treatment of cancer pain

Am J Cancer 2004; 3 (4): 247-256THERAPY IN PRACTICE 1175-6357/04/0004-0247/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

Treatment of Cancer PainSpecial Considerations in Patients with Renal Disease

Stephan A. Schug1,2 and Jennifer Morgan2

1 Department of Pharmacology, University of Western Australia, Perth, Western Australia, Australia2 Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, Western Australia, Australia

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2471. Renal Insufficiency and Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2482. Cancer Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248

2.1 Pharmacologic Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2492.1.1 General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2492.1.2 NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2492.1.3 Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2502.1.4 Co-Analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

2.2 Non-Pharmacologic Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2532.2.1 Psychological Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2532.2.2 Interventional Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

Pain is a common symptom in patients with cancer, and requires careful assessment and appropriate therapyAbstractin order to improve quality of life. Treatment for pain requires modification in the presence of renal disease.

NSAIDs should be avoided whenever possible, as they all (including the cyclo-oxygenase-2-specificinhibitors) have detrimental effects on kidney function.

Morphine is not the preferred opioid in renal insufficiency and renal failure as it causes retention of activemetabolites with subsequent adverse effects. Oxycodone and tramadol cause fewer adverse effects, and fentanylmay be the first choice in this setting as its pharmacokinetics are unaffected by renal function.

Of the commonly used co-analgesics, ketamine is not affected by renal disease, while tricyclic antidepres-sants and gabapentin show increased rates of adverse effects. Co-analgesics commonly used to treat bone painsuch as calcitonin and bisphosphonates need to be used with caution in renal disease.

Psychological interventions might be particularly useful in patients with renal disease as they effectivelyaddress issues of chronic disease management, and have no adverse effects in these patients.

The use of interventional techniques requires careful planning in patients with renal disease as co-morbiditiesmay affect outcome and cause adverse effects.

Most patients with a diagnosis of cancer experience pain; it is With appropriate multidisciplinary care, pain can be controlled inestimated that 25% of cancer patients present with pain, and up to 95% of patients.[2] Numerous practice guidelines for the manage-75% develop pain throughout the course of their illness.[1] Uncon- ment of cancer pain assist the practitioner and patient.[3,4]

trolled pain is a major fear of cancer patients and their families. Evidence-based guidelines stress the importance of comprehen-

248 Schug & Morgan

sive pain assessments throughout the duration of illness. Thorough renal and postrenal.[7] Of those causes related to malignancy,assessments should acknowledge significant medical conditions prerenal hypoperfusion and dehydration are often readily identi-such as renal disease. The presence of renal dysfunction may fied and treated with rehydration.[8] Hypercalcemia, an importantrequire alteration in the pain treatment strategy. cause of dehydration, should be identified and addressed in this

population.[9] Intrinsic renal damage may occur from prolongedThis article addresses pain management principles in patientsdehydration, direct glomerular or tubulointerstitial damage fromwith concurrent renal impairment and cancer pain.endogenous precipitants, nephrotoxins, or direct vascular obstruc-

1. Renal Insufficiency and Failure tion.[10] Chemotherapeutic drugs may have agent-specific nephro-toxic adverse effects.[7]

The healthy kidney has an excess number of nephrons to enablePostrenal obstruction may occur secondary to tumor or renalit to maintain normal renal function and homeostasis. With loss of

calculi.[7] Urologic emergencies are common in the cancer patient.nephron function, this reserve is initially lost without affectingThese include upper and lower urinary tract obstruction, bladderhomeostasis or biochemical markers. Plasma creatinine levels arehemorrhage and urinary tract infection.[11] Pain is often a concomi-within normal limits in patients with up to 50% reduction intant symptom early in these conditions. Detection of these compli-glomerular filtration rate (GFR).[5] As more function is lost, renalcations is important as investigation and further specialist consul-insufficiency that may be associated with very mild symptoms oftation may be required.fatigue, nocturia and mild biochemical derangement develops.

Depending on the prognosis, estimated life span, and wishes ofWith further progression, renal failure ensues. Renal functionthe patient, evaluation and optimization of renal function may bestatus along this disease continuum is usually assessed by estima-indicated. This should occur concurrently with initiation of paintion of the GFR or creatinine clearance (CLCR); the degree of renalmanagement.impairment will alter the patient management.

Table I outlines a checklist for assessment of renal impairmentThe glomerular filtrate is the ultrafiltrate of plasma that passesin cancer patients.through a nephron. This basic function of the renal mass can be

measured. The volume of filtrate formed per unit time is the GFR,2. Cancer Pain Managementand is expressed in milliliters/minute. There are several methods

available to estimate GFR and hence assess renal function. TheIn 1986, the WHO produced guidelines for cancer pain man-best method is to inject a suitable marker and then follow serum or

agement.[12] Since then, multiple working parties have expandedurine levels. However, these methods are expensive, invasive, andthe principles outlined in the WHO document. Multiple evidence-not readily available. A more commonly used technique is tobased guidelines are now available to the practitioner.[3,13,14] Aestimate GFR from CLCR. CLCR is a derived number using plasmasummary of suggested pain management principles from thesecreatinine (PCR) measurements that are readily available (equationguidelines is listed in table II.1).[6]

Pain treatments are broadly divided into pharmacologic andnon-pharmacologic treatments. Although pharmacotherapy hasbecome the mainstay of cancer pain management, other modalities

(140 − age [y]) × weight [kg]

72 × PCR [mg / dL]

For women the value of CLCR is 15% lower than in men.

For men: CLCR (mL / min) =

are employed in selected situations. The type and sequence ofThis method is useful only when the plasma creatinine level is

>2 mg/dL; it is not reliable for creatinine measurements that arewithin the normal range or slightly elevated. Likewise, gender,height, weight, age, and race can alter the estimation and lead toabnormal estimates. Therefore, equation 1 should be used withknowledge of its possible deficits.[5] The normal values for CLCR

are approximately 95 mL/min in women and 120 mL/min in men.

Renal disease has many causes and may be treatable. In thecancer population, renal impairment may be directly related to thecancer, a consequence of cancer treatment, or unrelated to malig-nancy. Causes of renal dysfunction can be classified as prerenal,

Table I. Assessment of renal impairment in cancer patients

1. Is the impairment acute or chronic?

2. What is the cause of the renal impairment?

3. What is the degree of impairment?

4. Is the cause reversible?

5. Can the impairment be stabilized?

6. Are there any systemic effects (hematologic, hepatic, bone) fromthe renal impairment?

7. Does this impairment represent a urological emergency?

8. What is the psychosocial effect of this concomitant disease?

© 2004 Adis Data Information BV. All rights reserved. Am J Cancer 2004; 3 (4)

Cancer Pain Treatment in Renal Disease 249

treatments must be individualized as explained in the practiceguidelines. The treatments mentioned in sections 2.1 and 2.2 arenot inclusive of all pain treatments available; selected treatmentsare discussed that may require special consideration in patientswith renal impairment.

2.1 Pharmacologic Treatment

2.1.1 General Principles

Renal disease can alter the pharmacokinetics and pharmaco-

Table II. Steps in cancer pain management

1. Regular and thorough pain assessments

2. Detection and classification of the nature of the pain (neuropathic,nociceptive or a combination)

3. Detection of oncologic emergencies

4. Consideration of patients beliefs and preferences

5. Determination of cancer prognosis and estimation of lifeexpectancy

6. Initiation of the most appropriate treatment with review andadjustment

dynamics of many drugs. Drug absorption, bioavailability, volumewhen inflammation is contributing to the pain, but may also beof distribution, renal and hepatic metabolism and clearance may beeffective against other pain including neuropathic pain.[19] Theyimpaired. In addition, an alteration in drug sensitivity can alter theare also widely used as an adjunct to opioid therapy; they maypharmacologic or toxic response to a specific serum drug level.reduce the amount of opioid required and improve the quality ofThe severity of renal impairment and the pharmacokineticanalgesia.[20] Indometacin, ibuprofen and naproxen are not re-features of the drug will determine the fate and effect of a drug.moved by hemodialysis; there is insufficient data on the effect ofStudies have shown that mild renal impairment (GFR >2.4 L/h ordialysis on the remaining drugs in this class.[21] The renal effects ofCLCR >50–90 mL/min) has little effect on drug pharmacokinetics,these agents have been well documented and careful considerationand no changes in prescribing are necessary.[15] However, largerof risks is necessary in the renal patient. NSAIDs inhibit renaldoses of drugs are often required in palliative care. When prescrib-prostaglandins that are necessary to maintain glomerular filtrationing large quantities of drugs, caution may be required even in mildin the impaired kidney.[22] Administration of NSAIDS can result inrenal impairment.deterioration of renal function or may even precipitate acute renalDepending on the estimated reduction in CLCR, many drugs arefailure.[23]administered in smaller amounts and less frequently. Unfortunate-

ly, this prescribing rationale only applies to medications that are Cyclo-oxygenase (COX)-2-specific inhibitors are considered toprimarily cleared by the kidney.[16] Renal disease can also alter the have similar renal effects to the NSAIDs.[24] Although evidence ispharmacokinetics of drugs that are not renally cleared. Drug still limited concerning the effect of these agents on the renalabsorption can be slowed secondary to prolonged gastric emptying system, data do indicate similar caution as with the nonselectivetime and increased gastric pH. Reduced protein levels and altered NSAIDs.pH-dependent protein binding may affect drug distribution. Liver The decision to use any NSAID, including COX-2 inhibitors,metabolism of drugs in patients with renal disease is reduced by an will depend upon the likely cause of pain and the degree of renalunclear mechanism. In particular, drugs metabolized in the liver impairment. Patients with moderate-to-severe renal impairmentby oxidation or conjugation may have reduced hepatic clearance in have little reserve, and even slight deterioration in renal functionpatients with renal impairment. Hence, drugs with no renal clear- may necessitate dialysis; NSAIDs are best avoided in this group.ance can also be affected by renal insufficiency.[17]

In less critical renal impairment, alternative analgesics (such asDialysis is used for the control of symptoms in renal failure. acetaminophen [paracetamol]) should be tried initially; NSAIDs

Drug removal and clearance by this method is dependent on a should only be used when other analgesics have failed. The mostnumber of factors, including drug characteristics, type of dialysis, difficult scenario arises with presumed inflammatory pain andand equipment used.[18] Intermittent hemodialysis or peritoneal intolerance to other analgesics. If the decision to use NSAIDs ordialysis are the most common methods employed; rarely, continu- COX-2 inhibitors is made, regular assessment of renal functionous hemofiltration or hemodialysis is used. Patients undergoing should occur. It has been suggested that a 20% reduction in renaldialysis need assessment of their pain relief medications to ensure function is an acceptable deterioration but this will depend on theadequate maintenance of analgesia and avoidance of toxicity. initial degree of impairment.[24] Regular checks of serum creati-

nine levels are advised until a stable state has been reached.[24]2.1.2 NSAIDs

NSAIDs are used in cancer pain as primary agents in the first With cessation of NSAIDs, renal dysfunction is reversible instep of the WHO analgesic ladder.[12] These agents are most useful the majority of cases (approximately 95% of patients have no


250 Schug & Morgan

further renal risk factors). However, a small proportion of patients seizures, allodynia, sedation, and cognitive impairment and arewill develop progressive renal failure despite cessation of the analogous to those produced by morphine-3-glucuronide, a metab-drug.[23,25] olite from morphine.[36] Recently it has been shown that H3G is

largely excreted by the kidneys.[35]

2.1.3 Opioids The renal excretion of H3G may have implications for thecancer patient with renal impairment taking large doses of hydro-Morphinemorphone. A small retrospective study of cancer patients withMorphine has long been the gold standard of opioids used formild-to-severe renal failure demonstrated no adverse effects whenthe treatment of moderate-to-severe nociceptive cancer pain. Ex-patients were switched from morphine to hydromorphone.[37]

perience has shown it to be a well tolerated, effective analgesicHowever, further case reports of cognitive impairment and poss-when prescribed appropriately and in adequate amounts.[26] How-ible accumulation of hydromorphone metabolites in renal failureever, the pharmacology of morphine is altered in patients withpatients provides reason for caution.[38,39] Although the problemsrenal impairment and extreme caution should be applied whenwith M6G and morphine are avoided with the use of hydromor-treating these patients.phone, the renal patient may be at risk for accumulation of H3GMorphine is metabolized by hepatic glucuronidation andand its neuroexcitatory effects.5–10% is biotransformed to morphine-6-glucuronide (M6G).

M6G is more potent than morphine and is renally excreted.[27]

FentanylAdequate renal function is required for excretion of M6G. Cere-The introduction of transdermal fentanyl patches has providedbrospinal fluid (CSF) levels of M6G are 15 times higher in renal

cancer patients with an alternative strong opioid and route offailure patients than in the healthy population.[28]

administration. It has proved to be a well tolerated and effectiveThe dose and frequency of administration of morphine needs tomode of analgesia for cancer patients.[40,41] In addition, this drugbe reduced, depending on the severity of renal impairment.[29]

has been administered for cancer pain control by more traditionalPatients with moderate-to-severe renal impairment require smallerroutes. Fentanyl is versatile and, given its high lipid solubility, candoses of morphine for similar analgesic effect: 5mg, 4 hourlybe administered parentally and transmucosally. Compared withcompared with median 20mg, 4 hourly.[30] In addition to dosemorphine, subcutaneous and transmucosal fentanyl is equally ef-reduction, prolonged duration of effect and adverse effects must befective and possibly superior for breakthrough cancer pain.[42,43]

considered.[31]

The pharmacokinetics of fentanyl are variable. Of particularTime to achieve steady state and effects of accumulation mayimportance is the rapid redistribution of fentanyl to various bodyboth be delayed in renal insufficiency. Hence, the ideal regimen oftissues following administration of a moderate or small doserapid titration to achieve pain control may be more difficult with(10 μg/kg) intravenously.[44] Because of this rapid redistribution,morphine and concurrent renal impairment.plasma levels fall quickly and this explains the short duration ofContinuous infusions and slow release preparations pose theaction with moderate or small doses of fentanyl. With higher dosesgreatest risk for toxicity and are probably best avoided; multiple(100 μg/kg), once this redistribution phase is completed, the ex-cases of severe respiratory depression have been described.[32]

cess fentanyl will result in comparatively much higher plasma andMorphine is not removed by peritoneal or hemodialysis in signif-CSF levels.[45] The rate of decline of these higher levels is thenicant amounts.[21] Overall, an alternative opioid should be consid-dependent on the much slower elimination via hepatic metabolismered as a first-line opioid in patients with renal impairment.and subsequent renal excretion of metabolites. Hence, in large

Hydromorphone doses or with very prolonged continuous administration, fentanylHydromorphone has been marketed as an alternative to mor- becomes a long-acting analgesic.[45] Although fentanyl has long

phine with possible reduction in adverse effects such as nausea, been the opioid of choice in renal failure, data are limited regard-pruritus, and sedation.[33] While many metabolites of hydromor- ing the influence of renal disease on fentanyl pharmacokinetics.phone have been identified, the primary metabolite is Only 10% of fentanyl is excreted unchanged in the urine. Fentanylhydromorphone-3-glucuronide (H3G).[34,35] H3G is primarily ex- metabolites are renally excreted but have minimal or no pharma-creted by the kidneys and is believed to have no intrinsic analgesic cologic effect. The hepatic metabolism by N-dealkylation andeffect, but contributes to neuroexcitatory adverse effects in high subsequent hydroxylation is unlikely to be altered in renal pa-plasma levels.[35,36] Such adverse effects include myoclonus, tients.[17] The clearance of fentanyl is actually higher in anephric



patients than in surgical patients with normal renal function.[46] at risk of seizures or on concomitant drugs that could increaseHence, renal impairment should not have a significant effect on serotonin levels (such as selective serotonin reuptake inhibitors).moderate doses of fentanyl such as those used for analgesia in Almost 90% of tramadol and its metabolites are renally excret-cancer patients. However, in a small prospective clinical trial ed – including the active metabolite M1. Thirty percent of the(n = 8), a significant inverse relationship between the degree of parent drug is excreted unchanged and <7% is removed byazotemia and fentanyl clearance was found in patients undergoing hemodialysis.[57]

renal transplantation. With higher levels of uremia, fentanyl clear- Patients with renal impairment (CLCR <80 mL/min) have dem-ance was reduced in the perioperative setting and possibly necessi- onstrated reduced rates of tramadol and M1 excretion.[57] Drugtated postoperative ventilation in these patients.[47] administration guidelines suggest an increased administration in-

In summary, fentanyl is a convenient, effective, strong opioid terval to counteract the reduced excretion rate when CLCR is <30with pharmacokinetic benefits over morphine in patients with mL/min. The suggested dose is 50–100mg, 12 hourly. Death,renal impairment. However, clearance may be reduced in patients seizures, or serotonergic syndromes in renal patients who receivedwith severe renal impairment and opioid toxicity may result, tramadol have not been reported, but a single case of respiratoryespecially with continuous administration.[47,48] depression due to retention of the M1 metabolite has been de-

scribed.[58]

Tramadol Overall, tramadol metabolites can accumulate in patients withTramadol is a synthetic codeine analogue with weak μ-receptor renal failure, but the evidence for clinically relevant complications

agonist activity, which contributes to only around 40% of its is sparse. Limitation of doses in severe renal impairment is justi-analgesic effect. Inhibition of norepinephrine and serotonin reup- fied. Tramadol provides a viable alternative to morphine fortake in synapses of the dorsal horn of the spinal cord contributes to treatment of moderate-to-severe cancer pain in renal patients.the analgesic effect of tramadol and therefore it is often not

Oxycodonedescribed as an opioid, but an atypical centrally acting analge-

Oxycodone is a semi-synthetic opioid agonist with μ- and κ-sic.[49] Tramadol has been incorporated into the second step for the

receptor effects[59] that is increasingly used as an effective alterna-treatment of cancer pain in the WHO ladder of analgesics[12] as it

tive to oral morphine to treat chronic and cancer pain world-provides a useful alternative to conventional opioids in moderate-

wide.[14] However, a recent systematic review showed no clinical-to-severe pain. Studies have demonstrated fewer opioid-like ad-

ly significant advantage of oxycodone in comparison with mor-verse effects with tramadol compared with conventional opioids in

phine and methadone, but much higher costs.[60] Oxycodone isthe treatment of cancer pain; constipation in particular,[50] but also

mainly metabolized in the liver; noroxycodone and oxymorphonenausea, are reduced with long-term use, while sleep patterns and

are the main metabolites of this CYP2D6 reaction in humans, ofactivities of daily living are reportedly improved.[51,52]

which oxymorphone is thought to be the active metabolite with aReduced analgesic effects with tramadol may occur in 7% of

μ-receptor effect.[61]

Caucasians because of deficiency of cytochrome P450 (CYP)Excretion of oxycodone and its metabolites is impaired in end-

2D6. This enzyme is responsible for metabolism of parent tram-stage renal failure thus prolonging elimination half-lives; this

adol to its metabolite mono-O-desmethyltramadol (M1), whichneeds to be considered when treating such patients.[62] Oxycodone

has significantly higher affinity to the μ-receptor than the parentmay have theoretical advantages over morphine in patients with

compound.[53,54] However, more commonly, inadequate analgesiarenal insufficiency,[63] but this has not yet been addressed in

is due to inappropriately low doses of tramadol. Equianalgesicclinical trials. The effects of dialysis are also yet not known.[21]

doses of tramadol to morphine are at least four times higher whenadministered orally (i.e. morphine 100mg orally = tramadol Methadone

400mg orally)[52] and 10–12 times higher when administered par- Methadone is a widely used synthetic opioid with high oralenterally (i.e. morphine 100mg intravenously = tramadol bioavailability and a prolonged duration of action.[64] Its use as an1000mg).[55] effective alternative to other opioids in cancer pain is advocated by

The product information suggests a maximum dose of tramadol a number of guidelines,[14] although its use should be restricted to400mg orally or 600mg parenterally over 24 hours. However, experienced practitioners because of its interindividual variabilityhigher doses are widely used internationally with no impairment in half-life, potency, and duration of effect.[65] Methadone also hasof safety.[56] Higher doses should be used with caution in patients the advantage of low costs in most countries.


252 Schug & Morgan

Hepatic metabolism as well as renal excretion are important ered inactive, alteration in dosage regimens should not be requiredroutes of elimination.[32] Limited studies in patients with renal in renal disease. In addition, in this study, patients were adminis-disease suggest unchanged pharmacokinetics in anuric patients tered continuous intravenous ketamine for 3 days at a dosage ofelimination seems to change to the fecal route.[66] However, only 1 mg/kg/h. This dosage is significantly greater than that which is<1% of the drug is eliminated by peritoneal or hemodialysis commonly required for analgesia – we use 0.1–0.5 mg/kg/h as anbecause of its high protein binding and large volume of distribu- intravenous infusion.tion.[66] We do not alter the dosage regimen in renal failure but the

On the basis of these limited data it can be concluded that paucity of evidence is cautionary. Periodic review for unaccept-methadone is suitable for patients with renal disease and might able adverse effects, such as nightmares or hallucinations, shouldonly require minor dose adjustments; however, controlled studies be undertaken in this special population. Respiratory depressionin larger patient populations are needed. has not been reported with low-dose ketamine and this drug is

utilized during anesthesia for its ability to maintain ventilatoryOther Opioids drive.[71] These benefits suggest ketamine may provide useful co-The pharmacokinetics of alfentanil, sufentanil, remifentanil, analgesia in cancer patients with renal impairment.

and buprenorphine are not clinically altered in patients with renalfailure.[48] Although these agents are not commonly used in cancer Tricyclic Antidepressantspain control outside the acute care setting, they do provide a less A systematic review by Fishbain[72] indicated that antidepres-common alternative in patients with renal impairment. sants have an independent antinociceptive effect in chronic pain

and that they were effective for neuropathic pain. Amitriptyline is2.1.4 Co-Analgesicsoften the antidepressant of choice, and clinical trials have demon-A considerable number of patients with cancer pain have spe-strated analgesic efficacy in patients with non-malignant neuro-cific conditions such as neuropathic or bone pain, which are poorlypathic pain.[73]

responsive to classic analgesics. Diagnosis and appropriate treat-Renal patients are often more sensitive to the anticholinergicment of such conditions can enhance analgesia and minimize

adverse effects of tricyclic antidepressants (TCAs). Likewise,opioid requirements and adverse effects. Appropriate treatmentterminally ill patients may also exhibit increased sensitivity evenoften involves drugs not usually thought of as analgesics. Renalat lower doses. The TCAs undergo extensive hepatic metabolism;impairment has implications for the use of some of these co-<2% of the parent drug is excreted unchanged. All TCAs are notanalgesics.removed by dialysis.[21] Levels of the parent drug do not differ

Ketamine between healthy controls and patients with renal impairment.Ketamine is an NMDA receptor antagonist, initially introduced However, grossly elevated conjugated metabolites are measured in

as an anesthetic agent. The potent analgesic effect present with this population (500–1500% of normal levels).[74] These metabo-sub-anesthetic doses was noted in 1956. Since then, ketamine has lites are not pharmacologically active, but they may be responsiblebeen administered parentally, orally and intrathecally in cancer for the excessive anticholinergic adverse effects in these patients.patients. Ketamine is used as a sole agent in the treatment of Hence, doses should be low initially and adjusted according toneuropathic pain or as an adjuvant to other analgesics.[67] The adverse effects. Alternatively, an antidepressant with fewer anti-addition of ketamine to oral opioids has resulted in improved pain cholinergic adverse effects may be substituted, such as nor-control in moderate and severe cancer pain.[68] triptyline or desipramine.

Ketamine undergoes rapid hepatic metabolism; only 3% isAntiepileptic drugsexcreted unchanged through the kidneys.[69] The major metabo-

lites are norketamine and 5-hydroxynorketamine. The effect of Antiepileptic drugs have been used in the treatment of chronicdialysis is unknown.[21] Both metabolites appear to have minimal pain for almost 40 years. A Cochrane database systematic reviewpharmacologic activity at plasma levels found in healthy subjects. revealed only one randomized controlled trial concerning cancer

There are limited data regarding the pharmacokinetics of keta- pain and antiepileptic drug treatment.[75] There is only one trialmine in renal disease. A single human study has shown signifi- comparing different antiepileptic drugs in neuropathic pain. Itcantly higher levels of 5,6-dehydronorketamine, but not ketamine shows clonazepam to be the most effective of the older antiepilep-in patients with renal impairment.[70] As this metabolite is consid- tic drugs, with least adverse effects.[76]



Most interest in this area has now focused on gabapentin, which often asymptomatic in the acidotic renal patient. The administra-is the only antiepileptic drug approved for the treatment of neuro- tion of calcitonin in these patients may precipitate a hypocalcemicpathic pain. In addition, there is some interest in its ability to event. Serum calcium and phosphate levels should be measuredenhance the analgesic effect of morphine in nociceptive pain.[77] before treatment. Consideration of alternative treatments toGabapentin has gained popularity given its safety profile, lack of calcitonin should be made if hypocalcemia is present.drug interactions, and generally minor adverse effects.

BisphosphonatesGabapentin is excreted unchanged in the urine, hence it reliesBisphosphonates are also used in oncology to treat hyper-upon normal glomerular function for its elimination. In this respect

calcemia associated with metastases. These agents also reduceit differs from the other commonly used antiepileptic drugs for thispain related to osteolytic metastases.[84,85]

indication, carbamazepine and valproate sodium (valproic acid),Bisphosphonates are synthetic analogues of pyrophosphate thatwhich undergo extensive hepatic metabolism. Gabapentin is re-

bind to the hydroxyapatite found in bone. Inhibition of bonemoved by hemodialysis.[78]

resorption is mediated by an unclear mechanism. Either directThe pharmacokinetics of gabapentin have been studied in pa-osteoclast inhibition or recruitment of mononuclear cells occur.[83]

tients with various degrees of renal impairment.[79] A single dosePain relief may occur subsequent to inhibition of bone resorp-of gabapentin 400mg was given to patients, and plasma and urinetion.[86]

samples were collected. Impaired renal function resulted in higherBisphosphonates are administered either orally or intra-plasma levels and longer elimination half-lives. The estimated

venously. Intravenous administration works more quickly and isCLCR in patients correlated linearly with plasma and renal clear-more widely used in the treatment of metastatic bone pain. Agentsance.include pamidronic acid, clodronic acid, alendronic acid, andThere have been case reports of overdose with gabapentin withnewer agents including ibandronic acid and zoledronic acid. Theno serious sequelae. However, a case of respiratory depressionhalf-life of circulating bisphosphonates is short and, 6 hours afterfrom minor increases in dose with elevated plasma levels has beenadministration, plasma-circulating levels are reduced by 95%. Thereported in end-stage renal failure.[80] This indicates that the doseskeleton takes up 50% and the remaining 50% is excreted in theof gabapentin should be adjusted to the estimated degree of renalurine over 72 hours.impairment, and that the safety of elevated plasma levels cannot be

The dosage of bisphosphonates should be reduced in severeassumed.renal impairment. Dosage adjustment needs to occur when esti-mated CLCR is <35 mL/min. In addition, fast infusion rates haveCalcitoninbeen associated with potential renal toxicity; clodronic acid andBone pain is a common symptom associated with skeletallarger doses of zoledronic acid when given by rapid intravenousmetastasis. Up to 80% of patients with breast, prostate, or lunginfusion may cause severe adverse effects on kidney function.[83,87]

cancer can expect to develop bone metastases.[81] The mechanismof pain with bone metastases is not well understood. Proposed

2.2 Non-Pharmacologic Treatmentstheories include microfractures and disruption and stretching ofrichly innervated periosteum.[82] Cytokines that mediate osteoclastactivity may also activate pain receptors. Direct nerve root infiltra- 2.2.1 Psychological Techniques

tion and nerve compression with collapsed vertebrae may also be a Most practitioners and patients generally accept the cause ofsource of neuropathic pain.[83] Calcitonin is used to treat hyper- cancer pain as somatic.[88] Consequently, psychological tech-calcemia and bone pain in cancer patients. The endocrine effects niques to modify pain behavior are often overlooked in the cancerof calcitonin are lowered serum calcium and phosphate levels. It patient. The uses of psychological techniques in cancer patientsmediates these effects via bone and kidney mechanisms. Osteo- with pain have been assessed.[89] Patient psychoeducation, sup-clast activity is inhibited in bone; calcium and phosphate reabsorp- portive psychotherapy and cognitive-behavioral interventions aretion are reduced in the kidney. useful techniques to manage cancer pain.[90,91] Physicians are often

Renal disease also affects the regulation of calcium and phos- hesitant to suggest psychological treatment modalities to cancerphate. Serum levels of these electrolytes vary, depending upon the patients. However, it has been shown that cancer patients respondseverity and chronicity of renal impairment. Free serum calcium positively when their primary physician suggests such treat-levels may be low, normal, or even elevated. Hypocalcemia is ment.[89]


254 Schug & Morgan

An important goal in psychosocial management of and minimal complications, consultation with the proceduralistbefore the intervention is advised.nonmalignant pain is to encourage the patient to regain a sense of

personal control. This is even more important in the patient with3. Conclusioncancer. Pre-existing significant renal disease may impede and

complicate this aim. Renal disease is a chronic illness that can beCancer patients with renal impairment and pain are a challenge

associated with much social disruption and psychological change.to those involved in their care. With appropriate knowledge and

The ‘sick’ role is commonly adopted and accepted by renal pa-utilization of guidelines, it is possible to safely treat pain in this

tients and their families. Many factors including severity andgroup of patients. Multiple pain treatment options are available to

duration of renal impairment, personality type, and family dynam-the physician. Coexistent renal impairment should not preclude

ics determine the development of this dependent state. Earlymaximal pain relief in malignant disease, but requires adjustment

experienced psychological assistance may be beneficial in theof established techniques to the individual needs of the patient.

cancer patient with pre-existing renal impairment.

Acknowledgment2.2.2 Interventional Techniques

The authors have provided no information on sources of funding or onInterventional treatments for cancer pain management are nu-conflicts of interest directly relevant to the content of this review.

merous. Possible interventions available to manage cancer pain are

listed in table III. General considerations for invasive and surgicalReferencesprocedures apply to the renal patient. With progressive renal

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Table III. Interventional treatments for cancer pain

Peripheral nerve blocks

Sympathetic nerve blocks

Intrathecal or epidural drug administration

Neuroablative surgical procedures

Surgery for oncologic emergencies

Radionuclide or hormonal therapies

Radiation therapy

Chemotherapy

Vertebroplasty



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