Chester Clinic

Es22

in treatment of patients with cancer havebeen associated with avascular necrosisof the hip and subsequent fracture. Post-surgical pain commonly occurs in Controlling Cancer Pain
patients who have had thoracotomy,mastectomy, or amputations to manage their neoplastic disease. Inadequate treatment and under- Gregory H. Pharo, DO treatment are associated with increased pain scores, decreased functional ability,and increased depression and anxiety.8,9The American Pain Society and the JointCommission on Accreditation of Health-care Organizations (JCAHO) recentlyplaced emphasis on this problem with amovment to have pain become the "fifth Cancer remains the second most common cause of death in the United States
vital sign" because this important param- despite advances in prevention, early detection, and newer treatment protocols.
eter, like other vital signs such as blood Pain continues to be the most feared complication of this diagnosis. Numerous
pressure, heart rate, respiratory rate, and studies have shown that when the World Health Organization treatment guide-
body temperature, needs frequent assess- lines are followed, 90% of patients are pain-free. Although clinical evidence is
ment. The Visual Analog Scale and 11- convincing that opioids are effective in treating patients for cancer pain, physi-
point (0 to 10) numeric scale are used for cian reluctance to prescribe them and patient unwillingness to take such med-
measurement, a process that allows fre- ication continue. Barriers to opioid use are multifactorial, but with education
quent reassessment and therefore ade- of healthcare providers and patients, pharmacotherapy for pain management
quate treatment. will be more effective.
The World Health Organization (WHO) in 1986 established a stepladder J Am Osteopath Assoc. 2007;107(suppl 7):ES22-ES32 approach for treatment of patients withcancer pain (Figure).2,4 The goal was toprovide treatment guidelines that health-care practitioners could easily follow.
Despite treatment advances, cancer decline as the result of screening guide- The initial step consisted of acetamino-
remains the second leading cause lines that allow early detection and phen or nonsteroidal anti-inflammatory of death in the United States.1 The inci- advances in treatment.1 drugs (NSAIDs) with or without adju- dence of cancer continues to rise as the Pain continues to be a major vant therapy. If pain is not controlled, result of increases in population, as well problem in patients with cancer, affecting medications combining mild to mod- as longer average life expectancy. Inci- 25% to 30% of patients with recently erate opioids with acetaminophen are dence also decreased as the result of diagnosed cancers. The incidence of such added to step one. If pain persists, increased surveillance (ie, screening for discomfort in advanced stages of cancer stronger opioids such as morphine sul- prostate-specific antigen, colonoscopy, approaches 70% to 80%.2-6. A major fear fate are added and titrated to pain relief.
and breast and testicle self-examination).
of cancer patients is associated pain,5 Around-the-clock dosing schedules are Mortality rates for certain cancers (colon, which can occur as a result of the cancer used to minimize the frequent use of prostate, female breast) continue to itself, treatment, or from other causes.
medications for breakthrough pain. Cancer can spread by metastasis or direct Most pain in patients with cancer invasion, and 90% of patients with pro- can be controlled by morphine oral doses liferation to osseous structures report of less than 200 mg/d. Greater than 80% Dr Pharo is currently in private practice in Philadel- pain.7 Patients with cancer can have neu- of patients with cancer can be pain-free phia, Pa, with Professional Pain ManagementAssociates; he was previously affliliated with Jef- ropathic pain due to direct compression when physicians follow WHO guide- ferson Medical College and Jefferson Pain Center, of nerves, a plexus and/or spinal cord. lines and use higher doses as needed to where Dr Zhou is assistant professor of physical Chemotherapeutic drugs such as obtain relief.4,6 medicine and rehabilitation and anesthesiology,and an attending physician, vinca alkaloids or radiation therapy can To provide adequate analgesia in Dr Pharo is on the speakers bureau of Pfizer produce neuropathic pain. Steroids used patients with cancer, WHO guidelines Inc. Dr Zhou has no commercial, proprietary, orfinancial interest in the products discussed in thisarticle Address correspondence to Gregory H. Pharo, DO, PPMA, Suite 308, 829 Spruce St, Philadelphia, This continuing medical education publication is supported by an unrestricted educational grant from Purdue Pharma LP. ES22 • JAOA • Supplement 7 • Vol 107 • No 12 • December 2007
Pharo and Zhou • Controlling Cancer Pain With Pharmacotherapy list major classes of pain medications the US market because of associated with their respective mechanisms of increased rates of stroke and myocardial Management of cancer pain with opi- action and doses, in addition to adjuvant oids remains the "gold standard" with drugs such as ketamine, antidepressants, The entire class of NSAIDs is now which other treatment modalities are anticonvulsants, steroids, biphospho- under increased scrutiny as these compared.2,4,5,14 The second step of WHO nates, topical analgesics, anxiolytics, lax- unwanted adverse reactions effects may guidelines involves use of mild to mod- atives, hormones, antihistamines, and not be class-specific.10,12 Therefore, new erate opioids in combination with black box warnings have been applied acetaminophen or ASA. Administration to all NSAIDs, not just celecoxib, the of medications used in step one is con- NSAIDs, COX-2 Inhibitors,
remaining COX-2 inhibitor. Despite these tinued because NSAIDs, COX-2 ASA, and Acetaminophen
concerns, NSAIDs and COX-2 inhibitors inhibitors, and acetaminophen have been Prostanoids play important roles in many are promising as anticancer drugs shown to increase analgesia when added cellular responses and pathophysiologic because they inhibit tumor angiogenesis to opioids. Adjuvant medications are also processes, including modulation of and induce tumor cell apoptosis. indicated here as well as in all steps of the inflammatory reactions, erosion of car- NSAIDs play a key role in the first WHO ladder (Figure). tilage and juxta-articular bone, gastroin- step of WHO guidelines for management In 1973, several teams of researchers testinal cytoprotection and ulceration, of cancer pain. Nearly 90% of patients found the presence of an "opioid angiogenesis and cancer, hemostasis and with bone metastasis present with pain,9 receptor" in the nervous system.15 It was thrombosis, renal hemodynamics and and since prostaglandins appear to play believed that endogenous substances progression of kidney disease.10 Non- an important role in this condition,7 when released subsequently bound to steroidal anti-inflammatory drugs NSAIDs are the most effective agents. A opioid receptors and provided analgesia; (NSAIDs), cyclooxygenase type 2 (COX- 2004 systematic review showed NSAIDs this binding was reversed by naloxone.
2) inhibitors, and acetylsalicylic acid are more effective than placebo for con- These endogenous substances were later (ASA) prevent formation of prostanoids trolling cancer pain and that they all are identified as enkephalins, ␤-endorphins, from arachidonic acid. This synthesis of comparable in safety profile and effec- and dynorphin. Three separate opioid prostaglandins from arachidonic acid is tiveness.6 Comparisons of opioid com- receptors (as well as new individuals controlled by two separate cyclooxyge- bination preparations with NSAIDs alone subtypes) were identified and labeled: nase enzymes (COX-1 and COX-2). showed no, or at most, only slight dif- ␮, ␬, and ␦. The major receptor associ- Traditional nonselective NSAIDs ferences that were not statistically sig- ated with analgesia is ␮, and develop- inhibit both COX-1 and COX-2, a non- ment of synthetic opioids has centered selective inhibition that results in notonly an anti-inflammatory response butalso reduced gastrointestinal cytopro-tection; this latter effect causes gastricmucosal ulceration and bleeding. NewerCOX-2 inhibitors were designed to selec-tively inhibit only this enzyme, thusmaintaining an anti-inflammatory response with low risk of side effects thatoccur with nonselective inhibitors of COXenzymes.10,11 Recently, however, COX-2 inhibitors have received attention because of anincreased incidence of stroke and myocardial infarction when used in highdoses to decrease the incidence of can-cerous polyps (in familial polyposis).
Two COX-2 inhibitors (rofecoxib andvaldexcoxib) have been removed from Figure. World Health Organization (WHO)
"stepladder" guidelines for pain relief. (Pub-
lished with permission from the WHO. Avail-
able at: http://www.who.int/cancer/pallia-
tive/painladder/en/. Accessed November 19,
2007.)
Pharo and Zhou • Controlling Cancer Pain With Pharmacotherapy JAOA • Supplement 7 • Vol 107 • No 12 • December 2007 • ES23
on targeting this site while avoiding com- mulation offers no advantage over only as a guide because incomplete or plexation to other opioid receptors that another for pain control. Experience of decreased cross-sensitivity may play a produce unwanted side effects (eg, the healthcare provider and cost seem part in the conversion process. In nausea and respiratory depression). to be the determining factors in choosing switching from one opioid to another, Oral morphine is the primary opioid one preparation over another.5,14 60% to 70% of the total daily dosage of used in the United States for treatment of Long-term use of opioids is associ- the current opioid calculated from an patients with severe pain in advanced ated with physical dependence and tol- equianalgesic conversion table should stages of cancer. In the United Kingdom, erance. These two physiologic processes be used and accompanied by frequent diamorphine (heroin) is used secondarily have nothing to do with addiction, which supplementation with as-needed rescue because of its greater solubility, but it is psychological. Tolerance is defined as a has no clinical advantage over morphine.
physiologic phenomenon of progressive Because dosing and conversion of Methadone hydrochloride, a drug com- decline in the potency of an opioid with opioids are complex processes requiring monly prescribed to prevent withdrawal continued use, manifested by the require- knowledge of opioid properties, profes- in recovering drug users, is used in hos- ment of increasing opioid dose to achieve sional skill, and caution, this article does pice programs in the United Kingdom the same therapeutic effect.5 Tolerance not include a conversion table. Readers and Canada. It is also employed in the may occur in any patient taking narcotics instead should refer to prescribing infor- United States for treatment of patients daily for more than 1 or 2 weeks, though mation and available resources for cal- with refractory or neuropathy-associated the degree to which tolerance occurs in culating opioid conversion. patients with cancer-related pain is uncer- Dependence is a physiologic process Numerous opioid preparations are that is independent of tolerance and char- now available (Table). Increased doses can continue to pro- acterized by withdrawal symptoms on Currently, morphine can be vide adequate analgesia as there appears abrupt reduction or discontinuation of obtained in an immediate-release (IR) to be no ceiling, but escalating doses can chronic administration. Addiction is a psy- form (eg, oxycodone IR, fentanyl IR, oxy- increase side effects (eg, nausea, vom- chological and behavioral syndrome morphone IR) and a sustained-release iting, constipation, sedation, respiratory manifested by drug-seeking behavior, (SR) form (eg, oxycodone SR) with depression, abdominal pain, pruritus) loss of control over drug use, and con- dosing of every 8, 12, or 24 hours. Newer that may limit their use.8,19 Tolerance tinued use despite adverse effects. In extended-release technology allows for 1980, Porter and Jack19 reported that sprinkling pellets in applesauce, which 䡺 increased activation and/or upregu- addiction is rarely seen in patients with was not possible with the previously lation of the N-methyl-D-aspartate cancer pain when use is appropriate; available preparations. Other long-acting (NMDA) receptor because of repeated however, patients with a history of pre- formulations could not be given via gas- exposure of ␮ receptors to opioids; use of vious addiction may be at an increased trotomy tube because of problems with an NMDA-receptor antagonist can risk for this behavior. uncontrolled and variable release if pills diminish or reverse tolerance. were crushed or cut. Additional prob- 䡺 downregulation or possible confor- Adjuvant Medications
lems with newer SR preparations have mational changes in opioid receptors (or for Analgesia
been associated with high and unpre- both) that are thought to occur with long- dictable serum levels when exposed to term opioid exposure.8,19,20 This agent, a derivative of phencyclidine, ethanol (black box warning).17 N-methyl-D-aspartate receptors are has been used in anesthesia for more Fentanyl, an analgesic commonly present in the periphery as well as the than 40 years. Ketamine provides both used in anesthesia, is widely used via central nervous system (CNS). Activa- amnesia and intense analgesia resulting the intravenous route. This strong opioid tion of these sites is associated with in "dissociative anesthesia," a state of is also available for transdermal or trans- memory, learning, neural development, catatonia in which the patient appears mucosal administration with predictable plasticity, and acute and chronic pain awake yet is unable to respond or com- drug concentrations comparable to that states. Acute and chronic stimulation of municate. Use of ketamine has been lim- achieved via the intravenous route.
peripheral pain fibers (A-␦ and C) can ited because of emergence delirium,24 Recently, the US Food and Drug Admin- result in activation and recruitment of which can be partially inhibited by pre- istration (FDA) issued a warning that NMDA receptors; when these two events operative doses of a benzodiazepine. several deaths and other serious adverse develop, symptoms of both allodynia and The mechanism of action is non- events occurred following use of a fen- hyperalgesia can occur, especially in competitive blockade of the NMDA tanyl buccal tablet; the actual statement patients with neuropathic pain.21-23 receptor. Ketamine has been shown to from the FDA MedWatch site is, "These Rotating opioids reduces tolerance.
attenuate and reverse morphine toler- deaths occurred as a result of improper Rapid switching from one opioid to ance by inhibition of NMDA receptors.22 patient selection (e.g., use in opioid non- another can be easily accomplished with Ketamine has been used in a variety tolerant patients), improper dosing minimum periods of inadequate anal- of pain conditions that are refractory to and/or improper product substitution."18 gesia. A standard equianalgesic table for high-dose opioids and other conventional In terms of efficacy, one opioid for- conversions from one to another is used modes of therapy. Low-dose continuous ES24 • JAOA • Supplement 7 • Vol 107 • No 12 • December 2007
Pharo and Zhou • Controlling Cancer Pain With Pharmacotherapy Common Opioid Analgesics With Usually Recommended Doses*
Indications, Contraindications,
and Strength
and Warnings
䡵 Codeine
Weak analgesic with no effect in 10% of patients 15 mg, 30 mg, 60 mg 䡺 With acetaminophen 15 mg/mL, 30 mg/mL Maximum: See PI for acetaminophen dosing Do not prescribe to patients who 䡺 (Darvocet N-100) are suicidal or addiction prone.
100 mg propoxyphene/ 1-2 tablets every 4 h Prescribe with caution for patients 325 mg acetaminophen taking tranquilizers, antidepressants 6 tablets per day or patients who use alcohol in excess,and elderly.
High dose of acetaminophen per tablet.
PO: 5 mg-15 mg every 4 h Less potent and shorter acting 䡺 With ibuprofen Elderly: 2.5 mg-5 mg 䡺 With acetaminophen 2.5 mg/500 mg, 5 mg/500 mg, 7.5 mg/500 mg, 10 mg/500 mgElixer:2.5 mg hydrocodone/167 mg acetaminophen 䡵 Fentanyl
Injectable: 50 ␮g/mL Not recommended for intermittent 25 ␮g-50 ␮g IV use because of short half-life.
Consider PCA use for acute After initial dosing: postoperative pain.
initial with 10 ␮g/h to 20 ␮g/h. Titrate togoal pain control in 10-␮g/h incrementsuntil 100 ␮g/h 䡺 Transdermal — (Duragesic) Starting dose: 25 ␮g Transdermal patches are contra- 12.5 ␮g, 25 ␮g, 50 ␮g, every 72 h in opioid-naïve indicated in the management of 75 ␮g, 100 ␮g patients with dose acute or postoperative pain, for increases every 3 days mild or intermittent pain response to PRN opioids or nonopioids and indoses⬎25 ␮g/h at initiation of opioid therapy. Fentanyl patch reaches peak effectin 24 h, maintains constant bloodlevel for 18 h after removal.
* Adapted with permission from Schechter L, Meadows S. Adult Pain Management Guidelines. Philadelphia, Pa: Thomas Jefferson University Hospital; 2007.
This table is a derivative collection from several sources, including the 2007 manufacturers' full prescribing information available as package inserts or in the latest edition of the Physicians' Desk Reference. † Primary entries of opioids are by generic name; proprietary names appear in parentheses.
Abbreviations: CNS, central nervous system; CR, controlled release; ER, extended release; G-tube, gastrostomy tube; IR, immediate release; IV, intravenous; MAOI,
monoamine oxidase inhibitor; PCA, patient-controlled analgesia; PI, manufacturer's prescribing information; PO, by mouth; PR, per rectum; PRN, as needed.
Pharo and Zhou • Controlling Cancer Pain With Pharmacotherapy JAOA • Supplement 7 • Vol 107 • No 12 • December 2007 • ES25
Table (continued)
Common Opioid Analgesics With Usually Recommended Doses*
Indications, Contraindications,
and Strength
and Warnings
䡵 Fentanyl (continued)
䡺 Lozenges— (Actiq) Oral lollilet: 200 ␮g/unit, Initial dose 200 ␮g Indicated only for the management 400 ␮g/unit, 600 ␮g/unit, May use 1 additional unit of breakthrough cancer pain in 800 ␮g/unit, 1200 ␮g/unit, 15 min after previous unit completed for single Contraindicated in the manage- breakthrough episode ment of acute or postoperative Maximum 4 units/d pain or opioid naïve patient.
Only approved for cancer pain in opioid-tolerant patients.
Unit should be allowed to dissolve, not chewed or bitten.
Caution around children. Must be disposed of properly according to manufacturer's recommendations.
Slightly shorter duration of action Tablet: 1 mg, 2 mg, than morphine.
PCA use for acute postoperative Suppository: 3 mg Less pruritus than with morphine.
Injectable: 1 mg/mL, Short half-life, a good choice for elderly.
Injectable: 25 mg/mL, Toxic metabolite accumulates with 50 mg/mL, 75 mg/mL repetitive dosing to cause CNS IV use limited to: treatment of rigors, Contraindication: renal failure, documented allergy to history of seizures, or MAOI use all other opioids, within 2 weeks.
moderate sedation Use with caution in patients (patient with normal receiving St John's Wort.
renal function and no history of seizures)IV: 25-50 mg every 1-2 hMaximum dose:600 mg/24 h * Adapted with permission from Schechter L, Meadows S. Adult Pain Management Guidelines. Philadelphia, Pa: Thomas Jefferson University Hospital; 2007.
This table is a derivative collection from several sources, including the 2007 manufacturers' full prescribing information available as package inserts or in the latest edition of the Physicians' Desk Reference. † Primary entries of opioids are by generic name; proprietary names appear in parentheses.
Abbreviations: CNS, central nervous system; CR, controlled release; ER, extended release; G-tube, gastrostomy tube; IR, immediate release; IV, intravenous; MAOI,
monoamine oxidase inhibitor; PCA, patient-controlled analgesia; PI, manufacturer's prescribing information; PO, by mouth; PR, per rectum; PRN, as needed.
intravenous administration of ketamine to 90%. Ketamine can provide analgesia neuropathic pain and those presenting can provide analgesia with a minimum without the sedation of high-dose opioid with pain syndrome and comorbid incidence of associated cardiovascular administration. Tachyphylaxis can depression. Doses effective for neuro- or neurologic side effects.2,22 Infusion develop with prolonged use of either pathic pain are usually lower than those rates of 0.1 to 5.0 milligrams per kilo- intravenous or oral ketamine, and used for depression. TCAs have no dif- gram of body weight per hour bioavailability from oral administration ferences in their effectiveness.13 In this (mg/kg/h) titrated to sedative effects can also limit long-term effectiveness.4 group, both tertiary amines (eg, have been used to treat patients with amitriptyline, imipramine, doxepin, and refractory pain resistant to opioid clomipramine) and secondary amines therapy. During titration, opioid con- Tricyclic antidepressants (TCAs) have (nortriptyline and desipramine) have sumption can be slowly reduced by 10% efficacy in treatment of patients with analgesic effects in patients with cancer, ES26 • JAOA • Supplement 7 • Vol 107 • No 12 • December 2007
Pharo and Zhou • Controlling Cancer Pain With Pharmacotherapy Common Opioid Analgesics With Usually Recommended Doses*
Indications, Contraindications,
and Strength
and Warnings
Cardiac and respiratory deaths Tablet: 5 mg, 10 mg have been reported during initiation and conversion of patients to methadone.
1 mg/mL, 10 mg/mL Respiratory depression is the chief Injectable: 10 mg/mL hazard associated with metha-done administration.
Cases of QT interval prolongation and serious arrhythmia have been observed during methadone treatment.
Accumulates with repeated dosing and requires decreases in dose and frequency especially on days 2-5.
Long half-life, peak effect in 4-10 days.
Dose decreased for renal impairment. Consult a conversion chart for converting from another opioid to methadone.
䡵 Morphine IR
Metabolites may accumulate with 䡺 (MSIR, Roxanol) Tablet: 10 mg, 15 mg, prolonged use, especially in renal failure leading to sedation, pruritus, Liquid: 2 mg, 4 mg, confusion, respiratory depression. PCA use for acute postoperative Suppository: 5 mg, 10 mg, Liquid contains alcohol.
Injectable: 2 mg/mL, 4 mg/mL, Continuous infusion:8 mg/mL, 10 mg/mL Initiate at 1 mg/h to2 mg/h.
Titrate to goal paincontrol in 1-mg/hincrements, until6 mg/h, then increasein 2-mg/h increments. 䡵 Morphine CR
Tablet: 15 mg, 30 mg, Tablet not to be cut, crushed, 60 mg, 100 mg, 200 mg Elderly: 15 mgevery 12 h Dose should be based on or adjusted to IRrequirements. * Adapted with permission from Schechter L, Meadows S. Adult Pain Management Guidelines. Philadelphia, Pa: Thomas Jefferson University Hospital; 2007.
This table is a derivative collection from several sources, including the 2007 manufacturers' full prescribing information available as package inserts or in the latest edition of the Physicians' Desk Reference. † Primary entries of opioids are by generic name; proprietary names appear in parentheses.
Abbreviations: CNS, central nervous system; CR, controlled release; ER, extended release; G-tube, gastrostomy tube; IR, immediate release; IV, intravenous; MAOI,
monoamine oxidase inhibitor; PCA, patient-controlled analgesia; PI, manufacturer's prescribing information; PO, by mouth; PR, per rectum; PRN, as needed.
especially for concurrent neuropathic tachycardia, arrhythmia, anticholinergic retention, constipation, cardiovascular dis- pain syndrome.25 The major mechanism effects (dry mouth, blurred vision, and ease, or impaired liver function. These of the analgesic effect was believed to urinary retention). agents should be avoided in patients with be related to inhibition of norepinephrine Tricyclic antidepressants should be severe liver disease, second- or third- or serotonin reuptake or both. Common administered cautiously in elderly patients degree heart block, arrhythmias, QT pro- side effects include sedation, confusion, and in those with angle-closure glaucoma, longation, and those with a history of orthostatic hypotension, weight gain, benign prostatic hypertrophy, urinary recent myocardial infarction. Pharo and Zhou • Controlling Cancer Pain With Pharmacotherapy JAOA • Supplement 7 • Vol 107 • No 12 • December 2007 • ES27
Common Opioid Analgesics With Usually Recommended Doses*
Indications, Contraindications,
and Strength
and Warnings
䡵 Morphine ER
Indicated for once-daily administra- 30 mg, 60 mg, 90 mg, tion for the relief of moderate to severe pain requiring continuous, 20 mg, 30 mg, 50 mg, PO: 50% of other oral around-the-clock opioid therapy 60 mg, 80 mg, 100 mg for an extended period of time.
Capsules should be swallowed whole or sprinkled on applesauce.
Dose should be based Do not chew or crush because of risk on or adjusted to IR of rapid release and absorption of a potential fatal dose of morphine.
Consumption of alcohol while taking Avinza may result in the rapid release and absorption of a potentially fatal dose of morphine.
G-tube administration: flush 16 French or larger G-tube with 10 mL of water. Open capsule and sprinkle into 15 mL of apple juice. Using 30-mL catheter tip syringe, draw up juice and medication. Holding the syringe horizontally, slowly administer the solution into the G-tube. Flush with another 10 mL of apple juice.
䡵 Oxycodone (IR)
Tablet: 5 mg, 15 mg, Simultaneous use of aspirin, ibuprofen, or acetaminophen limits Solution: 5 mg/5 mL Elderly: 2.5 mg- 5 mg dose of combination products.
䡺 With acetaminophen — (Percocet, Endocet 7.5 mg/500 mg, 10 mg/650 mg 䡵 Oxycodone (CR)
Tablet: 10 mg, 20 mg, Indication for the management of moderate to severe pain when analgesics needed for an extended period of time.
Tablet not be crushed or chewed because of rapid release and absorption of potentially fatal oxycodone.
* Adapted with permission from Schechter L, Meadows S. Adult Pain Management Guidelines. Philadelphia, Pa: Thomas Jefferson University Hospital; 2007.
This table is a derivative collection from several sources, including the 2007 manufacturers' full prescribing information available as package inserts or in the latest edition of the Physicians' Desk Reference. † Primary entries of opioids are by generic name; proprietary names appear in parentheses.
Abbreviations: CNS, central nervous system; CR, controlled release; ER, extended release; G-tube, gastrostomy tube; IR, immediate release; IV, intravenous; MAOI,
monoamine oxidase inhibitor; PCA, patient-controlled analgesia; PI, manufacturer's prescribing information; PO, by mouth; PR, per rectum; PRN, as needed.
In general, secondary amines have apeutic level. Trazodone hydrochloride pain.27 It is reported that doxepin oral fewer sedative and anticholinergic effects is as effective as amitriptyline in cancer- rinse is effective for debilitating oral than tertiary amines; therefore, these related neuropathic pain syndrome.13 The mucositis induced by cancer therapy.28 former TCAs may be more desirable in selective serotonin and norepinephrine elderly patients.26 In this latter popula- reuptake inhibitor duloxetine hydrochlo- tion, the starting dose is usually 10 mg at ride, an antidepressant, has also been Anticonvulsants have been used in treat- bedtime, then gradually titrated to a ther- shown to be effective for neuropathic ment of neuropathic pain for many ES28 • JAOA • Supplement 7 • Vol 107 • No 12 • December 2007
Pharo and Zhou • Controlling Cancer Pain With Pharmacotherapy Common Opioid Analgesics With Usually Recommended Doses*
Indications, Contraindications,
and Strength
and Warnings
䡵 Oxymorphone (IR)
Tablet: 5 mg, 10 mg Not indicated as first- or second- line therapy for pain management.
Patients stabilized on oxymorphone as outpatients may continue therapy when admitted.
Must be given on an empty stomach 1 h before or 2 h after a meal.
䡵 Oxymorphone ER
Tablet: 5 mg, 10 mg, Indicated for the management of moderate to severe pain when Dose should be based a continuous, around-the-clock on or adjusted to IR opioid analgesic is needed for an extended period of time.
Not intended for use as a PRN analgesic.
Tablets are to be swallowed whole and are not to be broken, chewed, dissolved, or crushed. Taking broken, chewed, dissolved or crushed tablets leads to rapid released and absorp-tion of a potentially fatal dose of oxymorphone.
Patients must not consume alcoholic beverages, or prescription or non-prescription medications containing alcohol. The co-ingestion of alcohol may result in increased plasma levels and a potentially fatal overdose of oxymorphone.
* Adapted with permission from Schechter L, Meadows S. Adult Pain Management Guidelines. Philadelphia, Pa: Thomas Jefferson University Hospital; 2007.
This table is a derivative collection from several sources, including the 2007 manufacturers' full prescribing information available as package inserts or in the latest edition of the Physicians' Desk Reference. † Primary entries of opioids are by generic name; proprietary names appear in parentheses.
Abbreviations: CNS, central nervous system; CR, controlled release; ER, extended release; G-tube, gastrostomy tube; IR, immediate release; IV, intravenous; MAOI,
monoamine oxidase inhibitor; PCA, patient-controlled analgesia; PI, manufacturer's prescribing information; PO, by mouth; PR, per rectum; PRN, as needed.
years. The mechanism of the analgesic reduces release of neurotransmitters from neuropathic pain.30 It has been shown to activity of carbamazepine, phenytoin, presynaptic terminals.29 Advantages of be efficacious in different neuropathic and valproic acid is thought to be asso- pregabalin compared with gabapentin pain syndromes and to possess a good ciated with blocking sodium channels include 90% absorption with predictable safety profile. Most of the controlled trials and increased membrane stability. Clon- serum levels. There is less chance of drug of gabapentin in patients with various azepam increases ␥-aminobutyric acid interactions since these two agents are neuropathic pain syndromes demon- (GABA) levels and also activates the ben- not protein-bound, nor do they cause strate that it reduces both pain and sleep zodiazepine receptor; this receptor acti- induction or inhibition of cytochrome interference and improves the quality of vation causes an increase in chloride ion life. It is the only antiepileptic that has which inhibits neuronal activity.
Caution should be taken when been tested to be effective in cancer- Gabapentin, initially was designed to be administering carbamazepine, pheny- related neuropathic pain.29 Gabapentin is an analog of GABA receptor. Modula- toin sodium, or valproic acid because not metabolized and has no known drug- tion of the ␣ 2 ␦ subunit of the N-type they have known severe adverse effects drug interactions; most of it is excreted voltage-dependent Ca2⫹ channels is the such as bone marrow depression and unchanged in the urine, but some elim- probable reason for its antiepileptic and liver toxicity. Baseline evaluation of liver ination (10%-23%) occurs via the feces.
analgesic properties. function and a complete blood cell count Treatment usually starts with 100 mg/d Pregabalin, a newer anticonvulsant, should be done before initiating use of to 300 mg/d. Gradual dose titration con- also modulates the ␣ 2 ␦ subunit of N- these medications. tinues until benefit occurs, side effect type voltage-gated calcium channels on At present, gabapentin is the most supervenes, or the total daily dose neural tissue. Activation of this subunit commonly used adjuvant analgesic for reaches 3600 mg. Occasionally, patients Pharo and Zhou • Controlling Cancer Pain With Pharmacotherapy JAOA • Supplement 7 • Vol 107 • No 12 • December 2007 • ES29
receive benefits at even higher doses. An nostic and therapeutic treatment prior adequate trial should include to neurolytic procedures (celiac plexus 1 to 2 weeks at the maximum tolerated Bone pain secondary to tumor expan- block) used to treat patients for refrac- level. The most common side effects are sion and inflammation is a common tory cancer pain (pancreatic cancer).
dizziness and somnolence; others include symptom of some cancers. Radiation Common adverse effects are paresthe- confusion, and peripheral edema. There- therapy with corticosteroids is highly sias (fingers), abnormal taste, tinnitus, fore, gabapentin should be titrated slowly effective for the treatment of patients blurred vision, drowsiness, dysarthria, in patients who are elderly and those with focal bone lesions. Some medica- or local skin rash secondary to topical with impaired renal function.29 tions useful for managing bone pain by application of the anesthetic. Like gabapentin, pregabalin and lev- inhibiting osteoclast activity include bis- Severe systemic toxicity due to high etiracetam have proven efficacy for neu- phosphonates, calcitonin, and radionu- plasma levels can cause seizure or result ropathic pain. Dunteman31 reported a in cardiotoxicity with cardiac arrest. For 70% reduction of opioid use with the The analgesic efficacy of bisphos- intravenous lidocaine infusion, the dose administration of levetiracetam, as well phonates, particularly the second-gener- is 1 mg/kg or 5 mg/kg given over as improved pain relief in patients with ation bisphosphonate pamidronate di- 2 hours. When administered topically, neoplastic plexopathies previously resis- sodium and ibandronate sodium, have 5% of lidocaine gel or patch is placed tant to standard analgesic approaches.
been well established.34,35 For tumor- directly on skin over painful regions; Tiagabine hydrochloride is a new GABA related bone pain, 60 mg to 90 mg of there is minimal systemic absorption.
reuptake inhibitor, and compared with pamidronate disodium or 2 mg to 6 mg Mexiletine hydrochloride, an antiar- gabapentin, it has similar effectiveness of ibandronate sodium injected intra- rhythmic with structural similarity to in pain reduction but greater efficacy for venously is recommended every lidocaine, has been used off label to treat sleep improvement.29 3 to 4 weeks. Adverse effects include patients with neuropathic pain from hypocalcemia, and a flu-like syndrome.
numerous etiologies and is the preferred Zoledronic acid, a new bisphosphonate, oral local anesthetic. Topical capsaicin, Corticosteroids are given as adjunctive is approximately two to three times more a peptide that depletes substance P in therapy for cancer-related neuropathic potent than—and as effective as— small primary afferent neurons, has been pain, especially for metastatic spinal com- shown to significantly decrease cancer- pression, pain associated with soft tissue Calcitonin is usually administered related neuropathic pain.39 A major side infiltration, and visceral distension. subcutaneously and intranasally. The ini- effect, localized irritation that causes a Mechanisms of action include: tial dose is 200 IU in one nostril a day, burning sensation, limits use of capsaicin. 䡺 inhibiting prostaglandin production alternating nostrils every day. Apart fromand reducing inflammation; infrequent hypersensitivity reactions Miscellaneous Adjuvants
䡺 decreasing capillary permeability and associated with subcutaneous injections, Other medications are sometimes used asreducing peritumor edema; and the main side effect is nausea.24 adjuvants for pain or symptom man- 䡺 directly affecting membrane stabi- Radionuclides that are absorbed at agement related to cancer treatment. lization, which decreases neuronal areas of high bone turnover have been 䡵 Baclofen for spasticity, trigeminal neu- assessed as potential therapies for ralgia, and central pain secondary to Administering these drugs can pro- metastatic bone pain.13 Strontium-89 spinal cord lesions; its mechanism of duce significant adverse effects such as chloride and samarium-153 are available action is activation of GABA receptors. hypertension, hyperglycemia, immuno- in the United States. Studies demon- 䡵 Benzodiazepines can reduce cancer suppression, gastrointestinal ulceration, strated that these radiopharmaceuticals pain by reducing fear, apprehension, and and psychiatric disorders. Dexametha- are effective in the palliation of metas- anxiety related to cancer. sone is the corticosteroid most commonly tases whose pain is not controlled with 䡵 Psychostimulant drugs (dextroam- used for spinal cord compression because conventional analgesic regimens.36,37 phetamine, methylphenidate) can reduce of a decreased tendency for salt and fluid opioid-induced somnolence, improve retention.32 The doses range from 10 mg Local Anesthetics
cognition, treat patients for depression, to 20 mg administered intravenously Evidence has been presented showing a and alleviate fatigue.
every 6 hours. Corticosteroids are also higher density of Na⫹channels after 䡵 Antihistamines, anticholinergic drugs, used to enhance appetite, reduce nausea nerve damage and subsequent sponta- antipsychotics, and laxatives are some- and malaise, and improve overall quality neous firing.38 By inhibiting sodium times used to treat patients for cancer- of life. When given with docetaxel and channels, local anesthetics are effective related symptoms or complications of mitoxantrone to treat patients for in treating patients with nonmalignant cancer treatment, such as dizziness, ver- metastatic hormone-refractory prostate and cancer-related neuropathic pain syn- tigo, nausea and vomiting, confusion and cancer, these medications increase anal- drome. These agents should be consid- delirium, and constipation. This group gesia and the quality of life.33 ered after trials of anticonvulsants or of medications should be used cau- antidepressants have failed. Local anes- tiously, with precautions taken to reduce thetics (eg, lidocaine) are used for diag- side effects and drug-drug interactions. ES30 • JAOA • Supplement 7 • Vol 107 • No 12 • December 2007
Pharo and Zhou • Controlling Cancer Pain With Pharmacotherapy 䡵 Hormonal therapy for breast or plained of severe drowsiness, but with his problem. Management is affected notprostate cancer pain (eg, tamoxifen or medications at lower doses, his pain on the 11- only by the system disease, but also by leuprolide , respectively) can provide point numeric scale was 10. the need to provide pain relief, yet also beneficial effects.
Jeff's oncologist requested a pain man- allow for quality-of-life issues in a ter- The following case presentation agement consultation. Recommendations minally ill patient. This patient's concern describes a patient whose name and included intravenous ketamine with dose was primarily pain relief, but without other possible identifiers have been titration to effect and low-dose amitriptyline the systemic effects associated with high changed to maintain privacy. This case (10 mg/d). Because of the neuraxial metastasis doses of opioids. The quality-of-life issues vignette illustrates the issue and com- and anticoagulation, intrathecal catheter involved family interaction including his plexity involved in treating patients for implantation was not considered. Neurolytic 7- and 5-year-old sons. Jeff wished to be cancer-related pain. blocks were also not considered secondary to able to spend quality time with his family Jeff's ambulatory status. without the excessive sedation and An infusion of ketamine was started at lethargy that he had experienced.
0.1 mg/kg/h (1000 mg ketamine in 1000 mL Ketamine allowed him to have this Jeff, a 32-year-old man, was evaluated in con- of 0.9% saline solution). Hourly titration quality of life without the CNS effects, sultation for intractable leg pain. Past his- with increases of 0.1 mg/kg/h was continued. but with satisfactory pain relief. tory included metastatic colon cancer with During this time, morphine infusion was The other issue was the institution of both liver, pelvic, and bone involvement. Ini- also slowly reduced. After 5 hours, Jeff's pain. hospice at the last few days of life. Unfor- tial presentation of illness was bowel obstruc- score was 2/10 with a ketamine infusion of tunately, institution of hospice care occurs tion with abdominal pain and emesis. Surgical 0.5 mg/kg/h and morphine at 20 mg/h. Mor- too late when the usefulness of the hos- exploration revealed colon cancer with local- phine infusion was slowly reduced to 5 mg/h pice team's services cannot be used to ized lymph node involvement. Treatment with the same dosage of ketamine. Jeff rated his the fullest extent. Hospice care not only included bowel resection and several rounds pain at a score of 2/10 and reported no central includes control of pain, but it also pro- of chemotherapy. Jeff had remained symptom nervous system effects. After 5 days, the deci- vides support for both the family and free with serial computed tomography (CT) sion was made to send Jeff home with infusion the patient's medical, physical, and emo- scans showing no other regions of involve- therapy of both ketamine and morphine. Vis- tional needs.
ment of lymph nodes or liver. iting nurses assessed Jeff's pain daily and Two years after his initial presentation, consulted with a board-certified anesthesiol- Jeff sought evaluation for dyspnea, tachy- ogist specialist in pain management for rec- Pain management is an important goal in cardia, and tachypnea. Spiral CT scan showed ommendations for dosage adjustments. The holistic care of patients with cancer.
significant pulmonary embolism to the right patient remained on this therapy for 28 days. Studies have shown that effective pain pulmonary artery as well as liver metastasis. Salvage chemotherapy was planned, but control can be achieved in 90% of patients Further workup including CT scanning of because of limited intravenous access, the by following the WHO stepladder the abdomen and pelvis and bone scan. Metas- ketamine infusion was stopped. The hope was system. Major obstacles still exist that tases were present in the sacrum and femur that after prolonged infusion, NMDA recep- prevent reduction of pain in patients with bilaterally. After insertion of a vena cava tors had been reset and benefits of pain relief cancer. Education of patients, families, filter, prophylactic intramedullary rods were would continue. Jeff did well for 5 days with healthcare providers, legislators, and law inserted. Treatment for recurrence included pain controlled with escalating dosage of mor- enforcement agencies is needed to additional chemotherapy and external beam phine. Salvage chemotherapy was instituted. improve the treatment of patients with On day 6, visiting nurses reported that Jeff cancer-related pain with all the pharma- After 6 months, Jeff had recurrent pul- had intractable pain despite administration of cologic therapeutic modalities available. monary embolism and was treated with low- additional boluses and elevations in infu- molecular-weight heparin and warfarin sodium. Jeff complained of pain involving his The family decided to place Jeff in hospice 1. Jemal A, Tiwari RC, Murray T, Ghafoor A,
right leg in the distribution of L5 and S1. care and to discontinue any further inter- Samuels A, Ward E, et al. Cancer Statistics, 2004. CA:Cancer J Clin. 2004;54:8-29. Repeated CT studies showed epidural ventional therapies. Ketamine infusion was metatasis as well as infiltration with tumor in restarted with rapid escalation of dosage to 2. Fine PG. The evolving and important role of
anesthesiology in palliative care. Anesth Analg.
the body of L5. Jeff continued to complain of 0.8 mg/kg/h and morphine to 120 mg/h. Pain 2005;100:183-188. burning, searing, stabbing pain despite high was well controlled on this dosage; Jeff died 3. Abrahm JL. Promoting symptom control in pal-
doses of oral morphine sulfate in immediate- 4 days later. liative care. Semin Oncol Nurs. 1998;14(2):95-109. and sustained-release preparations and 4. Mercadante S, Fulfaro F. World Health Orga-
gabapentin. He remained hospitalized for pain nization guidelines for cancer pain: a reappraisal.
control. Despite, parenteral morphine with This case illustrates the complexity of Ann Oncol.2005;16(suppl 4):iv132-iv135. continuous infusion of 50 mg/h and inter- dealing with patients with metastatic dis- 5. Wootton M. Morphine is not the only anal-
mittent bolus of 10 mg per every 15-minute ease and its associated complications.
gesic in palliative care: literature review. J AdvNurs. 2004;45:527-532. demand, Jeff's pain was still uncontrolled The management of the pain suffered by and side effects were unsatisfactory. Jeff com- patients with cancer presents a unique Pharo and Zhou • Controlling Cancer Pain With Pharmacotherapy JAOA • Supplement 7 • Vol 107 • No 12 • December 2007 • ES31
6. McNicol E, Strassels S, Goudas L, Lau J, Carr D.
19. Cady J. Understanding opioid tolerance in
32. Demoly P, Chung KF. Pharmacology of cortico-
Nonsteroidal anti-inflammatory drugs, alone or cancer pain. Oncol Nurs Forum. 2001;28:1561-1568. steroids. Respir Med. 1998;92:385-394. combined with opioids, for cancer pain: a system-atic review. J Clin Oncol. 2004;22:1975-1992. 20. Guo-xi X, Palmer PP. RGS proteins: new players
33. Collins R, Trowman R, Norman G, Light K,
in the field of opioid signaling and tolerance mech- Birtle A, Fenwick E, et al. A systematic review of the 7. Haegerstam GAT. Pathophysiology of bone
anisms. Anesth Analg. 2005;100:1034-1042. effectiveness of docetaxel and mitoxantrome for pain: a review. Acta Orthop Scand. 2001;72:308-317. the treatment of metastatic hormone–refractory 21. Petrenko AB, Yamakura T, Baba H, Shimoji
prostate cancer. Br J Cancer. 2006;95:457-462.
8. Ballantyne JC, Mao J. Opioid therapy for chronic
K. The role of N-methyl-D-aspartate (NMDA) recep- pain. N Engl J Med. 2003;349:1943-1953. tors in pain: a review. Anesth Analg. 2003; 97:1108- 34. Gordon DH. Efficacy and safety of intravenous
bisphosphonates for patients with breast cancermetastatic to bone: a review of randomized, 9. Silvestri GA, Sherman C, Williams T, Leong SS,
22. Hocking G, Cousins M. Ketamine in chronic
double-blind, phase III trials. Clin Breast Cancer.
Flume P, Turrisi A. Caring for the dying patient pain management: an evidence-based review.
2005;6(2):125-131. with lung cancer. Chest. 2002;122:1028-1036.
Anesth Analg. 2003;97:1108-1116. 35. Guay DRP. Ibandronate, an experimental intra-
10. Patrignani P, Tacconelli S, Scuilla MG, Capone
23. Shimoyama N, Shimoyama M, Inturrisi CE,
venous bisphosphonate for osteoporosis, bone ML. New insights into COX-2 biology and inhibition.
Elliot KJ. Ketamine attenuates and reverses mor- metastases and hypercalcemia of malignancy. Phar- Brain Res Brain Res Rev. 2005;48:352-359. phine tolerance in rodents. Anesthesiology.
1996;85:1357-1366. 11. Stockler M, Vardy J, Pillai A. Warr,D.
36. Bauman G, Charette M, Reid R, Sathva J. Radio-
Acetaminophen (paracetomal) improves pain and 24. Stoelting RK. Nonbarbiturate induction agents.
pharmaceuticals for the palliation of painful bone well-being in people with advanced cancer already In: Stoelting RK, ed. Pharmacology and Physiology metastasis—a systemic review. Radiother Oncol.
receiving a strong opioid regimen: a randomized, in Anesthesia Practice. Philadelphia, Pa: JB Lippin- double-blind, placebo-controlled crossover trial.
cott Co; 1987:134 -135. J Clin Oncol. 2004;22:3389-3394.
37. Ripamonti C, Fagnoni E, Campa T, Seregni E,
25. Lussier D, Huskey AG, Portenoy RK. Adjuvant
Maccauro M, Bombardieri E. Incident pain and 12. Nussmeier NA, Whelton AA, Brown MT, Lang-
analgesics in cancer pain management. Oncolo- analgesic consumption decrease after samarium ford RM, Hoeft A, Parlow JL, et al. Complications gist. 2004;9:571-591. infusion: a pilot study. Support Care Cancer.
of the COX-2 inhibitors parecoxib and valdecoxib 26. Maizels M, McCarberg B. Antidepressants and
after cardiac surgery. N Engl J Med. 2005;352:1081- antiepileptic drugs for chronic non-cancer pain.
38. Devor M, Govrin-Lippmann R, Angelides K.
Am Fam Physician. 2005;71:483-490. NaÄ channel immunolocalization in peripheral 13. Carr DB, Goudas LC, Balk EM, Bloch R, Ion-
27. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Ivengar
mammaliam axons and changes following nerve nidis JP, Lau J. Evidence report on the treatment of S. Duloxetine vs. placebo in patients with painful injury and neuroma formation. J Neurosci.
pain in cancer patients. J Nat Cancer Inst Monogr.
diabetic neuropathy. Pain. 2005;116(1-2):109-118. 28. Epstein JB, Epstein JD, Epstein MS, Oien H,
39. Padilla M, Clark GT, Merrill RL. Topical medi-
14. Mercadante S, Ferrera P, Villari P, Casuccio A.
Truelove EL. Management of pain in cancer cations for orofacial neuropathic pain: a review.
Rapid switching between transdermal fentanyl patients with oral mucositis: follow-up of multiple J Am Dent Assoc. 2000;131:184-195.
and methadone in cancer patients. J Clin Oncol.
doses of Doxepin oral rises. J Pain Symptom 2005;23:5229-5234. 15. Bailey PL, Egan TD, Stanley TH. Intravenous
29. Eisenberg E, River Y Shifrin A, Krivoy N.
opioid anesthetic. In: Miller RD, ed. Anesthesia.
Antiepileptic drugs in the treatment of neuro- Editor's Note
5th Ed. Philadelphia, Pa: Churchill Livingstone; pathic pain. Drugs. 2007;67:1265-1289. The JAOA advises readers to refer to the current edition of the Physicians' Desk 30. Adriaensen H, Plaghki K, Mathieu C, Joffroy A,
16. Manfredonia JF. Prescribing methadone for
Reference or drug manufacturers' package Vissers K. Critical review of oral drug treatments for pain management in end-of-life care. J Am inserts for full prescribing information for diabetic neuropathic pain—clinical outcomes based Osteopath. 2007;107(suppl 4):ES17-ES21. Available opioid and nonopioid analgesics and to on efficacy and safety data from placebo-con- keep current with US Food and Drug trolled and direct comparative studies. Diabetes Administration advisories and alerts Metab Res Rev. 2005;21:231-240. regarding COX-2 inhibitors and nonselective 17. Physicians' Desk Reference. 61st ed. Montvale,
31. Dunteman ED. Levetiracetam as an adjunc-
NSAIDs via documents posted to the FDA NJ: Thomson Healthcare; 2007.
tive analgesic in neoplastic plexopathies: case series Web page available at www.fda.gov/cder/drug/infopage/COX2. and commentary. J Pain Palliat Care Pharmacother.
htm#Fentora. Accessed November 19, 2007.
2005;19(1):35-43. ES32 • JAOA • Supplement 7 • Vol 107 • No 12 • December 2007
Pharo and Zhou • Controlling Cancer Pain With Pharmacotherapy

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