Practice Issues Address correspondence to Dr Michael D. Perloff, Department of Neurology, Boston University School of Medicine, 72 E. Concord St C3, Boston, MA 02118, [email protected]. Relationship Disclosure: Dr Perloff has provided expert testimony for legal cases on neurologic pain and opioid toxicity. Unlabeled Use of Products/Investigational Use Disclosure: Dr Perloff reports no disclosure. * 2015, American Academy of Neurology.

Practical Considerations in Opioid Use for Brain Neoplasm Michael D. Perloff, MD, PhD ABSTRACT Neurologists are often on the front lines of diagnosis for primary and metastatic brain tumors. Patients with brain tumors typically have multiple comorbidities and pain generators beyond headache, necessitating opioid therapy. Opioid-based pain relief and safety in the medically ill patient are complex. While using the lowest-potency opioid with adjunct medications is always prudent, patients with brain tumors frequently require dose escalation. Opioid selection and use is based on the patient’s respiratory and cardiac function as well as drug clearance capability. Specific opioid combinations, employing long-acting and short-acting drugs, have greater efficacy in specific patient profiles and make adverse drug reactions, toxicity, abuse, and diversion less likely. Continuum (Minneap Minn) 2015;21(2):480–486.

Case A 63-year-old woman with a history of lung adenocarcinoma (status post upper lobe resection and chemotherapy), type 2 diabetes mellitus, and peripheral neuropathy presented with worsening headache and left arm weakness. Over the previous 3 to 4 weeks, she developed holocephalic headaches with a pressure quality. At first, her headaches were adequately managed with nonsteroidal anti-inflammatory drugs (NSAIDs) and standing gabapentin and tramadol (for peripheral neuropathy). Her headaches then became much more painful, particularly in the morning. Over the previous week, she developed trouble using her left arm and hand, began dropping things, and felt clumsy. Her examination demonstrated left arm weakness in an upper motor neuron pattern as well as left-sided hyperreflexia and a left visual field deficit. CT scans demonstrated a contrast-enhancing right frontal brain mass with associated edema and a new lung mass. She was admitted to the hospital. IV dexamethasone was started, and her pain was controlled with IV morphine. Her internist held her tramadol because of seizure concerns, and he also held her gabapentin as her creatinine was 1.5 mg/dL compared to her previous level of 1.3 mg/dL.

As workup for suspected metastasis begins, acute pain and medical comorbidities must be managed. Although gabapentin clearance is completely renal,1 discontinuing gabapentin was likely a poor choice in this case. Not only are peripheral neuropathy symptoms exacerbated with the stasis of hospital admission, but gabapentin has proven adjunctive use in cancer and perisurgical pain.2 Concern about gabapentin

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toxicity with acute renal failure and medical comorbidities is reasonable, but the dose can be adjusted based on creatinine clearance in acclimated patients.1,3 Tramadol is a weak opioid, with central effects on serotonin and norepinephrine. Although it has wide use across pain spectrums, its abuse potential appears very low, likely secondary to its mechanism of action.4 Tramadol is usually well tolerated, with some patients having gastrointestinal upset or dizziness. Another concern with tramadol is a lowered seizure threshold. Postmarketing surveillance reported 124 new-onset seizure events in tramadol users in the first 2 years following US Food and Drug Administration (FDA) approval.5 Younger tramadol users are at much higher risk, with patients over age 59 rarely having tramadol-related seizure events.5,6 Furthermore, tramadol-related seizure events typically occur at doses of 200 mg or higher,7,8 while common practice clinical doses are 50 mg to 100 mg. Typical factors predisposing patients to seizure (eg, epilepsy, head trauma, alcohol and drug abuse, CNS infection, stroke) similarly make tramadol-evoked seizure more likely.6,9 The patient in this case had a new CNS lesion but no other seizure risk factors; low-dose tramadol could have been initially continued while she was transitioned to conventional opioids, as opposed to abrupt tramadol cessation.

Case Continued Overnight, the patient had dramatic worsening of her headache and lower extremity paresthesia. She had mild confusion at times but her examination was otherwise unchanged. Scheduled IV morphine dosing was required to control pain. Morphine ER (extended release) 15 mg every 8 hours was initiated in the morning. Over the late-day nursing shift, the patient became obtunded with slowed respirations. She was transferred to the medical intensive care unit. Mental status and respirations normalized with morphine cessation and IV naloxone. Her creatinine was noted to be 1.8 mg/dL, and IV fluids were initiated. Gabapentin was restarted at 300 mg 2 times a day and upward titration planned. A fentanyl patch 12 mcg every 72 hours was placed, and 1 mg oral hydromorphone up to 4 times a day as needed was started for pain control with good benefit and no noted adverse reactions.

Opioid management in patients with cancer is complex. Morphine is commonly used in the hospital setting because of its familiarity. While morphine has extensive hepatic metabolism, active metabolites morphine-6-glucuronide and normorphine require renal clearance. In the setting of renal impairment, respiratory suppression and CNS toxicity can easily occur at typical clinical doses. This occurs because of active metabolites present in CSF and plasma, even after the parent morphine is cleared.10 Complicating morphine use in patients with cancer, 20% have a creatinine clearance less than 60 mL/min, making renal failure four times more common in patients with cancer than in the general population.11 Oxycodone, hydromorphone, and fentanyl are all well tolerated in renal failure with little to no change in pharmacokinetics and dynamics,11,12 therefore, they are better choices for these patients. While acute renal failure can often be reversed, chronic hepatic failure is commonly encountered in patients with cancer. All opioids have some hepatic metabolism. Oxycodone is difficult to use in liver failure as metabolism and subsequent plasma levels can be more variable and therefore unpredictable.12 Hydromorphone, fentanyl, Continuum (Minneap Minn) 2015;21(2):480–486

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tramadol, and methadone can be used in liver failure. Dose reduction may be required with hydromorphone, tramadol, and methadone. Fentanyl does not usually require dose adjustment in mild liver failure owing to ease of cytochrome P450-mediated metabolism, extrahepatic metabolism (intestine and kidney), and inactive metabolites.12 Because fentanyl and methadone are heavily protein bound, dose reduction or slow titration should be considered in the setting of hypoalbuminemia or hypoproteinemia. In the setting of concurrent liver and renal failure, fentanyl and hydromorphone appear to be the best choices. Hydromorphone and fentanyl have the added advantage of more flexible administration with IV, transdermal/buccal (fentanyl), and oral (hydromorphone) forms. Transitioning patients from inpatient pain control to outpatient or hospice pain control usually involves changing drug administration to non-IV formulations. Prescribing opioids in the outpatient setting has the confounders of potential abuse, misuse, diversion, and overdose. These problems are well documented in people with and without cancer.13,14 Pre-evaluation of risk factors for abuse and patient drug monitoring are key for safe delivery of opioid therapy; these topics are well article on using opioids for neuropathic pain.15 described in a previous In chronic opioid therapy, a combination of a long-acting opioid with an alternative agent as a short-acting medication for breakthrough pain is optimal as two different opioids can often achieve lower total doses because of incomplete crosstolerance (Practice Table 1). Sustained-release morphine, oxycodone, and transdermal fentanyl are reasonable long-acting opioid choices, with sustained-release morphine and transdermal fentanyl having less abuse potential.16 Adverse outcomes with opioid use typically take place in the setting of abuse, overdose, medical illness (drug clearance failure), or inappropriate dosing in a patient who is opioid naı¨ve (Practice Table 2). Careful clinical assessment, with a good opioid knowledge base and close patient follow-up, is the best practice (Practice Table 3). of Common PRACTICE TABLE 1 Approximate Dose Equivalences Long-Acting Opioidsa,b Theoretical Doses Morphine ‘‘Equivalents’’ 50 mg/d

100 mg/d

300 mg/d

Morphine 30 mg divided extended release every 8Y12 hours

60 mg divided every 8Y12 hours

180 mg divided every 8Y12 hours

Oxycodone 20 mg/d divided extended release every 12 hours

40 mg/d divided every 12 hours

120 mg/d divided every 12 hours

Transdermal fentanyl

12 mcgY25 mcg every 37 mcg every 72 hours 72 hours

100 mcg every 72 hours

Methadone

7.5 mg/d divided every 8 hours

20 mg/d divided every 8 hours

10 mg/dY12.5 mg/d divided every 8 hours

a

When transitioning from one long-acting opioid to another, ‘‘incomplete cross tolerance’’ can be assumed and 50% to 70% of the dose equivalence can be used to achieve the same or improved pain efficacy. Short-acting opioids used to supplement as needed. b Morphine equivalents are based on available opioid dose equivalence charts or see the web-based Johns Hopkins opioid conversion program at www.hopweb.org.

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a PRACTICE TABLE 2 Adverse Reactions of Common Opioids

Common Adverse Reactions

Serious Adverse Reactions

Morphine

Pruritus, vomiting and gastrointestinal (GI) upset, constipation, headache, somnolence and mental clouding, dry mouth, diaphoresis, decreased libido (chronic)

Respiratory depression, cardiac arrest, hypotension, ileus, increased intracranial pressure, bradycardia, anaphylaxis

Oxycodone

Similar to morphine, but with fewer GI symptoms reported

Similar to morphine

Methadone

Similar to morphine; delayed adverse effects (days to 1 week)

Similar to morphine; QT prolongation/arrhythmia; serotonin syndrome

Transdermal fentanyl

Similar to morphine Similar to morphine, but with fewer GI symptoms reported; skin irritation, localized erythema, papules, itching, edema

Hydrocodone

Similar to morphine, but with fewer GI symptoms reported

Similar to morphine

Hydromorphone

Similar to morphine, but with fewer GI symptoms reported

Similar to morphine

Tramadol

Similar to morphine; CNS stimulation

Seizure, serotonin syndrome, respiratory depression, hypotension, Stevens-Johnson syndrome, anaphylaxis

Opioid

CNS = central nervous system. a Per package insert with clinical correlation.

Case Continued Over the next 2 months, the patient underwent stereotactic radiation and chemotherapy, and she developed worsening headache and chest pain. Additionally, premorbid peripheral neuropathy and orthopedic knee and low back pain became much more bothersome. The fentanyl patch was titrated to 75 mcg every 72 hours and hydromorphone 4 mg orally every 4 hours, but she still had trouble with pain control and in performing activities of daily living. After confirming a corrected QT interval (QTc) of 432 milliseconds on a recent ECG, fentanyl/hydromorphone was transitioned to methadone 5 mg every 8 hours with oxycodone 5 mg every 4 hours as needed. With this regimen, in conjunction with other medication adjuncts, she achieved good benefit. Physical therapy, local pain injections, and acupuncture were also added. She was able to perform activities of daily living independently and preserve social interactions with family and friends.

Continuum (Minneap Minn) 2015;21(2):480–486

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PRACTICE TABLE 3 Common Perceptions and Realities About Opioids Opioid

Common Perception

Reality

Morphine

Can easily cause respiratory suppression and delirium

Can easily cause respiratory suppression and delirium in the setting of renal failure

Oxycodone

Frequent abuse, diversion, and overdose

Can lead to abuse, diversion, and overdose

Methadone

Long half-life increases opioid Long half-life can cause side effects and risks delayed opioid side effects and risks; ECG QT elongation can lead to arrhythmia and death

Transdermal fentanyl

Patches have extremely variable fentanyl delivery to plasma

Hydrocodone

Hydrocodone is a weak opioid Hydrocodone has similar potency to morphine, or about 70% potency

Hydromorphone

Hydromorphone is 10 times more potent than morphine

Hydromorphone is 5Y6 times more potent than morphine

Tramadol

Commonly causes seizure

Rarely causes seizure at doses below 200 mg without other seizure risk factors

Typically patches deliver less fentanyl to plasma in first and last 12 hours (over 72 hours); some patients are rapid metabolizers and require dosing every 48 hours

ECG = electrocardiogram.

With an eye on safety and drug toxicity, variable patient comorbidities and acute disease burden drive opioid selection and titration. Transdermal fentanyl is established and commonly used with good efficacy, fewer adverse reactions, and lower abuse potential than oral opioids.17,18 Methadone is often considered a drug of choice when sustained-release morphine and transdermal fentanyl fail.19Y22 Methadone is comparable to morphine at the opioid mu receptor, and it has greater affinity at the opioid delta receptor.21 Furthermore, methadone is an N-methyl-D-aspartate (NMDA) antagonist, with potency similar to ketamine, attenuating central pain transmission independent from opioid receptors. Methadone is also a monamine uptake inhibitor that inhibits serotonin and norepinephrine synaptic reuptake,21 the same mechanism by which duloxetine benefits pain and depression. Methadone has a complex metabolism but no active metabolites. This leads to a variable half-life of 14 to 55 hours. It is well tolerated in renal failure (with no dose adjustment needed) and liver failure (little or no adjustment needed).12,21,23 Patient monitoring remains important as dose accumulation after initiation or delayed adverse effects (eg, sedation, nausea, dose-dependent QTc prolongation) can occur more than 1 week after drug initiation or increase. It is recommended to check ECG QTc prior to initiation (or dose increase) and more than 1 week later (at drug steady state) as methadone prolongs QTc and can increase the risk of arrhythmia and death.24 Most

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clinicians consider ECG QTc values of 475 milliseconds or less reassuring.21 Methadone is started at very low doses, having a threefold greater potency than a low-dose morphine equivalent (less than 50 mg oral morphine per day) and a higher than tenfold greater potency than a high-dose morphine equivalent (more than 300 mg oral morphine per day) (Practice Table 1).21,23 Methadone dosing for pain is approximately every 8 hours, as its pharmacodynamics for analgesia differ from its half-life.21,25 While opioids are useful medications for cancer-related pain, they should not necessarily be considered primary therapy. In most cases, trials of NSAIDs and neuropathic agents prior to opioids are recommended by the World Health Organization (WHO) for chronic pain.26 When morphine-equivalent doses are greater than 100 mg/d, it is best to involve an oncology-pain specialist. Treating noncancer pain and comorbid disease is also paramount for patient well-being. Physical therapy, joint injections, and acupuncture can often help with somatic symptoms. Employing psychology services, stress reduction therapies (eg, yoga, meditation, complementary/alternative medicine), and support groups can help depression and anxiety. REFERENCES 1. Miller A, Price G. Gabapentin toxicity in renal failure: the importance of dose adjustment. Pain Med 2009;10(1):190Y192. doi:10.1111/j.1526-4637.2008.00492.x. 2. Yan PZ, Butler PM, Kurowski D, Perloff MD. Beyond neuropathic pain: gabapentin use in cancer pain and perioperative pain. Clin J Pain 2014;30(7):613Y629. doi:10.1097/AJP.0000000000000014. 3. Zand L, McKian KP, Qian Q. Gabapentin toxicity in patients with chronic kidney disease: a preventable cause of morbidity. Am J Med 2010;123(4):367Y373. doi:10.1016/j.amjmed.2009.09.030. 4. Reeves RR, Burke RS. Tramadol: basic pharmacology and emerging concepts. Drugs Today (Barc) 2008;44(11):827Y836. doi:10.1358/dot.2008.44.11.1289441. 5. Kahn LH, Alderfer RJ, Graham DJ. Seizures reported with tramadol. JAMA 1997;278(20):1661. 6. Gardner JS, Blough D, Drinkard CR, et al. Tramadol and seizures: a surveillance study in a managed care population. Pharmacotherapy 2000;20(12):1423Y1431. 7. Jovanovic-Cupic V, Martinovic Z, Nesic N. Seizures associated with intoxication and abuse of tramadol. Clin Toxicol (Phila) 2006;44(2):143Y146. 8. Marquardt KA, Alsop JA, Albertson TE. Tramadol exposures reported to statewide poison control system. Ann Pharmacother 2005;39(6):1039Y1044. 9. Talaie H, Panahandeh R, Fayaznouri M, et al. Dose-independent occurrence of seizure with tramadol. J Med Toxicol 2009;5(2):63Y67. 10. D’Honneur G, Gilton A, Sandouk P, et al. Plasma and cerebrospinal fluid concentrations of morphine and morphine glucuronides after oral morphine. The influence of renal failure. Anesthesiology 1994;81(1):87Y93. 11. King S, Forbes K, Hanks GW, et al. A systematic review of the use of opioid medication for those with moderate to severe cancer pain and renal impairment: a European Palliative Care Research Collaborative opioid guidelines project. Palliat Med 2011;25(5):525Y552. doi:10.1177/0269216311406313. 12. Chandok N, Watt KD. Pain management in the cirrhotic patient: the clinical challenge. Mayo Clin Proc 2010;85(5):451Y458. doi:10.4065/mcp.2009.0534. 13. Anghelescu DL, Ehrentraut JH, Faughnan LG. Opioid misuse and abuse: risk assessment and management in patients with cancer pain. J Natl Compr Canc Netw 2013;11(8):1023Y1031. 14. Del Fabbro E. Assessment and management of chemical coping in patients with cancer. J Clin Oncol 2014;32(16):1734Y1738. doi:10.1200/JCO.2013.52.5170. 15. England JD, Franklin GM. Difficult decisions: managing chronic neuropathic pain with opioids. Continuum (Minneap Minn) 2012;18(1):181Y184. doi:10.1212/01.CON.0000411547.51324.38. Continuum (Minneap Minn) 2015;21(2):480–486

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16. Fischer B, Argento E. Prescription opioid related misuse, harms, diversion and interventions in Canada: a review. Pain Physician 2012;15(3 suppl):ES191YES203. 17. Hadley G, Derry S, Moore RA, Wiffen PJ. Transdermal fentanyl for cancer pain. Cochrane Database Syst Rev 2013;10:CD010270. doi:10.1002/14651858.CD010270.pub2. 18. Koyyalagunta D, Bruera E, Solanki DR, et al. A systematic review of randomized trials on the effectiveness of opioids for cancer pain. Pain Physician 2012;15(2 suppl):ES39YES58. 19. Rhondali W, Tremellat F, Ledoux M, et al. Methadone rotation for cancer patients with refractory pain in a palliative care unit: an observational study. J Palliat Med 2013;16(11):1382Y1387. doi:10.1089/jpm.2013.0222. 20. Wallace E, Ridley J, Bryson J, et al. Addition of methadone to another opioid in the management of moderate to severe cancer pain: a case series. J Palliat Med 2013;16(3):305Y309. doi:10.1089/jpm.2012.0335. 21. Davis MP, Walsh D. Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer 2001;9(2):73Y83. 22. Leppert W, Kowalski G. Methadone as an additional opioid for a cancer patient with severe neuropathic and bone pain not responsive to other opioids and adjuvant analgesics. J Palliat Care 2013;29(2):119Y121. 23. Pollock AB, Tegeler ML, Morgan V, Baumrucker SJ. Morphine to methadone conversion: an interpretation of published data. Am J Hosp Palliat Care 2011;28(2):135Y140. doi:10.1177/ 1049909110373508. 24. van den Beuken-van Everdingen MH, Geurts JW, Patijn J. Prolonged QT interval by methadone: relevance for daily practice? A prospective study in patients with cancer and noncancer pain. J Opioid Manag 2013;9(4):263Y267. doi:10.5055/jom.2013.0167. 25. De Conno F, Groff L, Brunelli C, et al. Clinical experience with oral methadone administration in the treatment of pain in 196 advanced cancer patients. J Clin Oncol 1996;14(10):2836Y2842. 26. Hanks G, Cherny N. Opioid analgesic therapy. In: Doyle D, Hanks G, McDonald N, editors. Oxford textbook of palliative medicine. 2nd ed. Oxford: Oxford University Press, 1998:331Y335.

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Practical considerations in opioid use for brain neoplasm.

Neurologists are often on the front lines of diagnosis for primary and metastatic brain tumors. Patients with brain tumors typically have multiple com...
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