Monday, April 5, 2010

#229 Seizure Management in the Dying Patient

FAST FACTS AND CONCEPTS #229

SEIZURE MANAGEMENT IN THE DYING PATIENT

Jennifer Connelly MD and David E Weissman MD

Background
 Management of seizures in the dying patient without intravenous access, such as is in the home environment, is challenging. Seizures in this population can be due to primary or metastatic brain cancers, strokes, toxic/metabolic causes including hypoglycemia, or pre-existing seizure disorders. The actual incidence of seizures in dying patients is unknown, and while likely uncommon, they can cause tremendous distress to patients and families. This Fast Fact reviews management strategies for seizures near the end of life.



Seizure Prophylaxis
 Up to 40% of patients with brain tumors have a seizure at the time of diagnosis and another 20% develop seizures during the course of the illness. Although antiepileptic drugs (AEDs) are commonly started as prophylaxis at the time of brain tumor diagnosis, they have not been found to prevent seizures and the American Academy of Neurology Clinical Practice Guidelines do not support this practice (1). Thus, prophylactic AEDs can be safely discontinued in patients with brain tumors who have never had a seizure. For patients with a seizure history, including those with brain tumors, AEDs should be continued as long as possible. For patients who lose an enteric route and have no intravenous access, rectal administration of prophylactic AEDs is possible. Clinical judgment should be used as to whether to continue AEDs in this setting; it can be appropriate to simply stop them, particularly if the patient’s prognosis is very short. Phenobarbital, pentobarbital, carbamazepine, valproic acid, and lamotrigine can all be given rectally. Rectal absorption of other prophylactic AEDs is undefined and they should not be administered. None of the aforementioned AEDs need dose adjustments for rectal administration. Carbamazepine should be divided into small doses administered 6-8 times a day. Lamotrigone is administered rectally by crushing and suspending the chewable tablets in 10 mL of water. When clinically indicated, drug levels of lamotrigine should be monitored as rectal absorption is erratic.



Seizure Management

• Single self-limited seizure: Check for treatable causes such as hypoglycemia. If no reversible cause is identified, initiation of maintenance AED therapy should be considered, particularly if the patient is expected to survive more than a few weeks.

• Acute seizure or status epilepticus:

o Non-intravenous routes: Rectal diazepam (0.2 mg/kg or 10-20mg) is the drug of choice for status epilepticus and acute seizures lasting greater than two minutes due to its bioavailability, ease of administration, and short time to peak serum concentration (< 20 minutes). Diazepam can be repeated hourly until the seizure stops. Some authors suggest continuing 20 mg per rectum nightly to reduce the occurrence of further seizure events. Other rectal benzodiazepines are available (clonazepam, lorazepam, and midazolam), but take longer to reach peak serum levels. Sublingual lorazepam and intranasal midazolam are also available, but their use in the adult population is not well-studied.

o Parenteral therapy: When available, intravenous and subcutaneous benzodiazepines can be used and are usually effective at stopping a seizure in progress; intravenous lorazepam is preferred due to its long half-life. Clonazepam and midazolam can be given subcutaneously at doses similar to the intravenous route. If seizure activity persists, additional anti-epileptic medication should be provided using a loading and then maintenance dose. Patients with refractory seizures who have short prognoses and comfort-oriented goals of care should be considered for an anti-epileptic sedative such as midazolam or a barbiturate with the goal of deep sedation (see Fast Facts #106,107).



Parenteral AED Dosing and Routes:

Drug Status loading dose Maintenance dose

Diazepam 0.2 mg/kg or 10-20 mg PR 20 mg PR nightly

Lorazepam 0.1 mg/kg IV or IM



Midazolam 0.1-0.3 mg/kg IV or SC Titrate to control refractory seizures if needed

Clonazepam 1 mg IV or SC

Phenytoin 20 mg/kg IV 4-5 mg/kg/day IV divided TID

Fosphenytoin 20 mg/kg IV or IM 4-5 mg/kg/day IV or IM divided TID

Phenobarbital 10-15 mg/kg 1-3 mg/kg/day IV or IM

1200 mg/day SC (2)



Family Education
Family members should be counseled that all medications used to manage seizures can cause sedation and cardiopulmonary depression. Family members who have witnessed prior seizures often have great fear about seizure recurrence. Many hospice agencies have established seizure protocols and medication kits which can be stored at home, and will collaborate with physicians and families on establishing a ‘seizure plan’ for acute seizures. It is important to review with the family seizure safety, including not putting anything in the patient’s mouth and making sure the patient is in a safe environment.



References

1. Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurol. 2000; 54:1886-1893.

2. Krouwer H, Pallagi J, Graves N. Management of seizures in brain tumor patients at the end of life. J Palliat Med. 2000;3:465-475.

3. Davis M, Walsh D, LeGrand S, et al. Symptom control in cancer patients: the clinical pharmacolog and therapeutic role of suppositories and rectal suspensions. Support Care Cancer. 2002; 10:117-138.

4. Brown L, Bergen DC, Kotagal P, et al. Safety of Diastat when given at larger-than-recommended doses for acute repetitive seizures. Neurol. 2001; 56:1112.

5. Voltz R, Borasio GD. Palliative therapy in the terminal stage of neurological disease. J Neurol. 1997; 244[Suppl 4]:S2-S10.

6. Droney J, Hall E. Status epilepticus in a hospice inpatient setting. J Pain Symptom Manage. 2008; 36:97-105.



Author Affiliations: Medical College of Wisconsin, Milwaukee, WI.



Fast Facts and Concepts are edited by Drew A. Rosielle MD, Palliative Care Center, Medical College of Wisconsin. For more information write to: drosiell@mcw.edu. More information, as well as the complete set of Fast Facts, are available at EPERC: http://www.mcw.edu/eperc. Readers can comment on this publication at the Fast Facts and Concepts Discussion Blog (http://epercfastfacts.blogspot.com).



Copyright/Referencing Information: Users are free to download and distribute Fast Facts for educational purposes only. Connelly J, Weissman DE. Seizure Management in the Dying Patient. Fast Facts and Concepts. April 2010; 229. Available at: http://www.eperc.mcw.edu/fastfact/ff_229.htm.

#228 Tapentadol

FAST FACTS AND CONCEPTS #228

TAPENTADOL

Rohtesh S Mehta MD, MPH and Robert M Arnold MD


Background
Tapentadol is a newly available oral analgesic, approved by the FDA in 2009 for the management of moderate to severe acute pain in adults. This Fast Fact reviews its pharmacology and use.


Pharmacology
Tapentadol is a centrally-acting, synthetic, oral mu-opioid receptor agonist which also inhibits norepinephrine and serotonin reuptake within the CNS. It is structurally and pharmacologically similar to tramadol.

Oral bioavailability ranges from 32% to 42%, with a half-life of 4 ½ hours.

The drug is metabolized in the liver (97% by Phase-2 conjugation) and excreted in the urine.

Tapentadol has no known pharmacologically active metabolites, no relevant CYP interactions, and no drug-drug interactions through cytochrome induction or inhibition (1).

There are no dosing adjustments required in mild-to-moderate renal or hepatic failure; it has not been studied in patients with severe impairments.


Research Data
The FDA approval was based on two industry-coordinated, randomized controlled studies conducted in patients with osteoarthritis and after bunionectomy. In these studies 50 mg doses of tapentadol was shown to be non-inferior to 10 mg of oxycodone immediate-release in the treatment of pain, but the incidence of nausea, vomiting, dizziness, and constipation was significantly lower (2,3). In another single-dose study involving patients undergoing molar extraction, tapentadol 200 mg demonstrated improved analgesia but higher sedation than 60 mg of oral morphine (4). Total daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have not been tested, nor has tapentadol been studied in children. Tapentadol has not been tested in cancer pain or in palliative care settings. There are not enough data to comment on whether the drug has a ceiling effect, or on its long-term safety and efficacy (the longest study was only 90 days). Finally, it has not been comparatively studied against tramadol.


Side Effects and Cautions
Tapentadol’s side effect profile is generally similar to opioids’ (although with milder GI side effects): nausea, vomiting, constipation, respiratory depression, pruritus, dizziness and drowsiness. As with tramadol, there is a theoretical increased risk of seizures, as well as serotonin syndrome if given with other serotonergic agents (e.g. antidepressants, drugs with monamine oxidase inhibitory effects). Abuse and addiction are possible as with any opioid agonist. An abstinence syndrome has not yet been described; in one study drug tapering was not required after 90 days of treatment (2).


Dosing and Cost
Tapentadol is available as 50, 75 and 100 mg immediate-release tablets. The initial dose is 50-100 mg every 4 hours (although a second dose can be given one hour after the initial dose). The average wholesale pricing for tapentadol is approximately $2 per 50 mg tab, $2.40 per 75 mg tab, and $3.20 per 100 mg tab. For comparison, tramadol costs $0.07/tab (50 mg), oxycodone costs $0.70 (15 mg tab), and morphine costs $0.18 (15 mg tab).


Summary
Tapentadol is a novel analgesic, with a 50 mg dose similar in efficacy to 10 mg of oxycodone. Currently its only clearly defined benefit over established opioids is its gentler GI side effect profile. Its cost, potential ceiling effect, safety concerns with drug interactions, and uncertainty about long-term efficacy and safety limit its current application otherwise, particularly in patients with chronic cancer pain.


References

1. Kneip C, Terlinden R, Beier H, Chen G. Investigations into the drug-drug interaction potential of tapentadol in human liver microsomes and fresh human hepatocytes. Drug Metab Lett. 2008; 2(1):67-75. PMID: 19356073.
2. Hale M, Upmalis D, Okamoto A, Lange C, Rauschkolb C. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr Med Res Opin. 2009; 25(5):1095-104. PMID: 19301989
3. Daniels S, Casson E, Stegmann JU, Oh C, Okamoto A, Rauschkolb C, Upmalis D. A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Curr Med Res Opin. 2009; 25(6):1551-61. PMID: 19445652.

4. Kleinert R, Lange C, Steup A, Black P, Goldberg J, Desjardins P. Single dose analgesic efficacy of tapentadol in postsurgical dental pain: the results of a randomized, double-blind, placebo-controlled study. Anesth Analg. 2008; 107(6):2048-55. PMID: 19020157.
Author Affiliations: University of Pittsburgh Medical Center, Pittsburgh, PA.

Fast Facts and Concepts are edited by Drew A. Rosielle MD, Palliative Care Center, Medical College of Wisconsin. For more information write to: drosiell@mcw.edu. More information, as well as the complete set of Fast Facts, are available at EPERC: http://www.mcw.edu/eperc.


Copyright/Referencing Information: Users are free to download and distribute Fast Facts for educational purposes only. Rohtesh MS, Arnold RM. Tapentadol. Fast Facts and Concepts. XXXX 2010; 228. Available at: http://www.eperc.mcw.edu/fastfact/ff_228.htm.