Adapted from oncologyse.com anesthesiologynews.com Q569 EDU240 July 2006 Provided as an educational service by painmedicinenews.com Three-Step Analgesic Ladder For Management of Cancer Pain 2006 Three-Step Analgesic Ladder For Management of Cancer Pain 2006 www.breakthroughpain.com
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These guidelines have been tabulated and developed by
Russell K. Portenoy, MDChairman
Department of Pain Medicine and Palliative CareBeth Israel Medical Center
New York, New York
DisclaimerThis pocket guide is designed to be a summary of information.While it is detailed, it is not an exhaustive pharmaceuticalreview. McMahon Publishing Group, Cephalon Inc., and theauthor neither affirm nor deny the accuracy of the informa-tion contained herein. No liability will be assumed for the useof this review, and the absence of typographical errors is notguaranteed. Readers are strongly urged to consult any rele-vant primary literature and the complete prescribing informa-tion available in the package insert of each drug andappropriate clinical protocols.
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Routes of Administration • 76 • Routes of Administration
Although the oral and transdermal routes are preferred, alter-native routes of administration will be required for a substan-tial number of patients at some point in their course.
Buccal: Supporting data meager (for oral suspensions, etc).Method currently unavailable and impractical.Epidural: Repetitive bolus; continuous infusion.Intracerebroventricular: Rarely indicated. Limited survey dataavailable.Intranasal: Available for butorphanol; not used in cancer painmanagement.Intrathecal: Repetitive bolus; continuous infusion: Clearestindication is pain in lower body with poor relief and sideeffects from systemic opioids. Epidural catheter can be percu-taneous (from lumbar region or tunneled to abdomen) or con-nected to subcutaneous portal, depending on patient’s lifeexpectancy. Intrathecal usually administered via implantedpump. Benefits of long-term intrathecal infusion in selectedpatients demonstrated in randomized trial (Smith TJ, et al.J Clin Oncol. 2002;20:4040-4049). Morphine, hydromorphone,fentanyl, and others in use, combined with local anesthetic orclonidine.
Intravenous: Repetitive bolus; continuous infusion; PCA (with orwithout infusion): Indicated if other routes are unavailable ornot tolerated, or if patient has an indwelling I.V. access device.Oral: Preferred route of administration for long-acting opioids incancer pain management. Transdermal available for fentanyl.Oral transmucosal: Available for fentanyl.Rectal: Available for morphine, oxymorphone, and hydromor-phone. Although few studies available, customarily used as ifdose is equianalgesic to oral dose.Subcutaneous: Repetitive bolus; continuous infusion; continu-ous infusion with PCA: Ambulatory infusion pumps permitoutpatient continuous infusion. Can be accomplished with anyparenteral drug. Drug mixtures to treat multiple symptomsand long-term hydration also feasible by this route.Sublingual: Buprenorphine effective, and sublingual tablet avail-able in the United States. Efficacy of morphine controversial.Transdermal: Available for fentanyl.
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1ST Step • 1514 • 1ST Step
Nonopioid Analgesics for mild to moderate pain1ST
STEP
p-Aminophenol derivative
COX-2–selective inhibitors
Patients who present with mild to moderate pain should be treat-ed with a nonopioid analgesic. An adjuvant drug should be used ifa specific indication for one exists. Adjuvant drugs include treat-ments for opioid side effects or other comorbid conditions and“adjuvant analgesics,” which are drugs with primary indicationsother than pain that are analgesic in selected circumstances.
Generic NameHalf-Life, h(approx)
Dosing Schedule
RecommendedStarting Dose,mg/d*
Maximum Recommended Dose, mg/d
Acetamin-ophen†
(paracetamol)
2-4 q4-6h 2,600 4,000
Comments
Overdose causes hepatic toxicity. Minimally anti-inflam-matory. May not be preferred as first-line analgesic orcoanalgesic in patients with bone pain. Its lack of GI orplatelet toxicity may be important in some cancerpatients. When used at high doses, liver function testsshould be done regularly.
Celecoxib† 11 q12h 200 600 Compared with other NSAIDs, COX-2 drugs are less toxic toGI tract and have no effect on platelets. Although expenseis a concern, many clinicians now prefer the COX-2–selec-tive drugs as first-line agents in medically frail or elderlypatients who may be predisposed to GI toxicity or unableto tolerate GI hemorrhage, should it occur. Adverse cardio-vascular effects that led to the withdrawal of rofecoxib andvaldecoxib are now believed to be a COX-2 effect, whichmay be important not only in the COX-2–selective subclassof NSAIDs, but also in the nonselective COX-1/COX-2 sub-class. In the US, the label for all NSAIDs now includes aboxed warning indicating that these drugs may increasethe risk of thrombotic events. Although the risk is small, itshould be assumed to be a class effect of NSAIDs generally.
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1ST Step • 1716 • 1ST Step
Aspirin† 3-12ll q4-6h 2,600 6,000 Standard for comparison. May not be tolerated as well assome of the newer NSAIDs.
Salicylates§
Choline magnesiumtrisalicylate†
9-17 q12h 1,500 × 1,then1,000q12h
4,000 Unlike other NSAIDs, choline magnesium trisalicylate andsalsalate cause minimal GI toxicity and have no effect onplatelet aggregation, despite potent anti-inflammatoryeffects. Although a better safety profile in cancer patients isnot confirmed, may be preferred in some cancer patientson this basis.
Diflunisal† 8-12 q12h 1,000 × 1,then 500q12h
1,500 Less GI toxicity than aspirin.
Salsalate 8-12 q12h 1,500 × 1,then1,000q12h
4,000 See comments for choline magnesium trisalicylate andendnote.
Generic NameHalf-Life, h(approx)
Dosing Schedule
RecommendedStarting Dose,mg/d*
Maximum Recommended Dose, mg/d Comments
Fenoprofen† 2-3 q4-6h 800 3,200 See endnote.
Flurbiprofen 5-6 q8-12h 100 300 See endnote.
Ibuprofen† 1.8-2 q4-8h 1,200 3,200 Available over the counter. See endnote.
Ketoprofen† 2-3 q6-8h 150 300 Available over the counter.
Propionic Acids§
Naproxen† 13 q12h 500 1,000 Available over the counter as tablets and as a suspension.Some studies show greater efficacy of higher doses, specifi-cally 1,500 mg/d, with little to no increase in adverseeffects; long-term efficacy of this dose and safety in amedically ill population are unknown. However, it shouldbe used cautiously.
See Key, Routes of Administration, and Endnotes, page 40.1STSTEP
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18 • 1ST Step 1ST Step • 19
Propionic Acids§
Generic NameHalf-Life, h(approx)
Dosing Schedule
RecommendedStarting Dose,mg/d*
Maximum Recommended Dose, mg/d Comments
Naproxen sodium†
13 q12h 550 1,100 Available over the counter. Some studies show greater effi-cacy of higher doses, specifically 1,650 mg/d, with little tono increase in adverse effects; long-term efficacy of thisdose and safety in a medically ill population are unknown.However, it should be used cautiously.
Oxaprozin 42-50 q24h 600 1,800 Once-daily dosing may be advantageous in some patients.
Diclofenac 2 q6h 150 200 Only immediate-release tablets are indicated for painmanagement.§
Etodolac† 7 q6-8h 600 1,200 See endnote.§
Indomethacin 4-5 q8-12h 75 200 Available in sustained-release and rectal formulations.Higher incidence of side effects, particularly GI and CNS,than with propionic acids.§
Ketorolac† 4-7 q6h 15-30 q6hI.V., IM 10 q6h PO
120 I.V., IM 40 PO
Parenteral formulation available. Use should be limited totreatment of acute pain; recommended maximum durationof treatment is 5 d.
Sulindac 7.8 q12h 300 400 See endnote.§
Acetic Acids
Tolmetin 2 q6-8h 600 1,800 See endnote.§
Nabumetone 20-35 q24h 1,000 2,000 Studies in noncancer populations suggest relatively goodsafety profile. Once-daily dosing may be advantageous.§
Naphthylalkanone
See Key, Routes of Administration, and Endnotes, page 40.1STSTEP
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1ST Step • 2120 • 1ST Step
Oxicams§
Generic NameHalf-Life, h(approx)
Dosing Schedule
RecommendedStarting Dose,mg/d*
Maximum Recommended Dose, mg/d Comments
Phenyl-butazone
50-100
q6-8h 300 400 Not a first-line drug because of risk for serious bone mar-row toxicity. Not preferred for cancer pain therapy. If used,need CBC every 2 wk for 1 mo, then monthly, in addition toother monitoring.
Meloxicam 15-20
q24h 7.5 15 COX-2 selective at lower doses.*
Piroxicam 50 q24h 20 40 Administration of 40 mg for >3 wk is associated with highincidence of peptic ulcer, especially in the elderly.
Meclofenamicacid†
1.3 q6-8h 150 400 See endnote.
Mefenamicacid†
2 q6h 500 × 1,then 250q6h
1,000 Not recommended for use longer than 1 wk, and thereforenot indicated in cancer pain therapy.
Pyrazole§
Fenamates§
See Key, Routes of Administration, and Endnotes, page 40.1STSTEP
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2nd Step • 2322 • 2nd Step
Generic Name Dosell Half-Life, h Peak Effect, h Duration h Toxicity
Meperidine(pethidine)
50 3-4 1-2 3-5 Same as morphine plusCNS excitation (eg, tremu-lousness, seizures) fromaccumulation of toxicmetabolite, normeperidine;prolonged, high dosingand renal insufficiencypredispose.
Morphine-Like AgonistsCodeine 32-65 2-3 1.5-2 3-6 Same as morphine.
Dihy-drocodeine
15-20 — — 4-5 Same as morphine.
Hydrocodone — 4 0.5-1 4-6 Same as morphine.
Short-Acting Opioids for moderate pain2ND
STEPPatients who fail the 1st-step regimen or who present with mod-erate pain should be treated with an oral opioid for moderatepain as well as with a nonopioid analgesic and an adjuvant drug,if the clinician has evidence for the efficacy of the adjuvant. Incurrent clinical practice, the 2nd step is applied flexibly; it may beskipped in lieu of treatment with a 3rd-step drug or primary
Comments
Usually combined with acetaminophen or an NSAID.
Only available combined withaspirin and caffeine.
Only available combined withacetaminophen, aspirin, oribuprofen.
Contraindicated in patientsusing MAO inhibitors, inwhom dangerous hyperther-mic syndrome may develop.
Oxycodone 2.5 — 1 3-6 Same as morphine. Considered a 2nd-step drugwhen combined with aspirinor acetaminophen. New com-bination product containingoxycodone and ibuprofenalso will be useful.
treatment with an adjuvant analgesic in selected syndromes. Inthe treatment of continuous pain, analgesics should be given ona regular basis—“by the clock”—so that the next dose is givenbefore the effect of the previous one wears off. These short-actingdrugs are also used as ”rescue” medications, given as needed forbreakthrough pain during treatment with a long-acting opioid.
See Key, Routes of Administration, and Endnotes, page 40.
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2nd Step • 2524 • 2nd Step
PropoxypheneHCl
65-130 12 2-2.5 3-6 Same as morphine plusseizures and cardiac toxicity with overdose.
Propoxyphenenapsylate
100-200
12 2-2.5 3-6 Same as hydrochloride.
Pentazocine 30 2-3 1.5-2 2-4 Same as morphine, withmore risk for psychotomi-metic effects and less riskfor respiratory depressionat high doses.
Generic Name Dosell Half-Life, h Peak Effect, h Duration h Toxicity
Morphine-like agonistsComments
Toxic metabolite, nor-propoxyphene, accumulateswith repetitive dosing but nor-propoxyphene toxicity doesnot appear to represent a clini-cally significant problem atthe doses typically used totreat pain (adults: 65 mg-130mg q4h prn, up to 3 dosesdaily); often combined withacetaminophen or an NSAID.
Same as propoxyphene HCI.
Can cause withdrawal symp-toms in opioid-dependentpatients; not recommendedfor cancer pain therapy.
Mechanism: binds to µ-opioidreceptor, weakly inhibits reup-take of norepinephrine andserotonin, enhances serotoninrelease; only 30% of analgesiais naloxone reversible; maxi-mum recommended dose400 mg/d (300 mg/d forpatients aged ≥75 y); higherdoses (eg, up to 600 mg/d)sometimes used. Seizure riskincreases if coadministeredwith drugs that lower seizurethreshold. Now also availablewith acetaminophen in acombination tablet.
Agonist–antagonist
Other
See Key, Routes of Administration, and Endnotes, page 40.2NDSTEP
Generic Name Dose¶ Half-Life, h Peak Effect, h Duration h Toxicity
Morphine-Like AgonistsComments
Standard of comparison foropioids. Multiple routes avail-able (see Routes of Adminis-tration). Survey data indicatethat a switch from immedi-ate-release morphine to con-trolled-release morphineshould be done at same mil-ligram dose. Pharmacokinet-ics of newer extended-releaseformulation may suggestonce-daily administration.
Hydro-morphone
1.5 IM;7.5 PO
2-3—
0.5-11-2
4-54-5
Same as morphine. Multiple routes available (see Routes of Administration).May become available as amodified-release formulationwith a long duration of effect.
Meperidine(pethidine)
75 IM;300PO
3-4 0.5-11-2
2-43-6
Same as morphine + CNSexcitation; contraindicatedin those on MAO inhibitors.
Not preferred for cancer painbecause of potential toxicity.
Patients who fail the 2nd-step regimen or who present with moderate to severe pain should be treated with an opioid indicated for such pain. The clinician should consider the additionof a nonopioid analgesic or an adjuvant drug. In the treatmentof persistent pain, analgesics should be given on a regular basis—“by the clock”—so that the next dose is given before the effectof the previous one wears off.
Short and Long-Acting Opioids for moderate to severe pain3RD
STEP
See Key, Routes of Administration, and Endnotes, page 40.Short-Acting
¶Dose that provides analgesia equivalent to 10 mg of IM morphine.
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3rd Step • 2928 • 3rd Step
Oxymorphone 1 IM;10 PR
——
0.5-11.5-3
3-64-6
Same as morphine.
Generic Name Dose¶ Half-Life, h Peak Effect, h Duration h Toxicity
Morphine-Like AgonistsComments
No oral formulation. Maybecome available as an oralformulation, including amodified-release formulation.
Oral transmucosalfentanyl citrate (OTFC®)
800mcgPO
6 0.3-0.5 Related to blood levels of the drug
Same as morphine. No relationship existsbetween effective OTFC® res-cue dose and baseline opioiddose. Therefore, all patientsshould be started on a rela-tively low dose (200 mcg) and dose should be titratedto effect. This contrasts withguidelines recommending rescue opioid dosing at 5%-15% of total daily opioid dose.
Oxycodone 20-30PO
2-4 1 3-6 Same as morphine. Available as a single agentand in combination withaspirin or acetaminophen;at higher doses used as a single agent for patients with severe pain or who havedeveloped tolerance; no parenteral formulation.
Agent Indicated for Breakthrough PainIn Patients With Cancer
See Key, Routes of Administration, and Endnotes, page 40.
¶Dose that provides analgesia equivalent to 10 mg of IM morphine.
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3rd Step • 3130 • 3rd Step
Mixed Agonists–Antagonists
Generic Name Dose¶ Half-Life, h Peak Effect, h Duration h Toxicity Comments
Butorphanol 2 IM 2-3 0.5-1 3-4 Same profile of effects aspentazocine, except forlower risk for psychoto-mimetic effects.
Partial Agonist
Agonist–antagonist. No oralformulation; may cause with-drawal in opioid dependentpatients; not recommendedfor cancer pain therapy.
Buprenorphine 0.4 IM 2-5 0.5-1 6-8 Same as morphine, exceptless risk for respiratorydepression at higher doses.
May cause withdrawal symp-toms in opioid-dependentpatients; has ceiling for anal-gesia and less abuse potential;sublingual tablets available inUnited States; may be usefulin nondependent/nontolerantpatients with cancer pain (ie,on the 2nd step of the anal-gesic ladder).
Nalbuphine 10 IM 4-6 0.5-1 3-6 Same as pentazocine,except for lower risk forpsychotomimetic effects.
Agonist–antagonist. No oralformulation; may cause withdrawal symptoms in opioid-dependent patients;not recommended for cancerpain therapy.
Pentazocine 60 IM;180 PO
2-3—
0.5-11-2
3-63-6
Same as buprenorphine,except for greater risk forpsychotomimetic effects.
Agonist–antagonist. Oral prepa-ration combined with naloxoneor acetaminophen in UnitedStates; may cause withdrawalsymptoms in opioid-dependentpatients; not recommended forcancer pain therapy.
Morphine-Like AgonistsLevorphanol 2 IM;
4 PO.11-16 0.5-1 6-8 Same as morphine. With long half-life, accumula-
tion occurs after dose is begunor increased.
See Key, Routes of Administration, and Endnotes, page 40.
Long-Acting
¶Dose that provides analgesia equivalent to 10 mg of IM morphine.
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3rd Step • 3332 • 3rd Step
Methadone 10 IM;20 PO
15-150+ 0.5-1.5 4-8 Same as morphine. Available as a racemate; theD-isomer is an NMDA an-tagonist, which may accountfor unexpectedly high poten-cy in some patients who areswitched from another drug.This uncertainty about poten-cy, together with concernabout a long and variablehalf-life, necessitates cautionin the use of this drug. Whena patient is switched fromanother drug, the calculatedequianalgesic dose should bereduced by 75% to 90%. Pro-longed monitoring may beneeded during dose titration.Multiple routes available.
Generic Name Dose¶ Half-Life, h Peak Effect, h Duration h Toxicity Comments
Fentanyl transdermalsystem
25mcg/h
17 24-72 72 Same as morphine. Patches of different sizes candeliver 12, 25, 50, 75, or 100mcg/h. Dosing interval is 48 to 72 h. Dose usually adjustedevery 3 d if needed, and multi-ple patches may be used.
Modified-release morphine
20-60PO**
2-3 3-4 8-24 Same as morphine. Available formulations vary induration of effect—from 8-12h, to 12-24 h, to 24 h.
Modified-release oxycodone
20-30PO
2-4 3-4 8-12 Same as morphine. Available as a single agentand in combination withaspirin or acetaminophen; athigher doses used as a singleagent for patients with severepain or who have developedtolerance; no parenteralformulation.
Morphine-like agonists
See Key, Routes of Administration, and Endnotes, page 40.
¶Dose that provides analgesia equivalent to 10 mg of IM morphine.
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Adjuvant Analgesics • 3534 • Adjuvant Analgesics
Adjuvant AnalgesicsAdjuvant analgesics comprise diverse classes of drugs that haveother indications but also have analgesic properties in specific circumstances. These drugs should be used when theclinician has evidence of their utility.
Extensive survey dataand controlledtrials supportefficacy in neuropathicpain.
Neuropathicpain
Carbamazepine,gabapentin,lamotrigine,pregabalin
Variable Variable Variable Gabapentin is nowwidely used, but manyother anticonvulsantscan be considered. Pre-gabalin, an anticonvul-sant with a mechanismsimilar to that ofgabapentin, was recent-ly approved and hasbeen studied extensive-ly as an analgesic.
Rationale for Use Application ExamplesDosing Schedule Starting Dose, mg/d
Usual Daily Dose, mg/d Comments
Anticonvulsants
AntidepressantsProven anal-gesics in a variety of non-malignantpain states.
Variable Variable Variable Begin after opioidtitrated. Evidence bestfor tricyclic drugs.Although minimal sup-porting data for sero-tonin-selective drugs,paroxetine has somesupport. Better supportfor mixed-mechanismdrugs including duloxe-tine and venlafaxine.
See Key, Routes of Administration, and Endnotes, page 40.
Other Sodium Channel BlockersControlledstudies in pain-ful diabeticneuropathy.
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Adjuvant Analgesics • 3736 • Adjuvant Analgesics
Rationale for Use Application ExamplesDosing Schedule Starting Dose, mg/d
Usual Daily Dose, mg/d Comments
Extensive anec-dotal experi-ence in thetreatment ofpain and othersymptoms confirmed by a single controlledstudy ofmethylpred-nisolone.
Pain frominfiltrationof neuralstructures;bone pain;pain in pa-tients withfar-advanceddisease
Dexamethasone q6-12h Variable (eg, 10-20 mg × 1, then 4 mgq6h or less)
2-24 Higher doses used inepidural cord com-pression and variouspain emergencies;lower doses suggestedin other conditions.Dexamethasone maybe preferred becauseof low mineralo-corticoid effect, butothers have been used(eg, prednisone).
Corticosteroids
Controlledstudy intrigeminalneuralgia.
Neuropathicpain
Baclofen q8h 15 30-120Miscellaneous
Controlledstudy andanecdotalreports.
Refractorybone painand neuro-pathic pain
Calcitonin q12h 200 IU 200-400 IU
See Key, Routes of Administration, and Endnotes, page 40.
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References
References • 41
* Consider using lower than recommended starting dose in the elderly, in patients on multiple drugs, and in those withrenal insufficiency (one half to two thirds recommended dose).Doses must be individualized. Low initial doses should be titrated upward if tolerated and clinical effectis inadequate. Doses can be increased in weekly increments.Studies of NSAIDs in the cancer population are meager;thus dosing guidelines are empiric.
† Although clinical experience suggests that any of the NSAIDs may be analgesic, pain is an approved indication only for those drugs noted.
‡ Half-life for aspirin increases with dose.
§ At relatively high doses, consider monitoring for adverseeffects, eg, by checking for occult fecal blood or for changes inliver function tests, blood urea nitrogen and creatinine assess-ments, or urinalysis.
ll Oral dose that provides analgesia equivalent to 650 mg ofaspirin. Starting dose may be higher or lower, and dose titration is needed after therapy is begun.
¶ Dose that provides analgesia equivalent to 10 mg of IMmorphine. The equianalgesic dose should not be interpreted as the starting, standard, or maximum dose,but rather as a guide; particularly useful in switching drugs or changing routes of administration. Dependingon patient characteristics and prior opioid exposure,the starting dose can be lower or higher, and dosetitration—either upward or downward—is repeatedlynecessary in virtually all patients.
** Extensive survey data suggest that the relative potency of IM to PO morphine of 1:6 changes to 1:2 or 1:3 with long-term dosing.
14. Carr DB, Goudas LC, Denman WT, et al. Safety and efficacy ofintranasal ketamine for the treatment of breakthrough painin patients with chronic pain: a randomized, double-blind,placebo-controlled, crossover study. Pain. 2004;108:17-27.
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17. Mercadante S, Villari P, Ferrara P, et al. Safety and effectivenessof intravenous morphine for episodic (breakthrough) painusing a fixed ratio with the oral daily morphine dose.J Pain Symptom Manage. 2004;27:352-359.
18. Mercadante S, Portenoy RK. Opioid poorly-responsive cancer pain. Part 1: Clinical considerations. J Pain SymptomManage. 2001;21:144-150.