. Moreover, most opioids—withthe exception of those that blockN-methyl-D-aspartate receptors (NMDA-R) orinhibit reuptake of norepinephrine—are not asuseful for managing neuropathies. Examples of theformer are methadone and levorphanol. Examplesof the latter are tramadol and tapentadol. 1• Pregabalin has to be adjusted for hepatic impairment,but is an option in this case if titrated slowly. 2• Gabapentin (100 mg po tid) can be used in thispatient even with hepatic injury, as it requires nometabolism in humans and is excreted renallyunchanged. 3 Gabapentin can be titrated weekly toa target dose of 3,600 mg daily in divided dosesuntil adequate effect or until unacceptable toxicity. 4• Rational polypharmacy is also an option. An examplehere might be low-dose gabapentin combinedwith morphine. 5 However, if an opioid is required,it may be more reasonable to try one of the agentsemphasized above first.Table 1. Physical and Laboratory ResultsVital Signs:••Blood pressure: 150/90 mm Hg••Temperature: 99.1 °F••Height: 5’9”••Weight: 100 kgSignificant Lab Results:••Fasting blood glucose: 200 mg/dL••Hemoglobin A1C: 9.2%••Hematocrit: 32.2%••CEA: 25.6 ng/mL••Serum creatinine: 1.9 mg/dL••INR: 1.5••PTT: 26••ALT: 837 U/L••AST: 1,030 U/L••Alkaline phosphatase: 255 U/L••Albumin: 2.5 g/dL••Total bilirubin: 2.4 mg/dL••WBC: 5.6 x 103/mcgLALT, alanine aminotransferase; AST, aspartate aminotransferase;CEA, carcinoembryonic antigen; INR, international normalized ratio;PTT, partial thromboplastin time; WBC, white blood cellsReferences1. Zorn KE, Fudin J. The role of unique opioid agents. Pract Pain Manage.2011;11(4):26-33.2. Lyrica [package insert]. New York, NY: Pfizer Inc. Revised June 2012.3. Neurontin [package insert]. New York, NY: Pfizer Inc. Revised 2012.4. Bennett MI, Simpson KH. Gabapentin in the treatment of neuropathicpain. Palliat Med. 2004;18(1):5-11.5. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine,gabapentin, or their combination for neuropathic pain. N Engl J Med.2005;352(13):1324-1334.April 2013 | Practical Pain Management65

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