Pain/Palliative

Breaking News: Federal Advisory Panel Recommends Ban on Vicodin and Percocet

July 1, 2009

tylenolAalok Turakhia MD

In an attempt to err on the side of safety, an advisory panel to the Federal Food and Drug Administration narrowly voted yesterday to ban the popular prescription pain medications Percocet and Vicodin, in a 20-17 vote.[1 ]Both medications are a combination of a narcotic and acetaminophen, and according to the New York Times, it was a growing concern over the safety of acetaminophen that prompted the Drug Safety and Risk Management Advisory Committee to assemble in Adelphi, Maryland early this week.[2]

Acetaminophen is one of the most popular pain medications in the world [2], and though highly effective in reducing fevers and treating headaches, there has always been great concern for hepatotoxicity. In fact, between 1998 and 2003, the most common cause of acute liver injury was this medication.[3] In the United States alone, it is estimated that nearly 400 people die and 42,000 patients are hospitalized resulting from overdose.[1] Almost half of these cases are unintentional.[2]

When ingested in large quantities, acetaminophen has the ability to cause severe centrilobular hepatic necrosis. Most of the medication is metabolized by a phase II reaction, but a small percentage is converted to NAPQI, a hepatotoxic metabolite via the cytochrome P450 pathway. Gluatathione is responsible for the detoxification by binding to NAPQI and forming the harmless, water-soluble mercaptopuric acid. However, when gluatathione levels are low, or when the CYP450 pathway is induced via alcohol, or Phenobarbital, or INH, the levels of NAPQI can quickly lead to acute liver injury.[4]

The panel’s recommendations were not limited to only banning the combination medications, however. It also proposes that the FDA reduce the highest allowed dose in over-the-counter pills from 500 milligrams to 325 milligrams, and to reduce to maximum daily dosage to less than 4000 milligrams. Interestingly, the panel voted against reducing the maximum number of pills allowed in each bottle- citing concern that imposing such a limit would ultimately hurt rural and poor consumers.[1]

Tylenol’s maker, Johnson and Johnson, “strongly disagrees” with the panel, and believes that limiting access to one pain medication will “lead to more serious adverse events as consumers shift to other over-the-counter products”.[1]
Starting in the 1990’s, the FDA has sought to reduce the incidence of liver injury resulting from acetaminophen and continues to expand public knowledge about acetaminophen overdose.[2] And though there is no obligation on the part of the federal agency to agree with and accept the panel’s recommendations, it typically does.[1]

Dr. Turakhia is a 1st year resident in internal medicine at NYU Medical Center.
1. Harris, Gardiner. “Ban Is Advised on 2 Top Pills for Pain Relief.” New York Times. 30 June 2009. Newspaper on-line. Available from http://www.nytimes.com/2009/07/01/health/01fda.html?_r=2&hp. Accessed 1 July 2009.

2. USA Food and Drug Administration. “Joint Meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee Meeting Announcement.” http://www.fda.gov/AdvisoryCommittees/Calendar/ucm143083.htm. Accessed 1 July 2009.

3. Larson, A.M., J. Polson, R.J. Fontana, et al., Acute Liver Failure Study Group (ALFSG), ‘‘Acetaminophen-Induced Acute Liver Failure: Results of a United States Multicenter, Prospective Study,” Hepatology 2005, Dec;42(6):1364-72.

4. Dienstag Jules L, “Chapter 299. Toxic and Drug-Induced Hepatitis” (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison’s Principles of Internal Medicine, 17th Edition: http://www.accessmedicine.com/content.aspx?aID=2873966.

 

Analgesia for Cirrhotics: A Practical Approach

November 20, 2008

liver.jpgCommentary by Albert B. Knapp MD, NYU Clinical Professor of Medicine (Gastroenterology)

THE CASE:
WS, a 49 yo year old Caucasian male with a known 35 year history of alcohol abuse, now presents with jaundice, tense ascites and a left shoulder fracture following a bar room brawl last night. He is admitted to the orthopedic service for elective pinning but is presently in great pain. You are consulted in regards to pain management….

THE QUESTION:
How should you approach the use of analgesia in patients with cirrhosis?

DISCUSSION:
The medical management of the cirrhotic patient is commonly fraught with peril and problems. Pain is a common complaint that ranges from a minor hindrance to a major impairment. The question of how and when to administer analgesia is a frequent and lively topic of ward management rounds.

Cirrhotic patients have a host of important problems that make straightforward analgesia potentially risky. These include profound impairments in synthetic and detoxification capacities, variable degrees of portal hypertension with resultant varices formation, frequent but sometimes subtle maldigestion and malabsorption, variable acute & and chronic mental status changes, and the omnipresent threats of pulmonary (hepatopulmonary syndrome, HPS) and renal compromise (hepatorenal syndrome, HRS).

The first clinical point to make is to assess the true extent of pain. The more intense the pain, the more powerful the analgesia required. One should always institute initial therapy with the mildest of medications and progress up the ladder of intensity analgesic strength should symptoms persist. Potential side effects vary by analgesic class but usually revolve around mental or hemodynamic status changes. This dovetails into clinical point number two, namely, to expect the unexpected.

The most efficacious way to think about analgesic agents is by class: The three most frequently used classes are acetaminophen (Tylenol, paracetamol), NSAIDs, and narcotics. I will also briefly discuss certain “crossover” compounds as well as non-classified drugs.

Tylenol (at low doses of 325mg PO every 4-6 hours) is eminently safe and bereft of any major CNS, hepatic, or hemodynamic side-effects. The medication is readily metabolized even in the most compromised of cirrhotic livers and no discernable changes in mental, portal, pulmonary or renal status are generally detected. Tylenol is a preferred analgesic, but unfortunately is too mild to meet the needs of most patients. “Extra strength” Tylenol (usually 650 mg per pill) must be used with caution as no patient with cirrhosis should receive more than 5-6 grams of Tylenol in a 24 hour period as this cumulative dose can result in sub-acute or even acute hepatic injury.

NSAIDs as a class offer far more relief than Tylenol but the potential side effects warrant careful thought. NSAIDs result in a host of metabolic changes including severe fluid retention, systemic and possibly portal hypertension, cytotoxic gastrointestinal mucosal injury as well as pronounced decreases in gastrointestinal and renal blood flow. To complicate matters, these effects are not always dose-dependent. Intravenous NSAIDs such as Toradol are very effective in acute situations but have significant gastric mucosal and hemodynamic complications. They are contraindicated for patients with chronic pain issues. Cirrhotics given NSAIDs must be carefully monitored and the need for these medications frequently re-assessed. As a rule, patients should be started concomitantly on either an H2-receptor antagonist or PPI to mitigate gastric mucosal damage and to thwart bleeding. Serum creatinine levels as well as a CBC should be performed on a daily basis. A small but reversible rise in serum creatinine is not unexpected while on therapy.

Narcotics are the most efficacious analgesics available and their major side effects are limited to mental status changes, constipation and hypotension. The first two are frequent and severe and hence preclude frequent use: Narcotics easily pass the blood-brain barrier and exacerbate underlying mental status changes. Constipation may result in an increased serum protein load with resultant CNS toxicity and frequently requires concomitant neomycin, lactulose or other cathartics for relief. Symptomatic hypotension is rare but readily manageable with IV fluids.

What about the combination class analgesics such as Tylenol with Codeine (Tylenol#3)? They are certainly effective and are used readily. Simply apply all pertinent rules and warnings for both classes when ordering.

Finally, let’s consider the use of a relatively novel agent, namely Neurontin (Gabapentin). Its true mode of action and metabolism are still open to debate but this has not stopped physicians from prescribing it. Its major side effects in healthy patients treated for post-herpetic neuralgia are asthenia and pronounced somnolence. Drug-mediated acute hepatitis has been described but is rare. Given the lack of safety data for cirrhotics and the plethora of already vetted analgesic agents, I personally deprecate their use.

In summary, the approach to analgesia in the cirrhotic population should be cautious, practical and incremental. Frequent monitoring and prompt discontinuation of the analgesic usually results in early detection and rapid resolution of untoward side effects. But again, remember to expect the unexpected…

THE ANSWER:
After performing both a thorough history and physical examination emphasizing prior medication usage/reactions as well as the extent of underlying liver and/or CNS disease, AND reviewing the patients admission blood & radiographic studies (CBC, SMA-20), INR, amylase/lipase levels, serum ammonia (if applicable) and CXR, I would have started the patient on Tylenol #3.

What is your opinion? Let me know….. albert@knappmd1.com

FDA Warns of Methadone Dangers When Used for Chronic Pain

December 12, 2006

Last week, the FDA issued a public health advisory regarding the use of methadone (trade name Dolophine) for chronic pain. Death and life threatening side effects have been reported in patients newly starting methadone treatment and patients who have switched to methadone after taking other narcotics for pain control.  According to the advisory, prescribing methadone is complex and should only be used when moderate to severe pain is not relieved by other non-narcotic pain relievers.

Although pain relief from a dose of methadone typically lasts from 4 to 6 hours, its half life ranges from 8 to 59 hours, leading to the build up of toxic levels of the drug.  The main hazard associated with methadone use is respiratory depression. Its peak respiratory depressant effects usually occur later and last longer than its peak analgesic effects. This becomes particularly dangerous during methadone initiation and dose titration.

Cases of QT prolongation and torsades de pointes can also occur with methadone use. Although these cases have largely been observed in patients taking large multiple daily doses, there have also been some cases reported in patients taking common doses.

The FDA advisory states that methadone treatment of chronic pain should only be initiated if the potential analgesic benefit exceeds the risks of treatment. Because a high degree of “opioid tolerance” does not eliminate the possibility of methadone overdose, methadone treatment should be initiated using small doses and gradual dose adjustments.

Link: FDA Advisory

Litvin, C. Clinical Correlations (NYU Internal Medicine Residency Blog) Dec. 12, 2006. Available from https://www.clinicalcorrelations.org/?p=54