Step Laddr

INDEPENDENTLY DEVELOPED BY MCMAHON PUBL ISH ING ANESTHES IOLOGY NEWS SPEC IAL ED IT ION 2007 33

ancer pain is extremely

prevalent, occurring in more

than three fourths of

patients with advanced disease.

Numerous studies have confirmed

that the experience of unrelieved

pain has potentially devastating

effects on quality of life. The

effective management of pain is a

therapeutic imperative and central

to the palliative care provided to

all cancer patients.

Pain continues to be undertreated, despite 2decades that have witnessed the development of con-sensus-based guidelines for the management of can-cer pain and intensive educational efforts on the partof professional societies, the philanthropic community,and industry. Undertreatment cannot be condoned,particularly in light of available evidence that pharma-cotherapy with both opioid and nonopioid drugs canprovide adequate relief to most patients. Although amultimodality strategy can augment pain relief, dimin-ish the effect of pain that persists, and improve relatedoutcomes, the mainstay approach to moderate orsevere cancer pain continues to be opioid-based ther-apy. The analgesic ladder, which was promulgated bythe World Health Organization in the late 1980s, wasthe first guideline to codify an opioid-based treatmentfor cancer pain. Combined with straightforward dosingguidelines, it has had a significant effect on practice

around the world. Although more recent guidelinesemphasize the need for flexibility and the potentialvalue of skipping steps and selecting specific drugsbased on patient assessment, all continue to empha-size the value of opioids for moderate to severechronic pain, the importance of dose individualizationthrough a process of repeated titration, the use of anal-gesic polypharmacy in many cases, and the ongoingneed to manage side effects to optimize the balancebetween pain relief and adverse drug effects.

Breakthrough pain (BTP)episodic pain thatbreaks through analgesic therapy in populationswith chronic painis a serious clinical problem, likelyafflicting thousands of patients. Despite its seriousness,BTP is underappreciated by clinicians.

The terminology used to describe BTP has been

Three-Step Analgesic Ladder For Management of Cancer Pain

C

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

PRINTER-FRIENDLY VERSION AT ANESTHESIOLOGYNEWS.COM

Update on Breakthrough Pain

Russell K. Portenoy, MD has, during the past five years, acted as a consultant,received grant support, or both from the following companies: Abbott Laboratories,Adolor Corporation, Alpharma, Anesiva, Inc., Archimedes Pharma Ltd., AscentBiomedical Ventures, Aveva Drug Delivery Systems, Baxter Laboratories, Bayer,BioDelivery Sciences, Biometrix, Biovail, Cephalon, Inc., CombinatoRx, Inc., CytogelInc., Endo Pharmaceuticals, Fralex Therapeutics Inc., Genentech, GlaxoSmithKline,GloboMax, GPC Biotech, GW Pharmaceutical, Janssen/Ortho-McNeilPharmaceuticals, Johnson & Johnson, King Pharmaceuticals Inc., LigandPharmaceuticals, Merck, Nektar Therapeutics, Neuromed Pharmaceuticals, Novartis,Organon, PainCeptor, Pharmos, Pfizer, PPD, Progenics Pharmaceuticals, SarentisTherapeutics, United BioSource & Co., Inc., Valeant Pharmaceuticals North America,Xenome Ltd, Xenon Pharmaceuticals, and Wyeth.

3-Step pain ANSE07 10/2/07 5:05 PM Page 33

Copyright 2007 M

cMahon Publishing Group unless otherw

ise noted.

All rights reserved. Reproduction in whole or in part w

ithout permission is prohibited.

widely debated, and various definitions have beencreated and published in the medical literature.1 Thebroadest definition is probably the most useful: BTP isany transient and clinically significant pain that flaresover baseline pain that is adequately controlled byany analgesic regimen.1-4

EPIDEMIOLOGY, IMPACT, AND CHARACTERISTICSStudies of populations of patients with cancer pain

have revealed that 50% to 90% of them experienceBTP.2-7 In a survey of hospice patients without cancer,63% had BTP.8 A survey of with chronic noncancerpain patients identified a prevalence of 74% amongthose taking opioid analgesics.9 Among cancerpatients, BTP is associated with a more severe painsyndrome,3-5 reduced responsiveness to opioid thera-py,10,11 pain-related functional impairment and psycho-logical distress,5 and an increase in the economic bur-den for patients and the healthcare system.12

Although characteristics and location of a patientsBTP are usually the same as those for the patientsbaseline pain, there are notable differences in howBTP manifests between individuals.1,3-9 The frequencyof flares varies from fewer than 1 per day to many perhour; most patients experience approximately 3 flaresper day. Most episodes are brief (

transmucosal administration.If the rescue dose causes treatment-limiting side

effects, various strategies may be considered in a man-ner identical to the approach to patients with a poorresponse to a regularly scheduled opioid regimen.19

These include rotation of the rescue drug or the entireregimen to a different opioid, coadministration of a drugto treat the side effect, and coadministration of a phar-macologic or nonpharmacologic approach to reducethe opioid requirement.

The importance of the opioid rescue dose shouldnot obscure the potential benefits of other approach-es. For example, neuropathic BTP may respond to theadministration of an adjuvant analgesic, usually an anti-depressant or anticonvulsant.13,20 Nonpharmacologictreatments are very helpful for some and include cogni-tive strategies (particularly if BTP is predictable), physi-cal therapy or bracing, and various complementarytreatments. Interventional approaches, such as injectiontherapies, neural blockade, and neuraxial analgesia, mustbe considered if BTP is refractory to other strategies.

References1. Mercadante S, Radbruch L, Caraceni A, et al. Episodic (break-

through) pain. Consensus conference of an expert working groupof the European Association for Palliative Care. Cancer. 2002;94:832-839.

2. Svendsen KB, Andersen S, Arnason S, et al. Breakthrough pain inmalignant and non-malignant diseases: a review of prevalence,characteristics and mechanisms. Eur J Pain. 2005;9:195-206.

3. Caraceni A, Martini C, Zecca E, Portenoy RK, a Working Group ofan IASP Task Force on Cancer Pain. Breakthrough pain characteris-tics and syndromes in patients with cancer pain: an internationalsurvey. Palliat Med. 2004;18:177-183.

4. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalenceand characteristics. Pain. 1990;41:273-281.

5. Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteris-tics and impact in patients with cancer pain. Pain. 1999;81:129-134.

6. Fine PG, Busch MA. Characterization of breakthrough pain by hos-pice patients and their caregivers. J Pain Symptom Manage.1998;16:179-183.

7. Hwang SS, Chang VT, Kasimis B. Cancer breakthrough pain charac-teristics and responses to treatment at a VA medical center. Pain.2003;101:55-64.

8. Zeppetella G, ODoherty CA, Collins S. Prevalence and characteris-tics of breakthrough pain in patients with non-malignant terminaldisease admitted to a hospice. Palliat Med. 2001;15:243-246.

9. Portenoy RK, Bennett D, Rauck R, et al. The prevalence and char-acteristics of breakthrough pain in opioid treated patients withchronic non-cancer pain. J Pain. 2006;7:583-591.

10. Mercadante S, Maddaloni S, Roccella S, et al. Predictive factors inadvanced cancer pain treated only by analgesics. Pain. 1992;50:151-155.

11. Bruera E, Schoeller T, Wenk R, et al. A prospective multicenterassessment of the Edmonton staging system for cancer pain. JPain Symptom Manage. 1995;10:348-355.

12. Fortner BV, Okon TA, Portenoy RK. A survey of pain-related hospi-talizations, emergency department visits, and physician office vis-its by cancer patients with and without breakthrough pain. Pain.2002;3:38-44.

13. Mercadante S, Villari P, Ferrera P, Casuccio A. Optimization ofopioid therapy for preventing incident pain associated with bonemetastases. J Pain Symptom Manage. 2004;28:505-510.

14. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomizeddouble-blind, placebo-controlled crossover study. Pain.2004;108:17-27.

15. Christie JM, Simmonds M, Patt R, et al. Dose-titration, multicen-ter study of oral transmucosal fentanyl citrate for the treatmentof breakthrough pain in cancer patients using transdermal fen-tanyl for persistent pain. J Clin Oncol. 1998;16:3238-3245.

16. Hanks GW, Nugent M, Higgs CM, et al. Oral transmucosal fentanylcitrate in the management of breakthrough pain in cancer: anopen, multicentre, dose-titration and long-term use study. PalliatMed. 2004;18:698-704.

17. Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, place-bo-conrolled study of fentanyl buccal tablet for breakthrough painin opioid-treated patients with cancer. Clin J Pain. 2006;22:805-811.

18. Mercadante S, Villari P, Ferrara P, et al. Safety and effectiveness ofintravenous morphine for episodic (breakthrough) pain using afixed ratio with the oral daily morphine dose. J Pain SymptomManage. 2004;27:352-359.

19. Mercadante S, Portenoy RK. Opioid poorly-responsive cancerpain. Part 1: Clinical considerations. J Pain Symptom Manage.2001;21: 144-150.

20. Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in cancerpain management. Oncologist. 2004; 9:571-591.

INDEPENDENTLY DEVELOPED BY MCMAHON PUBL ISH ING 35

Although the oral and transdermal routes are preferred,alternative routes of administration will be required for asubstantial 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 surveydata available.

Intranasal: Available for butorphanol; not used in cancerpain management.

Intrathecal: Repetitive bolus; continuous infusion: Clearestindication is pain in lower body with poor relief and sideeffects from systemic opioids. Epidural catheter can be per-cutaneous (from lumbar region or tunneled to abdomen) orconnected to subcutaneous portal, depending on patientslife expectancy. Intrathecal usually administered via implant-ed pump. Benefits of long-term intrathecal infusion inselected patients demonstrated in randomized trial (SmithTJ, et al. J Clin Oncol. 2002;20:4040-4049). Morphine,hydromorphone, fentanyl, and others in use, combined withlocal anesthetic or clonidine.

Intravenous: Repetitive bolus; continuous infusion; PCA(with or without infusion): Indicated if other routes areunavailable or not tolerated, or if patient has an indwellingI.V. access device.

Oral: Preferred route of administration for long-acting opioids in cancer pain management. Transdermal available forfentanyl.

Oral transmucosal: Controlled clinical studies of oral trans-mucosal fentanyl citrate show efficacy in cancer-relatedbreakthrough pain.

Rectal: Available for morphine, oxymorphone, and hydro-morphone. Although few studies available, customarily usedas if dose is equianalgesic to oral dose.

Subcutaneous: Repetitive bolus; continuous infusion; continu-ous infusion with PCA: Ambulatory infusion pumps permitoutpatient continuous infusion. Can be accomplished withany parenteral drug. Drug mixtures to treat multiple symp-toms and long-term hydration also feasible by this route.

Sublingual: Buprenorphine effective, and sublingual tabletavailable in the United States. Efficacy of morphine controversial.

Transdermal: Available for fentanyl.

Routes of Administration


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INDEPENDENTLY DEVELOPED BY MCMAHON PUBL ISH ING36

Generic NameDosingSchedule

Recom-mended StartingDose, mg/d*Class

Acetamino-phen (parac-etamol)

2-4 q4-6h 2,600 4,000p-Aminophenolderivative

Salicylates

Comments See Key, Endnotes, and Routes of Administration

Overdose causes hepatic toxicity. Minimally anti-inflammato-

ry. May not be preferred as first-line analgesic or coanalgesic

in patients with bone pain. Its lack of GI or platelet toxicity

may be important in some cancer patients. When used at

high doses, liver function tests should be done regularly.

Standard for comparison. May not be tolerated as well as

some of the newer NSAIDs.

Choline magnesium trisalicylate

9-17 q12h 1,500 1, then1,000q12h

4,000

Diflunisal 8-12 q12h 1,000 1, then500q12h

1,500 Less GI toxicity than aspirin.

Salsalate 8-12 q12h 1,500 1, then1,000q12h

4,000 See comments for choline magnesium trisalicylate and endnote.

NONOPIOID ANALGESICS For Mild to Moderate Pain

STST

STEPSTEP11

Celecoxib 11 q12h 200 600

Fenoprofen 2-3 q4-6h 800 3,200Propionic acids

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.

Ketoprofen 2-3 q6-8h 150 300 Available over the counter.

COX-2selectiveinhibitors

Compared with other NSAIDs, COX-2 drugs are less toxic to

GI tract and have no effect on platelets. Although expense is

a concern, many clinicians now use the COX-2selective

drugs as first-line agents in medically frail or elderly patients

who may be predisposed to GI toxicity or unable to tolerate

GI hemorrhage, should it occur. Adverse cardiovascular

effects that led to the withdrawal of rofecoxib and valde-

coxib are now believed to be a COX-2 effect, which may be

important not only in the COX-2selective subclass of

NSAIDs, but also in the nonselective COX-1/COX-2 subclass.

In the United States, the label for all NSAIDs now includes a

boxed warning indicating that these drugs may increase the

risk of thrombotic events. Although the risk is small, it should

be assumed to be a class effect of NSAIDs generally.

Half-Life, h(approx)

2,600 6,0003-12ll q4-6hAspirin

Unlike other NSAIDs, choline magnesium trisalicylate and

salsalate cause minimal GI toxicity and have no effect on

platelet aggregation, despite potent anti-inflammatory

effects. Although a better safety profile in cancer patients

is not confirmed, may be preferred in some cancer patients

on this basis.

Maximum Recom-mended Dose,mg/d


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Patients who present with mild to moderate pain should be treated with a nonopioid analgesic. An adjuvant drug should be used if a specific indication for one exists. Adjuvant drugs include treatments

for opioid side effects or other comorbid conditions and adjuvant analgesics, which are drugs with primary indications other than pain that are analgesic in selected circumstances.

Generic Name

Half-Life, h(approx)

DosingSchedule

RecommendedStarting Dose,mg/d*

Maximum Recommended Dose, mg/dClass Comments See Key, Endnotes, and Routes of Administration

Naproxen 13 q12h 500 1,000

Naproxen sodium

13 q12h 550 1,100

Oxaprozin 42-50

q24h 600 1,800 Once-daily dosing may be advantageous in some patients.

Diclofenac 2 q6h 150 Only immediate-release tablets are indicated for pain management.

Etodolac 7 q6-8h 600 See endnote.

4-5 75

Ketorolac 4-7 q6h

Sulindac 7.8 q12h

Tolmetin 2 q6-8h 600

See endnote.

Acetic acids

Propionic acids

(cont.)

Nabumetone 20-35

q24h 1,000Naphthyl-alkanone

Meloxicam 15-20 7.5Oxicams

Fenamates

COX-2 selective at lower doses.*

Phenylbutazone 50-100

q6-8h 300Pyrazole 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 to

other monitoring.

Piroxicam 50 q24h

Meclofenamicacid

1.3 q6-8h 150 See endnote.

Mefenamic acid

2 q6h 500 1,then 250q6h

Not recommended for use longer than 1 wk, and therefore

not indicated in cancer pain therapy.

Available over the counter as tablets and as a suspension.

Some studies show greater efficacy of higher doses,

specifically 1,500 mg/d, with little to no increase in

adverse effects; long-term efficacy of this dose and safety

in a medically ill population is unknown. However, it should

be used cautiously.

Available over the counter. Some studies show greater

efficacy of higher doses, specifically 1,650 mg/d, with little

to no increase in adverse effects; long-term efficacy of this

dose and safety in a medically ill population is unknown.

However, it should be used cautiously.

Indomethacin

15-30 q6hI.V., IM 10 q6h PO

200

1,200

200

120 I.V., IM40 PO

400

1,800

2,000

15

400

40

400

1,000

q8-12h

Available in sustained-release and rectal formulations.

Higher incidence of side effects, particularly GI and CNS,

than with propionic acids.

Parenteral formulation available. Use should be limited to

treatment of acute pain; recommended maximum duration

of treatment is 5 d.

300

See endnote.

Studies in noncancer populations suggest relatively good

safety profile. Once-daily dosing may be advantageous.

q24h

20 Administration of 40 mg for >3 wk is associated with highincidence of peptic ulcer, especially in the elderly.


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Generic Name Dose (mg)ll Half-Life, hPeak Effect, h Duration, hClass

Codeine 32-65 2-3 1.5-2 3-6Morphine-like agonists

Tramadol 6-7 2-3 4-6Other

Dihydrocodeine 15-20 4-5

Hydrocodone 4 0.5-1 4-6

Meperidine (pethidine)

50 3-4 1-2 3-5

Oxycodone 2.5 1 3-6

Propoxyphene HCl 65-130

12 2-2.5 3-6

Propoxyphene napsylate 100-200 12 2-2.5 3-6

Pentazocine 30 2-3 1.5-2 2-4Agonistantagonist

SHORT-ACTING OPIOIDS For Moderate Pain

NDND

STEPSTEP22


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Toxicity Comments See Key, Endnotes, and Routes of Administration

Same as morphine. Usually combined with acetaminophen or an NSAID.

Dizziness, nausea, constipation most common; seizure rare.

Mechanism: binds to mu-opioid receptor, weakly inhibits reuptake of norepinephrine

and serotonin, enhances serotonin release; only 30% of analgesia is naloxone

reversible; maximum recommended dose 400 mg/d (300 mg/d for patients aged

75 y); higher doses (eg, up to 600 mg/d) sometimes used. Seizure risk increases if coadministered with drugs that lower seizure threshold. Also available in an

extended-release formulation and with acetaminophen in a combination tablet.

Same as morphine. Only available combined with aspirin and caffeine.

Same as morphine. Only available combined with acetaminophen, aspirin, or ibuprofen.

Same as morphine plus CNS excitation (eg, tremulousness, seizures) from accumulation of toxic metabolite, normeperidine; prolonged, highdosing and renal insufficiency predispose.

Contraindicated in patients using MAO inhibitors, in whom dangerous

hyperthermic syndrome may develop.

Same as morphine. Considered a 2nd-step drug when combined with aspirin or acetaminophen. Newcombination product containing oxycodone and ibuprofen also will be useful.

Same as morphine plus seizures and cardiactoxicity with overdose.

Toxic metabolite, norpropoxyphene, accumulates with repetitive dosing but

norpropoxyphene toxicity does not appear to represent a clinically significant

problem at the doses typically used to treat pain (adults: 65 mg-130 mg q4h prn,

up to 3 doses daily); often combined with acetaminophen or an NSAID.

Same as hydrochloride. Same as propoxyphene HCI.

Same as morphine, with more risk forpsychotomimetic effects and less risk for respi-ratory depression at high doses.

Can cause withdrawal symptoms in opioid-dependent patients; not recommended

for cancer pain therapy.

Patients who fail the 1st-step regimen or who present with moderate pain should be treated with an oral opi-oid for moderate pain as well as with a nonopioid analgesic and an adjuvant drug, if the clinician has evidence

for the efficacy of the adjuvant. In current clinical practice, the 2nd step is applied flexibly; it may be skipped inlieu of treatment with a 3rd-step drug or primary treatment with an adjuvant analgesic in selected syndromes.In the treatment of continuous pain, analgesics should be given on a regular basisby the clockso that the

next dose is given before the effect of the previous one wears off. These short-acting drugs are also used asrescue medications, given as needed for breakthrough pain during treatment with a long-acting opioid.


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Generic NameDose(mg)

Half-Life, h

Peak Effect,h Duration, hClass

Fentanyl trans-dermal system

25mcg/h

17 24-72 72

Toxicity

Same as morphine.

Hydromorphone 1.5 IM7.5 PO

2-3

0.5-11-2

4-54-5

Same as morphine.

Levorphanol 2 IM4 PO

11-16 0.5-1 6-8 Same as morphine.

Meperidine(pethidine)

75 IM300 PO

3-4 0.5-11-2

2-43-6

Same as morphine + CNS excitation; contraindicated in those on MAO inhibitors.

Methadone 10 IM20 PO

15-150+

0.5-1.5

4-8 Same as morphine.

Morphine 10 IM20-60PO**

32-4

0.5-11-2

64-7

Constipation, nausea, sedation most common; respiratory depression most serious; itch, dry mouth, urinary retention uncommon; sexual dysfunction possible; hypotension and inappropriate ADH secretion rare.

Modified-releasemorphine

20-30PO**

2-3 3-4 8-24 Same as morphine.

Oxycodone 20-30PO

2-4 1-2 3-6

Modified-release oxycodone

15-20PO

2-4 3-4 8-12

Oxymorphone 1 IM10 PR

0.5-11.5-3

3-64-6

Same as morphine.

Butorphanol 2 IM 2-3 0.5-1 3-4Mixedagonistsantagonists

Same profile of effects as pentazocine, except for lower risk for psychotomimetic effects.

Nalbuphine 10 IM 4-6 0.5-1 3-6 Same as pentazocine, except for lower risk for psychotomimetic effects.

Pentazocine 60 IM180 PO

2-3

0.5-11-2

3-63-6

Same as buprenorphine, except for greater risk for psychotomimetic effects.

Buprenorphine 0.4 IM 2-5 0.5-1 6-8Partialagonist

Same as morphine, except less risk for respiratory depression at higher doses; may cause withdrawal symptoms in patients who are physically dependent to an opioid;sublingual formulations available for the office-based treatment of opioid addiction and may be used off-label for pain.

Same as morphine.

Morphine-like agonists

Oral transmucosal fentanyl citrate(OTFC)

800mcgPO

6 0.3-0.5

Related toblood levelsof the drug

Morphine-like agonists

Same as morphine.

Short-Acting

Long-Acting

Agents specifically indicated forbreathroughcancer pain in patients with cancer

Same as morphine.

Fentanyl buccaltablet

1.5-28

0.5-0.75

Same as morphine.

Modified-releaseoxymorphone

10-15 7-9 3-4 12 Same as morphine.

SHORT- AND LONG-ACTINGOPIOIDS for Moderate toSevere Pain

RDRD

STEPSTEP33


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Patients who fail the 2nd-step regimen or who present with moderate to severe pain should be treatedwith an opioid indicated for such pain. The clinician should consider the addition of a nonopioid analgesic

or an adjuvant drug. In the treatment of persistent pain, analgesics should be given on a regular basisbythe clockso that the next dose is given before the effect of the previous one wears off.

Comments See Key, Endnotes, and Routes of Administration

Patches of different sizes can deliver 12, 25, 50, 75, or 100 mcg/h. Dosing interval is 48 to 72 h. Dose usually adjusted every 3d if needed, and multiple patches may be used.

Multiple routes available (see Routes of Administration). May become available as a modified-release formulation with a longduration of effect.

With long half-life, accumulation occurs after dose is begun or increased.

Not preferred for cancer pain because of potential toxicity.

Available as a racemate; the D-isomer is an NMDA antagonist, which may account for unexpectedly high potency in some patients who are switched from another drug. This uncertainty about potency, together with concern about a long and variablehalf-life, necessitates caution in the use of this drug. When a patient is switched from another drug, the calculated equianalgesicdose should be reduced by 75% to 90%. Prolonged monitoring may be needed during dose titration. Multiple routes available.

Standard of comparison for opioids. Multiple routes available (see Routes of Administration). Survey data indicate that aswitch from immediate-release morphine to controlled-release morphine should be done at same milligram dose. Available inseveral modified-release formulations for once-daily or twice-daily administration.

Available formulations vary in duration of effectfrom 8-12 h, to 12-24 h, to 24 h.

Agonistantagonist. No oral formulation; may cause withdrawal symptoms in patients who are physically dependent to an opioid; not recommended for cancer pain therapy.

Agonistantagonist. No oral formulation; may cause withdrawal symptoms in patients who are physically dependent to an opioid; not recommended for cancer pain therapy.

Agonistantagonist. Oral preparation combined with naloxone or acetaminophen in United States; may cause withdrawal symptoms in patients who are physically dependent to an opioid; not recommended for cancer pain therapy.

May cause withdrawal symptoms in opioid-dependent patients; has ceiling for analgesia and less abuse potential; sublingualtablets available in United States; may be useful in nondependent/nontolerant patients with cancer pain (ie, on the 2nd step ofthe analgesic ladder).

Efficacy and safety in the treatment of cancer-related breakthrough pain has been established in controlled trials. Onset is fasterthan oral rescue doses. No relationship exists between effective OTFC rescue dose and baseline opioid dose. Therefore, allpatients should be started on a relatively low dose (200 mcg or 400 mcg) and dose should be titrated to effect. This contrastswith guidelines recommending rescue opioid dosing at 5% to 15% of total daily opioid dose.

Available as an immediate-release agent and in combination with aspirin or acetaminophen; no parenteral formulation.

Fraction absorbed transmucosally is twice that of OTFC, and therefore is twice as potent; peak effect is earlier than that ofOTFC.

Available as an immediate-release agent.

Available in a modified-release formulation for twice-daily dosing.

Available as a single agent and in combination with aspirin or acetaminophen; at higher doses used as a single agent forpatients with severe pain or or who have developed tolerance; available in a modified-release formulation for twice-daily orthree times daily administration; no parenteral formulation.


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ADJUVANT ANALGESICS

Extensive survey dataand controlled trials sup-port efficacy in neuro-pathic pain.

Neuropathic pain Clonazepam,gabapentin, lamotrigine, pregabalin

Variable VariableAnticon-vulsants

Proven analgesia in avariety of nonmalignantpain states.

Neuropathic pain; pain complicated bydepression or insomnia

Desipramine (a TCA),duloxetine and ven-lafaxine (SNRIs), parox-etine and citalopram(SSRIs)

Variable VariableAntidepres-sants

Controlled study intrigeminal neuralgia.

Neuropathic pain Baclofen q8h 15

Controlled studies andanecdotal reports.

Refractory bone painand neuropathic pain

Calcitonin Daily 200 IU

Controlled studies inpainful diabetic neuropathy.

Neuropathic pain q8hMexiletine 450Other sodiumchannel blockers

Extensive anecdotalexperience in the treat-ment of pain and othersymptoms confirmed by a single controlled studyof methylprednisolone.

Pain from infiltration ofneural structures; bonepain; pain in patientswith far-advanced dis-ease

Dexamethasone q6-12h Variable (eg, 10-20 mg 1, then 4 mg q6h or less)

Corticosteroids

Rationale for Use Application Examples Dosing Schedule Starting Dose, mg/dClass

Adjuvant analgesics comprise diverse classes of drugs that have otherindications but also have analgesic properties in specific circumstances.

These drugs should be used when the clinician has evidence of their utility.

Clinical experience and controlled trials of dextroamphetamine inpostoperative pain andmethylphenidate in cancer pain.

Reversal of opioid-induced sedation

MethylphenidateDextroamphetamineModafinil

bidbidqd

55100

Psycho-stimulants

Controlled studies andanecdotal reports.

Refractory bone pain Bisphosphonates(pamidronate)

Variable 60

Controlled study. Refractory bone pain Strontium 89Samarium 153

Anecdotal reports. Pain due to bowelobstruction

Anticholinergic drugs (eg, scopolamine and glycopyrrolate), octreotide

Variable Variable

Miscellaneous


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Variable Gabapentin is now widely used, butmany other anticonvulsants can be

considered. Pregabalin, an anticonvul-

sant with a mechanism similar to that

of gabapentin, was recently approved

and has been studied extensively as an

analgesic.

Variable Begin after opioid titrated. Evidence best for tricyclic drugs. Although

minimal supporting data for serotonin-

selective drugs, paroxetine has some

support. Better support for mixed-

mechanism drugs including duloxetine

and venlafaxine.

30-120

200-400 IU

600-900

2-24 Higher doses used in epidural cord com-pression and various pain emergencies;

lower doses suggested in other condi-

tions. Dexamethasone may be preferred

because of low mineralocorticoid effect,

but others have been used

(eg, prednisone).

Usual Daily

Dose, mg/d Comments See Routes of Administration

10-4010-40200

Variable

* Consider using lower than recommended starting dose in the elder-ly, in patients on multiple drugs, and in those with renal insufficien-cy (one half to two thirds recommended dose). Doses must be indi-vidualized. Low initial doses should be titrated upward if toleratedand clinical effect is inadequate. Doses can be increased in weeklyincrements. Studies of NSAIDs in the cancer population are meager;thus dosing guidelines are empiric.

Although clinical experience suggests that any of the NSAIDs maybe analgesic, pain is an approved indication only for those drugsnoted.

Half-life for aspirin increases with dose.

At relatively high doses, consider monitoring for adverse effects, eg,by checking for occult fecal blood or for changes in liver functiontests, blood urea nitrogen and creatinine assessments, or urinalysis.

ll Oral dose that provides analgesia equivalent to 650 mg of aspirin.Starting dose may be higher or lower, and dose titration is neededafter therapy is begun.

Dose that provides analgesia equivalent to 10 mg of IM morphine.The equianalgesic dose should not be interpreted as the starting,standard, or maximum dose, but rather as a guide; particularly usefulin switching drugs or changing routes of administration. Dependingon patient characteristics and prior opioid exposure, the startingdose can be lower or higher, and dose titrationeither upward ordownwardis repeatedly necessary in virtually all patients.

**Extensive survey data suggest that the relative potency of IM to POmorphine of 1:6 changes to 1:2 or 1:3 with long-term dosing.

ADH ........................................................................... antidiuretic hormone

bid ................................................................................................... twice daily

BTP .................................................................................. breakthrough pain

BUN .............................................................................. blood urea nitrogen

CABG ......................................................... coronary artery bypass graft

CBC ................................................................. complete blood cell count

CNS ........................................................................ central nervous system

COX-2 .............................................................................. cyclooxygenase-2

FBT ........................................................................... fentanyl buccal tablet

GI ............................................................................................ gastrointestinal

IM ............................................................................................... intramuscular

IU ...................................................................................... international units

I.V. .................................................................................................. intravenous

MAO ............................................................................. monoamine oxidase

NMDA ....................................................................... N-methyl-D-aspartate

NSAID ........................................ nonsteroidal anti-inflammatory drug

OTFC ................................................ oral transmucosal fentanyl citrate

PCA .............................................................. patient-controlled analgesia

PO ...................................................................................................... by mouth

PR ........................................................................................................... rectally

qd ..................................................................................................... once daily

SNRI ............................ serotoninnorepinephrine reuptake inhibitor

SSRI ........................................... selective serotonin reuptake inhibitor

TCA ........................................................................ tricyclic antidepressant

KEY

ENDNOTES


Copyright 2007 M


ise noted.



Patient Guide to

MANAGEMENT OF CANCER PAIN

RESOURCES

Pain Diary

Pain Rating Scale

0 1 2 3 4 5 6 7 8 9 10

No pain Worst pain imaginable

The National Pain Foundation

www.nationalpainfoundation.orgNational Cancer Institute Resources

Cancer Information Service1-800-4-CANCER (1-800-422-6237)

TTY: 1-800-332-8615www.cancer.gov

n order to help your clinician adequately monitor and treat your pain, it is

important for you or a member of your family to keep a daily diary of your pain.

There are several ways to measure your pain. One way is by selecting a

number on a scale from 0 to 10. This scale is called a pain rating: 0 means no

pain, and 10 means you have the worst pain imaginable.

Use a diary like the one shown below to record the date, time of day, a pain

scale rating, and things you did to make the pain better.

I

TimeDatePain Medication (Name,Dose, How Often Taken)

Pain Rating (0-10)

Side EffectsFrom PainMedicine

Other PainRelief MethodsTried

8 AMOctober 9 Morphine 30 mg

every 4 h

6 ConstipationMassage

M.D. Anderson Cancer Center

www.mdanderson.org/topics/paincontrol

American Cancer Society

www.cancer.org

Reprinted with permission from the National Cancer Institute.

PRINTER-FRIENDLY VERSION AT ANESTHESIOLOGYNEWS.COM


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