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Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Pain management of the cancer patient

Stephan A Schug & Chandani Chandrasena

To cite this article: Stephan A Schug & Chandani Chandrasena (2015) Painmanagement of the cancer patient, Expert Opinion on Pharmacotherapy, 16:1, 5-15, DOI:10.1517/14656566.2015.980723

To link to this article: http://dx.doi.org/10.1517/14656566.2015.980723

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1. Introduction

2. Guidelines for treating cancer

pain

3. Management of breakthrough

pain

4. Use of co-analgesics and

adjuvants

5. Conclusions

6. Expert opinion

Review

Pain management of thecancer patientStephan A Schug† & Chandani Chandrasena†The University of Western Australia & Royal Perth Hospital, Perth, Australia

Introduction: Cancer pain is one of the most important symptoms of

malignant disease, which has a major impact on the quality of life of cancer

patients. Therefore, it needs to be treated appropriately after a careful

assessment of the types and causes of pain.

Areas covered: The mainstay of cancer pain management is systemic pharma-

cotherapy. This is, in principle, still based on the WHO guidelines initially

published in 1986. Although these have been validated, they are not evi-

dence-based. The principles are a stepladder approach using non-opioids,

weak and then strong opioids. In addition, adjuvants can be added at any

step to address specific situations such as bone or neuropathic pain. Patients,

even if they are on long-acting opioids, need to be provided with immediate-

release opioids for breakthrough pain. In case of inefficacy or severe adverse

effects of one opioid, rotation to another opioid is recommended.

Expert opinion: There is a major need for more and better randomized

controlled trials in the setting of cancer pain as the lack of evidence is hamper-

ing the improvement of current treatment guidelines.

Keywords: cancer pain, co-analgesics, non-opioids, opioids, WHO guidelines

Expert Opin. Pharmacother. (2015) 16(1):5-15

1. Introduction

Cancer is a multifaceted complex condition affecting physical, psychological, socialand spiritual aspects of the life of an individual affected by it. Out of all accompanyingsymptoms, cancer pain has been recognized as one of the most important ones [1].A multidisciplinary evidence-based approach is recommended for its treatment,including pharmacological treatments, psychosocial and behavioral interventions,physical therapy and exercise, interventional procedures and spiritual support [2-4].

1.1 PrevalenceNearly 10 million patients are being diagnosed with cancer annually with an ever-increasing incidence [5,6]. Cancer patients present in 20 -- 50% of cases with painas a symptom [7]. The prevalence of cancer pain depends on the localization andtype of cancer; cancers of the head and neck show the highest pain prevalence of70%. The prevalence increases with progression of cancer and may reach 90% interminal patients [8]. Pain is also common in cancer survivors with a reportedprevalence of 26 -- 54% [7].

1.2 Undertreatment of cancer painDespite a plethora of guidelines and recommendations, cancer pain still is oftenundertreated [9]. According to systemic reviews of the literature, nearly half of thepatients in pain do not receive adequate treatment [10]. Morphine consumptiondata and the pain management index are two indicators, derived from WorldHealth Organization (WHO) guidelines, that have been utilized to assess the effi-cacy of cancer pain treatment; recent studies using these methodologies continueto find undertreatment of cancer pain in multiple settings [9].

10.1517/14656566.2015.980723 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 5All rights reserved: reproduction in whole or in part not permitted

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It is important to identify the reasons for this situation sothat deficiencies can be addressed, ultimately leading toimproved quality of care and thereby quality of life of cancerpatients. Patients’ beliefs such as fear of addiction and of possi-ble side effects of analgesics, misconceptions of pain meaningdisease progression, beliefs that treatment of disease is moreimportant than that of pain are some of the contributing factorsfor not seeking adequate pain treatment [11]. Healthcare pro-viders such as medical practitioners and nurses play a key rolein the delivery of pain management. Here physicians’ lack ofknowledge about cancer pain management, inadequate painassessment and inadequate opioid prescription as well as againfear of causing addiction need to be addressed to achieve betterquality of care [12]. System and institutional factors includeinadequate referral to appropriate specialties, unavailability ofor limited access to certain analgesics, in particular opioids,and inadequate allocation of funds to palliative care [12].

1.3 Characteristics of cancer painThe causes of pain in cancer patients can be classified as:

1) directly related to cancer, for example, direct invasionor compression of structures by the cancer;

2) related to cancer therapy, for example, due to surgery,chemotherapy or radiotherapy;

3) related to effects of cancer, such as bed sores or debility;4) other, often age-related, comorbidities such as chronic

back pain or osteoarthritis in patients with cancer.With current advanced cancer therapy, patients’ sur-vival has increased, and as a result, previous cancerpatients present increasingly with such issues.

From a therapeutic approach, it is important to classify painas either nociceptive or neuropathic. Nociceptive pain isdefined as ‘pain that arises from actual or threatened damageto non-neural tissue and is due to the activation of nociceptors(International Association for the Study of Pain Taxonomy at:http://www.iasppain.org/Education/Content.aspx?Item-Number=1698&navItemNumber=576) The pain originat-ing form somatic structures is described as localized, sharp,

throbbing pain or pressure sensation, whereas visceral pain isdescribed as dull, aching, cramping and diffuse type ofpain [1]. Neuropathic pain is defined as ‘pain caused by a lesionor disease of the somatosensory nervous system’. Cancer-related neuropathic pain could be related to cancer compress-ing or infiltrating nerves as well as related to cancer therapy.For example, nearly 90% of patients receiving neurotoxic che-motherapy experience chemotherapy-induced peripheral neu-ropathy [13]. Patients commonly complain of shooting,tingling or burning type of pain, accompanied by sensory def-icits in the painful area as well as paresthesia, hyperalgesia andallodynia. Often neuropathic pain may coexist with nocicep-tive pain, then commonly called ‘mixed’ pain.

1.4 Cancer pain assessmentCurrently, there are a number of validated cancer assessmenttools that can be applied according to the clinical con-text [14,15]. Because cancer pain is a multidimensional experi-ence, a comprehensive systematic assessment addressing alldomains plays a significant role in cancer pain management.The assessment has to be ongoing, complete and documented.Particular attention should be focused towards the functionalassessment of these patients. The ongoing multidimensionalassessment has to be multidisciplinary, involving other rele-vant specialties in patients care. Clinical practice guidelinesdeveloped by the National Comprehensive Cancer Networkprovide a comprehensive tool for this purpose [1,16].

The severity of pain is assessed either by visual analog scale,numerical rating scale or verbal rating scale. More complexassessment can be performed using the brief pain inventoryand McGill Short Form Questionnaire [17,18].

It is of note that most cancer patients have multiple pains,either at different sites or of different origin (e.g., inflamma-tory and neuropathic) [19]. It is important to consider thisfact when assessing pain, as it will influence treatment strate-gies. A number of rather specific individual pain syndromeshave been described and these may need to be recognized [20].

Breakthrough pain is acute exacerbation of pain of shortduration on the background of stable pain, commonly con-trolled with opioids [21]. A comprehensive assessment ofbreakthrough pain, encompassing the etiology, intensity,mechanisms and impact on patients’ daily activities shouldbe performed [21]. Assessment tools for the assessment ofbreakthrough pain are under development; the BreakthroughAssessment Tool is currently at initial validation stage andmay become a useful tool in pain assessment [22].

For cognitively impaired patients, assessment tools such asthe Abbey pain scale can be applied [23]; furthermore, observa-tion of behavioral patterns is useful [18].

2. Guidelines for treating cancer pain

The original guidelines, published by the WHO in 1986 [24]

and updated in 1996 [25], have governed and improved cancerpain relief worldwide and remain an important tool to

Article highlights.

. Cancer pain is the most important symptom ofmalignant disease.

. Cancer pain is commonly undertreated.

. The treatment of cancer pain should follow validatedestablished guidelines.

. Beside opioid analgesics as the mainstay, non-opioidsand co-analgesics play an important role in thepharmacological management of cancer pain.

. Despite all progress, the evidence base for cancer painmanagement remains limited and future better studiesaddressing multiple areas of uncertainty are required.

This box summarizes key points contained in the article.

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improve the current situation, in particular in the developingworld. Although these guidelines are not evidence-based, theirvalue in clinical practice is well validated [26,27]. According tothese guidelines, overall cancer pain management is based onpharmacological methods as the mainstay and non-pharmacological methods. Pharmacological management isbased on the 3-step analgesic ladder. Step 1 recommendsuse of non-opioids for mild pain, step 2 recommends intro-duction of weak opioids for moderate pain, and in step 3,strong opioids are introduced for severe pain [18,28]. Amongother issues addressed later in the review, one drawback tothe WHO stepladder approach is that drug choices are basedon severity of pain only, but does not provide guidance todosing strategies and temporal variations of pain.

The non-pharmacological methods such as physical, psy-chological and complementary therapies are outside the scopeof this paper [18]. Apart from pharmacotherapy, causal treat-ment options such as chemotherapy, radiotherapy, immunetherapy or surgical interventions should be considered as com-ponents of the pain management strategy; this may requirereferral and involvement of appropriate other specialties [29].

Multiple organizations have recently published guidelines forthemanagement of cancer pain [30]; the European Society ofMed-ical Oncology most recently updated its guidelines [10]. In addi-tion to analgesics recommended by WHO analgesic ladder,these guidelines highlight the role of adjuvant analgesics, pharma-cological management of opioid-related side effects and use ofother non-pharmacologicalmethods.Guidelines like these shouldgovern contemporary cancer pain management. Assessment ofoutcome should not only focus on the provision of pain reliefalone; a simple guidance to outcome assessment should look atthe so-called four As (analgesia, activity, adverse effects and addic-tion), commonly used in non-cancer pain settings.

2.1 Pharmacotherapy for mild cancer pain

(WHO step 1)For the treatment of mild cancer pain, non-opioids such asaspirin, acetaminophen (paracetamol) and NSAIDs are used.NSAIDs, in particular, are recommended as first-line therapyfor bone pain [31].

2.1.1 AcetaminophenAcetaminophen has antipyretic and analgesic properties.There is currently increasing discussion on the limited efficacyof paracetamol and the possibly underestimated adverseeffects [32]. In a systematic review, insufficient evidence wasfound to support the use of acetaminophen in combinationwith strong opioids [33]. Of particular concern are increasingreports of hepatic toxicity with paracetamol, particularly atdoses more than 4 g/day. Most of these overdoses are uninten-tional and related to multiple analgesics containing acetamin-ophen and to acetaminophen/opioid combinations and haveresulted in FDA advice on dose restrictions [34]. Certain anti-cancer drugs and paracetamol may interact to cause increasedhepatotoxicity [1].

2.1.2 NSAIDsNSAIDs inhibit cytokines and chemokines, which are media-tors of inflammation, in addition to their inhibitory effects onbiosynthesis of prostaglandins [35]. This group of drugs exertsanalgesic effects on the central and peripheral nervous system;details are still under evaluation [1]. COX, the enzyme blockedby NSAIDs, has two isoenzymes labeled COX-1 and COX-2.COX-1 is primarily a constitutive enzyme, responsible forsynthesis of protective prostaglandins that maintain integrityof gastric mucosa and platelet function as well as partially per-fusion of compromised kidney. COX-2 is primarily inducibleand mediates pain and inflammation, but is also protective inthe kidney [28]. The analgesic properties of NSAIDs are dose-dependent and have a ceiling effect; however, with increasingdosage, there is an increase in the incidence of side effectswithout a ceiling effect [36]. There is no evidence for oneNSAID being superior to another, but rotation may be usefulin case of poor efficacy; non-selective NSAIDs have similarefficacy to COX-2 selective ones [37]. It is useful to combineNSAIDs with acetaminophen, as the efficacy of the combina-tion is superior to each drug used on its own [38]. There isweak support from a systematic review that NSAIDs addedto strong opioids in cancer pain improve analgesia or reduceopioid requirements [33].

The classical non-selective NSAIDs such as naproxen andibuprofen can cause gastric and intestinal ulceration, renalimpairment and platelet inhibition. Substitution with a selec-tive COX-2 inhibitor such as celecoxib or etoricoxib reducesthe gastrointestinal (GI) toxicity significantly and causes noplatelet inhibition; there may even be a reduced risk of acutekidney injury with COX-2 selective agents [39]. The assumedincreased risk for cardiovascular complications such as myo-cardial infarction and stroke with COX-2 inhibitors [1] couldnot be confirmed [40]; thromboembolic adverse effects are aclass effect of all NSAIDs, and some COX-2 inhibitors suchas celecoxib are actually safer than some non-selectiveNSAIDs such as diclofenac [41].

Even in the elderly, NSAIDs could be an effective treat-ment option in spite of concerns about their safety profile aslong as contraindications are considered; they should be pre-scribed at the lowest effective dosage for the shortest possibleduration [42].

2.2 Pharmacotherapy for moderate cancer pain

(WHO step 2)For the management of moderate cancer pain, the clinicalrelevance of the recommendations of WHO analgesic ladderstep 2 to use so-called weak opioids is increasingly beingdebated [43,44]. Although the guidelines recommend weakopioids such as codeine, dihydrocodeine (DHC) and trama-dol administered orally in combination with non-opioids forthe management of moderate pain, there is increasing supportfor the omission of this step and direct progression to low-dose strong opioids [10]. However, there is ongoing debate

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on this issue [45]; in many countries, weak opioids are animportant option to treat cancer pain in view of poor accessto strong opioids as outlined above.

2.2.1 TramadolTramadol is a centrally acting atypical analgesic, which inhib-its re-uptake of serotonin and more importantly noradrena-line. It is metabolized into O-desmethyl tramadol (M1),which has µ-opioid receptor agonist activity [46,47]. Tramadolis usually administered orally, but can be given parenterally orrectally, if required. Its low abuse potential, worldwide avail-ability, reduced opioid-related adverse events (e.g., constipa-tion) and specific activity in neuropathic pain make it themost useful of the weak opioids [18,48]. However, there is aconcern that tramadol can precipitate serotonergic symptomsup to a serotonin syndrome either with significant overdose orwhen co-administered with other serotonergic drugs.

2.2.2 CodeineCodeine is an inactive prodrug of morphine; its analgesicefficacy relies on liver metabolism by the CYP2D6 enzyme,leading to its active metabolite morphine. Polymorphisms inCYP2D6 result in a range of metabolic patterns from ultra-rapid to ultra-slow metabolizers, who experience anythingfrom significant morphine effects (and adverse effects) to noanalgesia at all [1,49]. Further disadvantages are variable oralbioavailability and a high propensity to induce constipation;overall codeine is not a useful choice in the setting of cancerpain, as long as other opioids are available [18].

2.2.3 DihydrocodeineDHC is a semisynthetic analog of codeine, with an equivalentpotency of 1:3 ratio of subcutaneous DHC to morphine. As itdoes not require metabolic conversion [49], it is a more reliablestep 2 weak opioid than codeine, but advantages over lowdoses of strong opioids have never been shown.

2.3 Pharmacotherapy for severe cancer pain

(WHO step 3)Severe cancer pain is commonly treated with strong opioids, iffeasible by oral administration. Opioids are classified as fullagonists, partial agonists, agonist--antagonists or antagonistsaccording to their interaction with opioid receptors. Opioidswith full agonist properties do not show ceiling effect for anal-gesia and dose increase is limited by side effects. Opioids witheither agonist--antagonist or partial agonist properties haveceiling effect for analgesia; therefore, they may not be idealfor cancer pain management [28]. There is no evidence ofone opioid agonist being superior to another with regard toefficacy [1].

2.3.1 Strong opioids used in cancer pain treatment2.3.1.1 MorphineMorphine is a pure opioid agonist available as oral immediate(IR) or controlled release (CR) preparations (12 or 24 h

duration of effect) and for subcutaneous, intramuscular andintravenous (i.v.) administration as well as rectal administra-tion in most countries. The half-life of IR preparations is2 -- 3 h with 20 -- 30% bioavailability following oral adminis-tration. The oral to parenteral conversion is about 3:1 [50].Morphine is metabolized in the liver into morphine-6-glucuronide (M6G), an active metabolite having analgesicproperties exceeding those of morphine itself and morphine-3-glucuronide (M3G), devoid of analgesia. M6G accumula-tion in renal failure can cause increased adverse effects andpotentially respiratory depression. The neurotoxic and hyper-algesic effects of M3G may be responsible for reduced efficacyand increased adverse effects with escalating dosages of mor-phine. Genetic variability in morphine metabolism may playa role in the manifestation of these effects [28,50], but theeffects are also influenced, as are those of all other opioids,by genetic variants of the OPRM1 gene, encoding theµ-opioid receptor [51].

2.3.1.2 OxycodoneOxycodone is a synthetic opioid with comparatively highk-receptor affinity; the clinical relevance of this effect isdebated. A brain:plasma ratio of 3:1 of unbound drugexplains why oxycodone has relative less affinity for µ recep-tors than morphine, but a higher potency [52]. It is availablein oral IR and CR formulations as well as for parenteral use.Oxycodone has a bioavailability of 60 -- 87% following oraladministration. The half-life of IR oxycodone is about2 -- 3 h. Although oxycodone is metabolized in liver into nor-oxycodone and oxymorphone, analgesia is mainly attributableto the parent drug. The side effect profile of this drug is sim-ilar to morphine, although it causes less nausea, vomiting,pruritus and hallucinations [1,18,49]. Constipation is one ofthe known adverse effects of opioids and often refractory toconventional treatment in cancer patients. Combinationpreparations of slow-release naloxone and slow-release oxyco-done provide analgesia and reduce constipation at the sametime. When administered orally, naloxone acts primarily onGI opioid receptors reducing the constipating effect of oxyco-done. However, due to an extremely high first-pass effect, ithas very low oral bioavailability and does not antagonize theanalgesic effect of oxycodone in the CNS. Two recent studies,one in cancer patients and the other in non-cancer chronicpain patients, show that this combination was well toleratedby both groups, with significantly less GI complications andsimilar analgesic profile to oxycodone [53,54]. There is a recom-mended daily maximum dose of 80 mg to avoid systemic nal-oxone effects. In severe hepatic failure, naloxone may nolonger undergo significant first pass metabolism and may con-sequently antagonize central opioid receptors, impairing theanalgesic effect of oxycodone [6].

2.3.1.3 HydromorphoneHydromorphone is a semisynthetic opioid with mainlyµ-agonist activity. It is 5 -- 10 times more potent compared

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to morphine and therefore particularly useful, when adminis-tration of smaller volumes is preferred, as in subcutaneousinfusion. The half-life is about 2.5 h. CR preparations areavailable [55]. Hydromorphone is metabolized in the livermainly to hydromorphone-3-glucuronide (H3G) and smallamount of 6-hydroxy-hydromorphone. H3G may cause neu-rotoxic side effects, particularly when retained in patients withimpaired renal function and following prolonged use [49].

2.3.1.4 FentanylFentanyl is a lipophilic µ-receptor agonist, 100 times morepotent than morphine. Due to extensive first-pass metabo-lism, oral administration is ineffective. However, differentformulations for other routes of administration are available:parenteral as well as transdermal and transmucosal such asintranasal and sublingual [56]. There may be a reduced side-effect profile compared to morphine (nausea, vomiting,constipation, sedation and pruritus), in particular with trans-dermal use [57]. Fentanyl is metabolized by CYP3A4 into inac-tive metabolites; thus it is a safe option in patients with renalimpairment [58]. For breakthrough pain, IR preparation withrapid response, such as oral transmucosal fentanyl or intrana-sal fentanyl spray, is available [59]. Intranasal fentanyl is partic-ularly useful due to its rapid uptake, even in patients with drymouth [21].

2.3.1.5 MethadoneMethadone is a µ- and d-opioid receptor agonist, but also anNMDA receptor antagonist and a noradrenaline and seroto-nin reuptake inhibitor [60]. These properties might explainthe benefits some patients achieve when rotated from otheropioids to methadone and possibly its efficacy in neuropathicpain. The pharmacokinetics are complicated by large interin-dividual variability of the plasma half-life and is 15 -- 60 h; ittakes about 2 -- 5 days before steady-state plasma levels arereached. Due to this, dose escalation should be done care-fully [60]. In high doses, it may provoke cardiac dysrhythmiasdue to QT prolongation [61]. Compared to morphine, itcauses less nausea, vomiting and constipation. Methadone ismetabolized in the liver and GI tract into inactive metabolites.Drugs commonly used in cancer patients such selective sero-tonin reuptake inhibitors (SSRIs), ketoconazole, omeprazolecan potentiate methadone by inhibiting cytochrome enzymes(mainly CYP2B6) involved in its metabolism [62]. The inac-tive metabolites are eliminated via GI tract and kidneys,thus making it safer in patients with renal impairment. Meth-adone may become an opioid of choice for patients ondialysis [63]. Because of complex pharmacokinetics and equia-nalgesic conversion variability, prescribing should be done byexperts [1,18,49].

2.3.1.6 BuprenorphineBuprenorphine is an opioid agonist-antagonist that is about100 times more potent than morphine. Sharing featuresinherent to this group of drugs, it has potentially a ceiling

effect, but only at extremely high doses. Buprenorphine canbe given by the sublingual (as low oral bioavailability), trans-dermal or parenteral route and can substitute high doses ofother opioids contradicting previous concerns [64]. Buprenor-phine is metabolized in liver to active metabolites andexcreted through GI tract, thus making it safe in patientswith renal impairment. Compared to other opioids, it has bet-ter side effect profile in terms of nausea, vomiting and consti-pation and a lower risk of respiratory depression [65].Although there is increasing use of buprenorphine in cancerpain, data are still limited [66], but suggest potential advan-tages, for example, over transdermal fentanyl [67].

2.3.1.7 TapentadolTapentadol is centrally acting novel synthetic opioid devel-oped for the management of mild-to-moderate pain [68] andhas been used successfully in cancer pain [69]. It has less affin-ity for µ-receptors compared to strong opioids and inhibitoryeffects on central norepinephrine reuptake. Despite an opioidreceptor affinity 20 times less than that of morphine inhumans, a recent prospective study has shown a conversionratio of 1:3.3 between oral morphine and tapentadol bidirec-tionally [70]. The reduced µ-receptor affinity confers lessopioid-related side effects, mainly of GI origin (nausea, vom-iting and constipation) than equianalgesic doses of conven-tional opioids [68]. The monaminergic effects support theconcept of superior efficacy in neuropathic pain [71].

Other opioid agonists such as meperidine (pethidine) andpropoxyphene are not recommended for cancer pain manage-ment due to neurotoxicity of their metabolites. Partial ago-nists are not suitable as well due to their inherent ceilingeffect for analgesia [1].

2.3.2 Practical management of strong opiodsThere is ongoing debate on the method to initiate opioids incancer pain management, but only limited evidence to sup-port one single approach. Opioid titration using sustainedrelease oxycodone and IR morphine has been supported inpilot studies [72]. Subsequent to the titration phase, dosage isadjusted according to patient’s response. Conventionally, thedose increment is calculated 33 -- 50% of average total dailydosage during the preceding few days [73]. Transdermalopioids are recommended as second-line therapy when oraladministration is not applicable. In spite of recommenda-tions, the selection of an opioid is governed by factors suchas clinicians’ experience, patients’ prior experience, cost andavailability of specific opioids [73].

2.3.2.1 Opioid rotationOpioid rotation or opioid switching describes the process ofsubstituting a strong opioid in step 3 with another strong opi-oid [74]. The process is aimed to increase either opioid efficacyor reduce adverse events of opioids. The effectiveness ofanother opioid may be due to the phenomenon of incompletecross-tolerance or the presence of variable responses at

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multiple µ-receptor subtypes [75]. For dose calculation ofequivalency, conversion tables are being used; however, theseare based on data derived from studies on acute pain set-tings [76]. Such tables need to be used with caution due tothe interindividual variability of response to opioids; to min-imize the risk of overdose, dose reduction and clinicaljudgment is important. A careful approach taking into consid-eration other confounding factors such as associated medicaland psychological factors has been proposed [77].

3. Management of breakthrough pain

Breakthrough pain is defined as episodic bursts of pain ofshort duration on the background of stable pain controlledby opioids. Guidelines recommend comprehensive assessmentfollowed by individualized plan for the pain manage-ment [45,78]. IR opioid preparations are recommended as thefirst-line therapy for breakthrough pain. Advantages of IRopioid preparation are ease of administration, relatively fastonset of analgesia and quite extensive experience in theiruse. Morphine, oxycodone, hydromorphone, buprenorphineand methadone are available as IR preparations [21]. The otheroptions are intranasal or transmucosal fentanyl [56,59] and i.v.morphine. Studies have demonstrated the efficacy of intrana-sal fentanyl over transmucosal preparation [45]. Intranasal fen-tanyl has a high bioavailability (70 -- 90%) and peak plasmalevels are reached in about 13 min following administra-tion [21]. Two recent meta-analyses showed that transmucosalfentanyl preparations are more efficacious than oral morphinein this setting [79,80].Additionally non-opioid pharmacotherapy such as acet-

aminophen, NSAIDs, bisphosphonates, clonidine and keta-mine lozenges may be useful. In addition, guidelinesrecommend application of non-pharmacological methodssuch as radiotherapy, surgical interventions and regionaltechniques [78].

4. Use of co-analgesics and adjuvants

These are medications not commonly regarded as analgesicsbut can be used to enhance the effect of primary analgesicsor in certain selected situations as primary analgesics. Co-analgesics are used, in particular, in specific diagnoses or clin-ical scenarios such as neuropathic pain, bone pain or visceralpain. These drugs can be incorporated into each step of theanalgesic ladder depending on the clinical situation to achieveoptimum pain relief and relief from symptoms. Adjuvantsmay have other indications apart from achieving analgesia,which should be taken into consideration during prescription.

4.1 AntidepressantsAntidepressants play an important role in the managementof neuropathic pain conditions. Tricyclic antidepressants(TCAs) such as amitriptyline or nortriptyline and selectiveserotonin--norepinephrine reuptake inhibitors (SNRIs) such

as duloxetine or venlafaxine are commonly in use. SSRIssuch as fluoxetine have limited application in neuropathicpain due to low efficacy [81].

4.2 Tricyclic antidepressantsTCAs are generally considered first-line therapy in neuro-pathic pain, also in cancer patients. They are very effectivein a number of different neuropathic pain settings such aspain arising from nerve compression and infiltration andpost-chemo- and radiotherapy [81]. The numbers-needed-to-treat (NNTs) for TCAs in neuropathic pain are in the rangeof 2.1 -- 2.8 [13]. As a group, they inhibit reuptake of norepi-nephrine and serotonin thereby enhancing descending inhib-itory pathways of pain with additional effects on NMDAreceptors and sodium channels [81]. The antidepressant effectsmay be additionally beneficial, particularly in cancer patients,who are more prone to depression; furthermore amitriptylineenhances the antihyperalgesic effects of co-administered mor-phine [82]. The analgesic dose required is less than the antide-pressant dose. TCAs have anticholinergic properties causingdry mouth, blurred vision and in high doses can cause cardiacdysrhythmias, conduction abnormalities, narrow-angle glau-coma and prostatic hyperplasia. As a result, TCAs are oftennot suitable for elderly patients and poorly tolerated [1,13,28];they should be started at low doses at night to improve com-pliance. Abrupt discontinuation of higher doses of TCAs maycause withdrawal symptoms [81].

4.3 Serotonin--norepinephrine reuptake inhibitorsSNRIs are showing promising results in the treatment ofcancer-related neuropathic pain [31,81]. Compared to TCAs,these have a better side-effect profile. Both venlafaxine andduloxetine have also been found to be effective for hot flushesin patients on hormonal therapy for breast cancer. Duloxetineinteracts with concomitantly administered tamoxifen, reduc-ing the efficacy of the anticancer medication [1].

4.4 AnticonvulsantsAnticonvulsants are another group of medications that havebecome established as first-line treatment of neuropathicpain. The evidence is limited for older anticonvulsants suchas carbamazepine, phenobarbital and phenytoin with theexception of carbamazepine in trigeminal neuralgia. Theseare also hepatic P450 enzyme inducers and interact therebywith certain anticancer therapies and steroids, which aremetabolized by the same system. In general, anticonvulsantsare used for neuropathic pain at the same dosage as formanagement of seizures [28].

4.5 Gabapentin and pregabalinGabapentin and pregabalin are the two anticonvulsants withthe best evidence base for the treatment of neuropathic pain.Both act as modulators of the a2d subunit of voltage-gatedcalcium channels presynaptically, thereby inhibiting excit-atory neurotransmitter release. For both drugs, NNTs for

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neuropathic pain range from 4.2 to 6.4 [13]. Gabapentin givenorally has low bioavailability and shows non-linear pharmaco-kinetics with increasing dose due to saturation of the transportmechanism. Pregabalin is more potent, better absorbed andhas a linear pharmacokinetic profile [31,81]. Both these drugsare primarily excreted unmetabolized through the kidneyand have minimal drug interactions. Dosages have to bereduced in renal failure. Common side effects are somnolence,dizziness, peripheral edema and weight. Both drugs are alsoeffective in chemotherapy- or radiotherapy-induced mucositisand have significant anxiolytic properties [13,28,31].

4.6 Topical agentsTopical agents for the treatment of neuropathic pain includelidocaine and capsaicin [13]. Lidocaine 5% patches were devel-oped for post-herpetic neuralgia, but are also effective in otherlocalized neuropathies, in particular those accompanied byallodynia [13,31]. The major advantage is the lack of systemicside effects; local skin irritation following application maybe the only relevant complication. Capsaicin, acting on thevanilloid receptor TRPV1 was again found be effective forpost-herpetic neuralgia, when applied as a high-concentrationpatch (8%) [81].

4.7 CorticosteroidsCorticosteroids are widely used as co-analgesics in cancerpatients [81]. They are indicated to alleviate pain in spinalcord compression, superior vena cava syndrome, raised intra-cranial pressure headache, metastatic bone pain, hepatic cap-sular distension and neuropathic pain. Relieved pressure dueto anti-inflammatory effects is the most likely mechanism ofaction. Apart from analgesia, corticosteroids have been usedin cancer patients to improve appetite and mood and as anantiemetic. Dexamethasone has been preferred due to itsreduced mineralocorticoid activity, long duration of actionand potency [81]. With prolonged use, patients have to bemonitored for the well-known complications such hypergly-cemia, peptic ulcers, cushingoid habitus and neurologicalcomplications [1,83].

4.8 KetamineKetamine as an NMDA receptor antagonist is widely used incancer pain. Ketamine can be administered parenterally (i.v.or subcutaneously), but there are also increasing reports onoral, intranasal and transmucosal administration [84]. Thereis contradictory data on its efficacy; a recent randomized con-trolled trial (RCT) may have failed due to inappropriatepatient selection [85]. Use in increasing doses may be limitedby psychomimetic adverse effects and potential other toxicity.

4.9 CannabinoidCannabinoid use for therapeutic purposes in neuropathic painremains controversial with contradictory results on efficacyand potential abuse [50]. However, there are some positiveresults in neuropathic pain caused by cancer and a nasal spray

is licensed in some countries [13]. Other benefits are a potentanti-emetic effect and improvement of appetite.

4.10 BisphosphonatesBisphosphonates are beneficial in cancer-related bone pain, inparticular prostate and breast cancer [81]. They inhibit osteo-clastic activity and hence bone resorption, but further researchis needed to identify the most useful compound andtreatment schedule [86-88].

4.11 DenosumabDenosumab, a human monoclonal antibody against receptoractivator of nuclear factor kappa-B ligand (RANKL), hasbeen shown to reduce bone loss [18]. Positive outcome hasbeen seen in early studies on patients with bone metastases,who have been treated with denosumab. Compared tobisphosphonates, denosumab has better analgesic profile,prevents skeletal-related events and less adverse effects [89].

5. Conclusions

Cancer pain remains one of the most important and mostdistressing symptoms of malignancy. The management ofthis symptom requires proper assessment of the patient andshould establish a pain diagnosis. Often pain occurs in multi-ple locations and can have multiple causes and mechanisms.Treatment of cancer pain relies primarily on systemic phar-macotherapy and is based on guidelines, initially developedby the WHO and then fine-tuned in recent years. Althoughthere is increasing evidence in certain areas of cancer painmanagement, overall treatment is still based on recommenda-tions that rely primarily on weak data and expert opinion.However, this approach has resulted in successful treatmentin many patients. Future developments should focus on a bet-ter evidence base for the guidelines, but also on better accessto medications and appropriate therapies in the developingworld.

6. Expert opinion

The key problem with the whole issue of cancer pain manage-ment is the lack of definitive evidence in many areas. This ismost obvious with regard to the WHO guidelines, whichwere developed on the basis of expert opinion. Althoughthey have been validated and proven to be effective in a largenumber of patients, there is a significant lack of scientific evi-dence supporting many of the concepts including thestepladder approach.

For example, the European Palliative Care ResearchCollaborative attempted to support the concept of combiningopioids, a common clinical practice, by a meta-analysis [90].However, the authors were only able to identify two studieson relatively low evidence levels, which resulted in a weak rec-ommendation with caveats. The reason is the lack of any RCTexamining the issue of combining opioids.

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Similar issues can be found in many other key areas ofcancer pain management [91]. The notion, that morphine isthe first-line opioid for cancer pain treatment, repeated inguideline after guideline, might need to be revised, but gooddata are lacking. Similarly, possibly even more disappointing,dosing recommendations for treatment of breakthrough painhave not been established in RCTs. Again, all recommenda-tions in guidelines are primarily based on expert opinion [91].This list can be continued; the role of COX-2 inhibitors andthe choice of co-analgesics in neuropathic pain states have notbeen established on the basis of RCTs in cancer pain, but onlybased on results in patients with benign conditions. Even theoptimal treatment of bone pain is currently not based onproper scientific evidence and any recommendations onchoice of compound, doses and treatment intervals are againprimarily based on expert opinion.Another example is the concept that non-opioids should be

continued when opioids are started is supported primarily byliterature from acute post-operative pain management, wherethe concept of multimodal analgesia is well established andsupported by RCT and meta-analyses. However, the settingof chronic cancer pain is very different in many aspects.Here the data are very limited and evidence-based guidelinescan only make weak recommendations on the usefulness ofnon-opioids in the cancer pain setting [45].One of the completely unresolved issues in cancer pain

treatment is the role and relevance of the step 2 of theWHO ladder, that is, the use of so-called weak opioids.Already the term ‘weak opioids’ is poorly defined, the separa-tion from strong opioids arbitrary and a specific pharmacody-namic differentiation does not exist. Furthermore, advantagesof one weak opioid over another have not been properly eval-uated; the question of ceiling effects has also not been

addressed. Last but not the least, there remains the key ques-tion if step 2 is actually really a useful step or if it should notbe omitted in favor of low doses of strong opioids [45]. Thishas led some authors to question if the step 2 is only a ‘didacticinstrument’ [43] or an ‘educational substitute for morphine’ [92].In 2014, we are not closer to an answer to these questions; thiswas recently again expressed in an European Association forPalliative Care guideline publication that stated ‘The utilityof step II opioids in the WHO method has been addressed inthree trials, all of which have significant methodological flaws,insufficient statistical power, and selection bias.’ [45].

Overall, shortage of RCTs remains the key concern here.This is to a large extent a result of the difficulties of perform-ing RCTs in a cancer pain population. The reasons for this areobvious and include difficulties in standardizing treatmentsover often heterogeneous patient populations, ethical issuesof enrolling cancer pain patients in yet another clinical trial,the difficulties of identifying appropriate comparators andthe multiple other symptoms in cancer patients.

Nevertheless, continuing attempts need to be made todesign and perform proper RCTs answering key questionsin cancer pain management to permit better evidence-basedguideline development in the future.

Declaration of interest

The Anaesthesiology Unit of the University of WesternAustralia, but none of the authors personally, has receivedresearch and travel funding and speaking and consultinghonoraria from bioCSL, Bionomics, Eli Lilly, Grunenthal,Janssen, Mundipharma, Pfizer, Phosphagenics and iXBiopharma within the last 2 years.

BibliographyPapers of special note have been highlighted as

either of interest (�) or of considerable interest(��) to readers.

1. Paice JA, Ferrell B. The management of

cancer pain. CA Cancer J Clin

2011;61(3):157-82

.. An excellent review of the concepts

underlying cancer pain management.

2. Denlinger CS, Ligibel JA, Are M, et al.

Survivorship: pain version 1.2014. J Natl

Compr Canc Netw 2014;12(4):488-500

3. Puchalski CM. Religion, medicine and

spirituality: what we know, what we

don’t know and what we do. Asian Pac J

Cancer Prev 2010;11(Suppl 1):45-9

4. Choi M, Kim HS, Chung SK, et al.

Evidence-based practice for pain

management for cancer patients in an

acute care setting. Int J Nurs Pract

2014;20(1):60-9

5. Balding L. The World Health

Organisation analgesic ladder: its place in

modern Irish medical practice. Ir Med J

2013;106(4):122-4

6. Gaertner J, Schiessl C. Cancer pain

management: what’s new? Curr Pain

Headache Rep 2013;17(4):328

7. Marcus DA. Epidemiology of cancer

pain. Curr Pain Headache Rep

2011;15(4):231-4

8. Goudas LC, Bloch R, Gialeli-Goudas M,

et al. The epidemiology of cancer pain.

Cancer Invest 2005;23(2):182-90

9. Foley KM. How well is cancer pain

treated? Palliat Med 2011;25(5):398-401

10. Ripamonti CI, Santini D, Maranzano E,

et al. Management of cancer pain:

ESMO Clinical Practice Guidelines.

Ann oncol 2012;23(Suppl 7):vii139-54

.. Up-to-date evidence-based guidelines

for cancer pain management -- the

‘must read’ reference.

11. Cohen E, Botti M, Hanna B, et al. Pain

beliefs and pain management of oncology

patients. Cancer Nurs 2008;31(2):E1-8

12. Kwon JH. Overcoming barriers in cancer

pain management. J Clin Oncol

2014;32(16):1727-33

13. Fallon MT. Neuropathic pain in cancer.

Br J Anaesth 2013;111(1):105-11

14. Hjermstad MJ, Fainsinger R, Kaasa S.

Assessment and classification of cancer

pain. Curr Opin Support Palliat Care

2009;3(1):24-30

15. Knudsen AK, Aass N, Fainsinger R,

et al. Classification of pain in cancer

S. A. Schug & C. Chandrasena

12 Expert Opin. Pharmacother. (2015) 16(1)

Dow

nloa

ded

by [

Uni

vers

ity o

f T

oron

to L

ibra

ries

] at

09:

01 0

5 Se

ptem

ber

2017

patients--a systematic literature review.

Palliat Med 2009;23(4):295-308

16. Burton AW, Chai T, Smith LS. Cancer

pain assessment. Curr Opin Support

Palliat Care 2014;8(2):112-16

. An excellent review of current concepts

and tools for cancer assessment.

17. Stewart J. The challenges of cancer pain

assessment. Ulster Med J

2014;83(1):44-6

18. Auret K, Schug SA. Pain management

for the cancer patient - current practice

and future developments. Best Pract Res

Clin Anaesthesiol 2013;27(4):545-61

19. Twycross R. Cancer pain classification.

Acta Anaesthesiol Scand

1997;41(1 Pt 2):141-5

20. Caraceni A, Portenoy RK, Ashby MA,

et al. An international survey of cancer

pain characteristics and syndromes. Pain

1999;82(3):263-74

21. Leppert W. Role of intranasal fentanyl in

breakthrough pain management in cancer

patients. Cancer Manag Res

2010;2:225-32

22. Webber K, Davies AN, Zeppetella G,

Cowie MR. Development and validation

of the breakthrough pain assessment tool

(BAT) in cancer patients. J Pain

Symptom Manage 2014;48(4):619-31

23. Abbey J, Piller N, De Bellis A, et al. The

Abbey pain scale: a 1-minute numerical

indicator for people with end-stage

dementia. Int J Palliat Nurs

2004;10(1):6-13

24. WHO. Cancer pain relief. World Health

Organisation; Geneva: 1986

25. WHO. Cancer pain relief: with a guide

to opioid availability. 2nd edition. World

Health Organisation; Geneva: 1996

26. Schug S, Zech D, Dorr U. Cancer pain

management according to WHO

analgesic guidelines. J Pain

Symptom Manage 1990;5(1):27-32

. The first validation study of the World

Health Organization (WHO)

guidelines -- of historic value.

27. Zech DF, Grond S, Lynch J, et al.

Validation of World Health Organization

Guidelines for cancer pain relief: a 10-

year prospective study. Pain

1995;63(1):65-76

.. The largest validation study of the

WHO guidelines.

28. Cherny NI. The pharmacologic

management of cancer pain. Oncology

(Williston Park, NY) 2004;18(12):

1499-515; discussion 516, 520-1,

522, 524

29. Aapro M, Launay-Vacher V. Importance

of monitoring renal function in patients

with cancer. Cancer Treat Rev

2012;38(3):235-40

30. Fielding F, Sanford TM, Davis MP.

Achieving effective control in cancer

pain: a review of current guidelines. Int J

Palliat Nurs 2013;19(12):584-91

. An interesting comparative paper of

current cancer pain guidelines.

31. McGeeney BE. Adjuvant agents in cancer

pain. Clin J Pain

2008;24(Suppl 10):S14-20

32. Mercadante S, Giarratano A. The long

and winding road of non steroidal

antinflammatory drugs and paracetamol

in cancer pain management: a critical

review. Crit Rev Oncol Hematol

2013;87(2):140-5

33. Nabal M, Librada S, Redondo MJ, et al.

The role of paracetamol and nonsteroidal

anti-inflammatory drugs in addition to

WHO Step III opioids in the control of

pain in advanced cancer. A systematic

review of the literature. Palliat Med

2012;26(4):305-12

. A paper defining the current role of

non-opioids in cancer

pain management.

34. Blieden M, Paramore LC, Shah D,

Ben-Joseph R. A perspective on the

epidemiology of acetaminophen exposure

and toxicity in the United States.

Expert Rev Clin Pharmacol

2014;7(3):341-8

35. Wang XM, Hamza M, Wu TX,

Dionne RA. Upregulation of IL-6, IL-8

and CCL2 gene expression after acute

inflammation: correlation to clinical pain.

Pain 2009;142(3):275-83

36. Mercadante S. The use of anti-

inflammatory drugs in cancer pain.

Cancer Treat Rev 2001;27(1):51-61

37. Moore RA, Derry S, McQuay HJ,

Wiffen PJ. Single dose oral analgesics for

acute postoperative pain in adults.

Cochrane Database Syst Rev

2011;9:CD008659

. The largest comparative meta-analysis

of the efficacy of oral analgesics.

38. Ong CK, Seymour RA, Lirk P,

Merry AF. Combining paracetamol

(acetaminophen) with nonsteroidal

antiinflammatory drugs: a qualitative

systematic review of analgesic efficacy for

acute postoperative pain. Anesth Analg

2010;110(4):1170-9

39. Lafrance JP, Miller DR. Selective and

non-selective non-steroidal anti-

inflammatory drugs and the risk of acute

kidney injury.

Pharmacoepidemiol Drug Saf

2009;18(10):923-31

40. Moore RA, Derry S, McQuay HJ.

Cyclo-oxygenase-2 selective inhibitors

and nonsteroidal anti-inflammatory

drugs: balancing gastrointestinal and

cardiovascular risk.

BMC Musculoskelet Disord 2007;8:73

.. Excellent meta-analysis of the risks

related to the use of non-selective and

COX-2 selective NSAIDs.

41. Moore RA, Derry S, McQuay HJ,

Paling J. What do we know about

communicating risk? A brief review and

suggestion for contextualising serious, but

rare, risk, and the example of cox-2

selective and non-selective NSAIDs.

Arthritis Res Ther 2008;10(1):R20

42. McCarberg BH. NSAIDs in the older

patient: balancing benefits and harms.

Pain Med 2013;14(Suppl 1):S43-4

43. Freynhagen R, Zenz M, Strumpf M.

[WHO step II - clinical reality or a

didactic instrument?]. Schmerz

1994;8:210-15

44. Maltoni M, Scarpi E, Modonesi C, et al.

A validation study of the WHO analgesic

ladder: a two-step vs three-step strategy.

Support Care Cancer

2005;13(11):888-94

45. Caraceni A, Hanks G, Kaasa S, et al. Use

of opioid analgesics in the treatment of

cancer pain: evidence-based

recommendations from the EAPC.

Lancet Oncol 2012;13(2):e58-68

.. A summary of practical

recommendations on selection and use

of opioids in cancer pain management.

46. Liu HC, Liu TJ, Yang YY, Hou YN.

Pharmacokinetics of enantiomers of

trans-tramadol and its active metabolite,

trans-O-demethyltramadol, in human

subjects. Acta Pharmacol Sin

2001;22(1):91-6

47. Lai J, Ma SW, Porreca F, Raffa RB.

Tramadol, M1 metabolite and

enantiomer affinities for cloned human

opioid receptors expressed in transfected

HN9.10 neuroblastoma cells.

Eur J Pharmacol 1996;316(2-3):369-72

Pain management of the cancer patient

Expert Opin. Pharmacother. (2015) 16(1) 13

Dow

nloa

ded

by [

Uni

vers

ity o

f T

oron

to L

ibra

ries

] at

09:

01 0

5 Se

ptem

ber

2017

48. Leppert W. Tramadol as an analgesic for

mild to moderate cancer pain.

Pharmacol Rep 2009;61(6):978-92

49. Leppert W. Pain management in patients

with cancer: focus on opioid analgesics.

Curr Pain Headache Rep

2011;15(4):271-9

50. Glare P, Aggarwal G, Clark K. Ongoing

controversies in the pharmacological

management of cancer pain.

Intern Med J 2004;34(1-2):45-9

51. Crist RC, Berrettini WH.

Pharmacogenetics of OPRM1.

Pharmacol Biochem Behav

2014;123:25-33

52. Bostrom E, Hammarlund-Udenaes M,

Simonsson US. Blood-brain barrier

transport helps to explain discrepancies

in in vivo potency between oxycodone

and morphine. Anesthesiology

2008;108(3):495-505

53. Burness CB, Keating GM. Oxycodone/

Naloxone prolonged-release: a review of

its use in the management of chronic

pain while counteracting opioid-induced

constipation. Drugs 2014;74(3):353-75

54. Cuomo A, Russo G, Esposito G, et al.

Efficacy and gastrointestinal tolerability

of oral oxycodone/naloxone combination

for chronic pain in outpatients with

cancer: an observational study. Am J

Hosp Palliat Care

2013. [Epub ahead of print]

55. Pigni A, Brunelli C, Caraceni A. The

role of hydromorphone in cancer pain

treatment: a systematic review.

Palliat Med 2011;25(5):471-7

56. Grape S, Schug SA, Lauer S, Schug BS.

Formulations of fentanyl for the

management of pain. Drugs

2010;70(1):57-72

. A review of the wide-range of non-

parenteral fentanyl preparations used

in cancer pain management.

57. Cachia E, Ahmedzai SH. Transdermal

opioids for cancer pain. Curr Opin

Support Palliat Care 2011;5(1):15-19

58. Melilli G, Samolsky Dekel BG,

Frenquelli C, et al. Transdermal opioids

for cancer pain control in patients with

renal impairment. J Opioid Manag

2014;10(2):85-93

59. Paech MJ, Bloor M, Schug SA. New

formulations of fentanyl for acute pain

management. Drugs Today (Barc)

2012;48(2):119-32

60. Davis MP, Walsh D. Methadone for

relief of cancer pain: a review of

pharmacokinetics, pharmacodynamics,

drug interactions and protocols of

administration. Support Care Cancer

2001;9(2):73-83

61. Routhier DD, Katz KD, Brooks DE.

QTc prolongation and torsades de

pointes associated with methadone

therapy. J Emerg Med 2007;32(3):275-8

62. Kharasch ED, Stubbert K. Role of

cytochrome P4502B6 in methadone

metabolism and clearance.

J Clin Pharmacol 2013;53(3):305-13

63. Perlman R, Giladi H, Brecht K, et al.

Intradialytic clearance of opioids:

methadone versus hydromorphone. Pain

2013;154(12):2794-800

64. Lundorff L, Sjogren P, Hansen OB,

et al. Switching from high doses of pure

mu-opioid agonists to transdermal

buprenorphine in patients with cancer:

a feasibility study. J Opioid Manag

2013;9(4):255-62

65. Davis MP. Twelve reasons for

considering buprenorphine as a frontline

analgesic in the management of pain.

J Support Oncol 2012;10(6):209-19

. A nice summary of current knowledge

on buprenorphine.

66. Naing C, Yeoh PN, Aung K. A meta-

analysis of efficacy and tolerability of

buprenorphine for the relief of cancer

pain. SpringerPlus 2014;3:87

67. Mitra F, Chowdhury S, Shelley M,

Williams G. A feasibility study of

transdermal buprenorphine versus

transdermal fentanyl in the long-term

management of persistent non-cancer

pain. Pain Med 2013;14(1):75-83

68. Riemsma R, Forbes C, Harker J, et al.

Systematic review of tapentadol in

chronic severe pain. Curr Med Res Opin

2011;27(10):1907-30

69. Kress HG, Koch ED, Kosturski H, et al.

Tapentadol prolonged release for

managing moderate to severe, chronic

malignant tumor-related pain.

Pain Physician 2014;17(4):329-43

70. Mercadante S, Porzio G, Aielli F, et al.

Opioid switching from and to tapentadol

extended release in cancer patients:

conversion ratio with other opioids.

Curr Med Res Opin 2013;29(6):661-6

71. Niesters M, Proto PL, Aarts L, et al.

Tapentadol potentiates descending pain

inhibition in chronic pain patients with

diabetic polyneuropathy. Br J Anaesth

2014;113(1):148-56

72. Samolsky Dekel BG, Tomasi M,

Vasarri A, et al. Opioid titration with

sustained-release oxycodone and

immediate-release morphine for

moderate/severe cancer pain: a pilot

assessment of the CoDem protocol.

J Opioid Manag 2014;10(1):29-38

73. Portenoy RK, Ahmed E. Principles of

opioid use in cancer pain. J Clin Oncol

2014;32(16):1662-70

74. Vadalouca A, Moka E, Argyra E, et al.

Opioid rotation in patients with cancer:

a review of the current literature.

J Opioid Manag 2008;4(4):213-50

75. Pasternak GW. Opiate pharmacology

and relief of pain. J Clin Oncol

2014;32(16):1655-61

76. Vissers KC, Besse K, Hans G, et al.

Opioid rotation in the management of

chronic pain: where is the evidence?

Pain Pract 2010;10(2):85-93

77. Nalamachu SR. Opioid rotation in

clinical practice. Adv Ther

2012;29(10):849-63

78. Caraceni A, Davies A, Poulain P, et al.

Guidelines for the management of

breakthrough pain in patients with

cancer. J Natl Compr Canc Netw

2013.11(Suppl 1):S29-36

. An useful resource on breakthrough

pain management.

79. Jandhyala R, Fullarton JR, Bennett MI.

Efficacy of rapid-onset oral fentanyl

formulations vs. oral morphine for

cancer-related breakthrough pain: a meta-

analysis of comparative trials. J Pain

Symptom Manage 2013;46(4):573-80

80. Zeppetella G, Davies AN. Opioids for

the management of breakthrough pain in

cancer patients. Cochrane Database

Syst Rev 2013;10:CD004311

81. Mitra R, Jones S. Adjuvant analgesics in

cancer pain: a review. Am J Hosp

Palliat Care 2012;29(1):70-9

.. An excellent summary of the use of

adjuvant analgesics and their role in

cancer pain management.

82. Cegielska-Perun K,

Bujalska-Zadrozny M, Gasinska E,

Makulska-Nowak HE. Enhancement of

antinociceptive effect of morphine by

antidepressants in diabetic neuropathic

pain model. Pharmacol Rep

2014;66(2):228-34

S. A. Schug & C. Chandrasena

14 Expert Opin. Pharmacother. (2015) 16(1)

Dow

nloa

ded

by [

Uni

vers

ity o

f T

oron

to L

ibra

ries

] at

09:

01 0

5 Se

ptem

ber

2017

83. Leppert W, Buss T. The role of

corticosteroids in the treatment of pain

in cancer patients. Curr Pain

Headache Rep 2012;16(4):307-13

84. Tawfic QA. A review of the use of

ketamine in pain management.

J Opioid Manag 2013;9(5):379-88

85. Hardy J, Quinn S, Fazekas B, et al.

Randomized, double-blind, placebo-

controlled study to assess the efficacy and

toxicity of subcutaneous ketamine in the

management of cancer pain.

J Clin Oncol 2012;30(29):3611-17

86. Mhaskar R, Redzepovic J, Wheatley K,

et al. Bisphosphonates in multiple

myeloma: a network meta-analysis.

Cochrane Database Syst Rev

2012;5:CD003188

87. Wong MH, Stockler MR, Pavlakis N.

Bisphosphonates and other bone agents

for breast cancer. Cochrane Database

Syst Rev 2012;2:CD003474

88. Yuen KK, Shelley M, Sze WM, et al.

Bisphosphonates for advanced prostate

cancer. Cochrane Database Syst Rev

2006(4):CD006250

89. Wang X, Yang KH, Wanyan P, Tian JH.

Comparison of the efficacy and safety of

denosumab versus bisphosphonates in

breast cancer and bone metastases

treatment: a meta-analysis of randomized

controlled trials. Oncol Lett

2014;7(6):1997-2002

90. Fallon MT, Laird BJ. A systematic

review of combination step III opioid

therapy in cancer pain: an EPCRC

opioid guideline project. Palliat Med

2011;25(5):597-603

91. Davis MP, Walsh D, Lagman R,

LeGrand SB. Controversies in

pharmacotherapy of pain management.

Lancet Oncol 2005;6(9):696-704

92. Grond S, Meuser T. Weak opioids - an

educational substitute for morphine?

Curr Opin Anaesthesiol

1998;11(5):559-65

AffiliationStephan A Schug†1,2 MD FANZCA

FPMANZCA &

Chandani Chandrasena3 MBBS FANZCA†Author for correspondence1Professor, Chair of Anaesthesiology,

The University of Western Australia, School of

Medicine and Pharmacology, Pharmacology,

Pharmacy and Anaesthesiology Unit, Perth,

Australia2Consultant Anaesthetist and Director of

Pain Medicine,

UWA Anaesthesiology, Royal Perth Hospital,

Department of Anaesthesia and Pain Medicine,

Level 2, MRF Building, GPO Box X2213, Perth,

6847, Australia

Tel: +61 8 9224 0201;

Fax: +61 8 9224 0279;

E-mail: stephan.schug@uwa.edu.au3Senior Registrar and Clinical Lecturer,

Royal Perth Hospital, Department of Anaesthesia

and Pain Medicine, Perth, Australia

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