Absolute must-read: LA Times on the myth of OxyContin’s 12-hour analgesic effect

A-bottle-of-OxyContin-bra-007

Quick: how long does a dose of Oxycontin provide pain relief?

Most clinicians would probably say 12 hours, since the drug was extensively marketed as a twice-daily opioid analgesic and the manufacturer — Purdue Pharma — cited this originally unique convenience factor as justifying its high cost, which could exceed $630 a bottle.

In an explosive and masterfully written investigative piece by Harriet Ryan, Lisa Girion and Scott Glover,  the Los Angeles Times reported this week that in most patients the duration of the analgesic effect for OxyContin does not last nearly as long as claimed, and that this discrepancy may bear a large part of the blame for the current epidemic of opioid-related overdoses and deaths. The paper makes a number of bombshell allegations:

  • Purdue Pharma has known about this so-called “12-hour problem” from the time the drug began to be marketed, since early clinical trials had indicated that in many patients pain relief lasted only 8 hours or less.
  • Despite this, Purdue aggressively insisted that Oxycontin should only be prescribed for bid (twice daily) dosage to maintain a competitive business advantage.
  • The company and its sales representatives told physicians that if patients complained that pain relief wore off earlier than 12 hours, they should prescribe a higher bid dose rather than increasing the dosing frequency. As a result, many patients ended up on dangerously high doses of Oxycontin, were at increased risk for overdose,  were overly-sedated during much of the day, and still experienced breakthrough pain and withdrawal symptoms when the drug wore off before 12 hours were up.
  • Most importantly, the article cites experts who say that the recurring cycle of pain-relief/euphoria followed by renewed pain and withdrawal symptoms was a set-up for disaster, a scenario that one researcher called a “perfect recipe for addiction.”

The article is full of appalling facts and anecdotes:

  • The ongoing epidemic of opioid overdoses, often seen to have started when OxyContin was approved in 1995, has been associated with almost 200,000 deaths.
  • The doctor who led the Food and Drug Administration’s review of OxyContin, “left the FDA and within two years, was working for Purdue in new product development, according to his sworn testimony in a lawsuit . . .”
  • “Sales reps pitched the drug to family doctors and general practitioners to treat common conditions such as back aches and knee pain. Their hook was the convenience of twice-a-day dosing.”
  • “Company officials worried that if Oxycontin wasn’t seen as a 12-hour drug, insurance companies and hospital would balk at paying hundreds of dollars a bottle.”
  • “In an August 1996 memo headlined “$$$$$$$$$$$$$ It’s Bonus Time in the Neighborhood!” a manager reminded Tennessee reps that raising dosage strength was the key to a big payday.”
  • One Canadian study concluded that patients on higher doses of OxyContin had one chance in 32 of a fatal overdose.

This devastating article is one of the best pieces of medical reporting I’ve every seen. Absolutely, absolutely a must-read.

The Times’ editorial about the article is also well worth reading

To read my Emergency Medicine News column on “The Dark Truth Behind Pain as the Fifth Vital Sign,” click here.

Cardiac effects of loperamide overdose

Loperamide3 out of 5 stars

Not your regular high: cardiac dysrhythmias caused by loperamide. Wightman RS et al. Clin Toxicol 2016 Jun;54:454-458

Abstract

Loperamide is an over-the-counter anti-diarrhea medication that is available without prescription under a variety of brand names including Imodium. In therapeutic doses, loperamide acts as a peripheral mu-opioid receptor agonist but doesn’t cross the blood-brain barrier (BBB). However, in massive overdose loperamide can enter the brain and cause central opioid toxicity, including altered mental status and respiratory.

Although previously loperamide was thought to have little abuse potential, recent reports indicates that it’s increasing being used to produce a recreational “high” or to self-treat opioid withdrawal. It is sometimes called the “poor man’s methadone.”

A little-known manifestation of loperamide toxicity is cardiac dysrhythmias. This case report describes a 48-year-old woman who had ingested up to 40 tablets 2-mg loperamide daily for several weeks to “get a high.” On presentation to hospital she was somnolent and had slurred speech but had stable vital signs. EKG showed markedly increased QRS (164 ms) and QT (582 ms) intervals and no p-waves. After admission to the intensive care unit, she had repeated runs of non-sustained ventricular tachycardia that did not require specific treatment.

A loperamide level was sent and came back at 210 ng/mL (therapeutic ~ 1.2 ng/mL.) The authors state that this is the highest level ever reported in a non-fatal loperamide overdose.

In their discussion, the authors note that loperamide blocks cardiac potassium channels, an effect that would explain the QT prolongation. The authors speculate that QRS widening seen in this case was caused by sodium channel blockade.

Ii would point out that the authors claim that in 2 previously reported cases of loperamide overdose the resulting dysrhythmias were resistant to lipid emulsion rescue therapy. I pulled the relevant papers, and upon review it was not at all clear that neither the data reported by Marraffa et al nor by Enakpene et al were sufficient to support that claim

Bedside echocardiography findings in carbon monoxide-poisoned patients

4 out of 5 stars

Incidence and patterns of cardiomyopathy in carbon monoxide-poisoned patients with myocardial injury. Cha YS et al. Clin Toxicol 2016 Apr 11 [Epub ahead of print]

Abstract

At last year’s Social Media and Critical Care (SMACC) conference in Chicago, I gave a talk remarking on how bedside ultrasound imaging in critically ill toxicology patients is underused and little studied. I suggested that it could provide crucial information in a number of settings. For example, visualizing the inferior vena cava (IVC) in salicylate toxicity to help guide rehydration, or evaluating left ventricular (LV) function to distinguish myocardial dysfunction from vasodilation in the unstable hypotensive patient with calcium channel blocker overdose.

I suggested that a simple, two part protocol looking at the IVC and left ventricle in these patients was an idea whose time had come. Building on the rapid adoption of the FAST and RUSH exams, I suggested that this protocol should be called Toxicologic Ultrasound in SHock — the TUSH exam. (Pro tip: do not search this on Google, especially at work.)

Therefore, I was delighted to see this Korean study and the accompanying editorial. The authors did serial transthoracic echocardiograms on 43 consecutive patients with carbon monoxide poisoning and laboratory evidence of myocardial injury (elevated high-sensitivity troponin I.) The echocardiograms were read by 2 cardiologists.

Eleven of the 43 patients had normal LV systolic function (ejection fraction > 50%), 22 patients had global LV dysfunction and 10 had regional wall motion abnormality not reflecting coronary artery distribution but resembling Takotsubo cardiomyopathy.  The patients with global LV dysfunction recovered normal LV function more rapidly than those with findings suggestive of Takotsubo syndrome.

The authors list a number of limitations inherent in this study, including the small number of patients, the exclusion of patients who received hyperbaric oxygen therapy or had normal high-sensitivity troponin I levels, and the inability of this study design to evaluate if and how the echo findings should impact clinical management. At this point we really don’t know how to use these findings clinically, although the authors state that they are planning to study that question.

To be sure, this is a very preliminary study. However, the short accompanying commentary “The echoes of intoxication” by Gallic et al is a must-read. The authors emphasize two potential benefits of bedside echocardiography in evaluating critical poisoned patients:

“The first is the recognition that there exists a plurality of clinical manifestations of systemic insult, and that the cardiac manifestations that often contribute to hemodynamic instability are well identified with echocardiography. The second is the demonstration that beyond identifying pathology, echocardiography can be performed at the bedside to characterize the severity of cardiac dysfunction in acutely poisoned patients and directly impact the clinical management of hemodynamically unstable patients. The physician can quickly make rational decisions about intravenous fluid administration and vasopressors with information from echocardiography in addition to obtaining information about the patient’s likely disease progression . . .”

I could not agree more.

 

 

 

Metronidazole-induced cerebellar syndrome

Metronidazole_encephalopathy3.5 out of 5 stars

Metronidazole-Associated Encephalopathy. Farmakiotis D, Zeluff B. N Engl J Med 2016 Apr 14;374:1465

Full Text           

Exposure to metronidazole (Flagyl) can precipitate a subacute cerebellar syndrome, typically manifested with dysarthria and ataxia, with or without cognitive impairment. This adverse effect is uncommon and little-appreciated. Although usually associated with prolonged exposure to the antibiotic for treatment of conditions such as abscesses of Clostridium difficile-associated diarrhea and occurring after total cumulative dose > 20 gm, the syndrome can occur after lower doses. Risk factors include liver disease.

Typical MRI findings include symmetric, enhanced areas in the cerebellar dentate nuclei using a fluid-attenuated inversion recovery (FLAIR) technique. [NOTE: The MRI image above shows characteristic findings, but does not illustrate the case discussed in this article. The open-access full text has very good pictures.) MRI changes and neurological symptoms usually resolve when metronidazole is discontinued.

This case report is very brief, well illustrated, and worth reading.