Important FDA Public Health Advisory

Here is an important FDA Public Health Advisory:

Dolophine (Methadone Hydrochloride) - Reports of Death, Narcotic Overdose, and Cardiac Arrhythmias
MedWatch - The FDA Safety Information and Adverse Event Reporting Program

FDA notified healthcare professionals of reports of death and life-threatening adverse events such as respiratory depression and cardiac arrhythmias in patients receiving methadone. These adverse events are the possible result of unintentional methadone overdoses, drug interactions, and methadone's cardiac toxicities (QT prolongation and Torsades de Pointes).

The reports underscore the importance of knowing methadone's toxicities and unique pharmacologic properties, including dosing and monitoring recommendations.

FDA has reviewed reports of death and life-threatening adverse events such as respiratory depression and cardiac arrhythmias in patients receiving methadone. These adverse events are the possible result of unintentional methadone overdoses, drug interactions, and methadone’s cardiac toxicities (QT prolongation and Torsades de Pointes). Physicians prescribing methadone should be familiar with methadone’s toxicities and unique pharmacologic properties. Methadone’s elimination half-life (8-59 hours) is longer than its duration of analgesic action (4-8 hours). Methadone doses for pain should be carefully selected and slowly titrated to analgesic effect even in patients who are opioid-tolerant. Physicians should closely monitor patients when converting them from other opioids and changing the methadone dose, and thoroughly instruct patients how to take methadone. Healthcare professionals should tell patients to take no more methadone than has been prescribed without first talking to their physician.

This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.

Read the complete MedWatch 2006 Safety summary, including links to the FDA Healthcare Professional Sheet, Patient Information Sheet, and new prescribing information for Dolophine regarding this issue at this link.
_______________________________________________
Excerpt from the FDA Healthcare Professional Sheet [November 27, 2006 - Healthcare Professional Sheet - FDA]

Considerations

Methadone is an effective analgesic and may provide pain relief when other analgesics are ineffective. However, methadone can cause significant toxicities. We are highlighting important safety information from the new label about using methadone for pain. See the methadone label (Dolophine) for more details.

Methadone’s elimination half-life (8-59 hours) is longer than its duration of analgesic action (4-8 hours). Methadone’s peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects. During treatment initiation, methadone’s full analgesic effect is usually not attained until 3-5 days of dosing. Initiation and titration to analgesic effect and dose adjustments should be done cautiously and in consideration of these properties. In chronic use, methadone may be retained in the liver and then slowly released, prolonging the duration of action despite low plasma concentrations.

Cross-tolerance between methadone and other opioids is incomplete. This incomplete cross-tolerance makes the conversion of patients on other opioids to methadone complex and does not eliminate the possibility of methadone overdose, even in patients tolerant to other opioids. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists to methadone. It is critical to understand the pharmacokinetics of methadone when converting patients from other opioids to methadone. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose adjustments.

Methadone can cause serious cardiac conduction effects, including QT interval prolongation and Torsades de Pointes.

There are pharmacokinetic and pharmacodynamic drug interactions between methadone and many other drugs. Drugs administered concomitantly with methadone should be evaluated for interaction potential.

FDA homepage

Epidural (Cont-1)

Question:
What are the indications for epidural anaesthesia?

Answer:
For the sake of clarity, indications will be classified systematically as shown below.

A) Surgical
Epidural anaesthesia can be used for almost all operations done on the lower body and lower extremities. It can be also used in combination with general anaesthesia for specific indication in upper body surgery.

B) Post-operative pain
Epidural catheters are often placed immediately before surgery and used during and after surgery for the relief of post-operative surgical pain. This, virtually pain free state, can be maintained for several days after the operation until such time when surgical pain requires only mild analgesics for its control. Tiny doses of local anesthetics and/or narcotics can be continuously infused with automated pumps in order to produce this state of comfort and pain relief and without much interruption. Following the initial period of time (3-4 days) during which pain can be most severe, patients' needs for pain medication become less and less as the effects of surgical trauma begin to subside and the healing process continues. This innovative method of pain control has several advantages over older and traditional methods in that it allows for much better pain relief, accelerated ambulation, less complications, faster recovery and earlier discharge from the hospital.

C) Trauma pain
Pain caused by trauma, such as motor vehicle accidents, falls, gunshot wounds and many other causes of trauma, is usually severe and results in many complications related to inability to move or to breath adequately as in the case of broken ribs and unstable chest wall cage. If untreated, it can result in severe disabilities and complications. Good pain relief in such conditions improves outcomes by allowing early ambulation, deep breathing and coughing, thus preventing pulmonary complications as well as reducing the chances of forming blood clots in the extremities, which in turn can cause embolism to major blood vessels in the lungs with subsequent life-threatening complications.

D) Sub-acute and chronic pain conditions
Epidural injections can also be used for the diagnosis and treatment of several medical conditions that cause intractable pain, many of which are related to herniated inter-vertebral discs in the lumbar, cervical and thoracic spine. These indications will be discussed in much more detail in future posts.

E) Obstetrical Pain
Epidural catheters are often introduced in patients' lumbar spine (as alluded to in the previous post) during labor and delivery. Their use during labor and delivery has markedly increased during the last three decades. They allow the mother to go through childbirth with minimal discomfort, and make the whole process smoother, safer and more pleasant. Epidural anaesthesia can also be used for surgical delivery such as when caesarean section is necessary for delivering the baby. More will be written on this in future posts.

(Intrathecal means inside the spinal fluid)

F) Cancer related pain
Epidural catheters can be implanted and tunneled under the skin for long term use in the treatment of intractable, severe cancer pain. These catheters can be left in place for months and even years if necessary. They facilitate the ability to continuously infuse small amounts of pain relieving medications, such as morphine, directly into the spine, thus allowing the drug to be infused as close as possible to the central nervous system. Normally when narcotics are administered orally or by injection (intramuscular, under the skin or intravenous), they will have to cross a barrier between the blood and the brain in order to reach their target receptors in the central nervous system. By injecting these drugs directly into the spinal canal, close to the nerves and the spinal fluid, much smaller doses are required in order to accomplish the degree of pain relief that is possible with much higher doses of the drug when given systemically. The quality of pain relief is also far more superior when the drugs are delivered closer to the sites of their action. In other words, this method of administration allows us to get to the receptors in the central nervous system "by the back door." There will be more details on this particular subject in future posts.

To be Continued....

Epidural

Question:
What is an epidural?

Answer:
An epidural is a procedure done to either provide a painless state in order to perform surgery and to have childbirth without significant pain, or is used for the diagnosis & treatment of certain chronic pain conditions.

Anatomy: there is a potential space (epi- or extra-dural) located outside the dura which is a thick membrane surrounding the spinal cord and its terminal nerve structures that are called cauda equina. The spinal cord and all these nerve structures are bathed in a watery fluid medium called cerebrospinal fluid which provides the central nervous system with protection, pressure balance, suspension and nutrition. The spinal fluid is contained in between an internal membrane called pia mater and two external coverings (membranes), the first of which is called arachnoid mater and the second and outermost layer is called dura mater.

Just outside the dura mater there is a narrow space containing veins, fat, lymphatics, and through which the nerves travel on their way exiting the spinal canal towards their target sites in the body. This narrow space is termed Epidural Space, and is surrounded on the outside with strong ligaments, periosteum (a strong layer of tissue on the surface of bone) and bony structures that form the spine.

When a person receives an "epidural" it implies the placement of a needle into that space (epidural space), and through that needle a catheter is introduced into the epidural space, then the needle is removed and the catheter is secured in place so that medications can be delivered over extended periods of time. For other specific indications, the medications can be injected directly through the needle as a "one shot" technique, and the needle is then removed.


To be continued....