Dept Of Anesthesiology & Critical Care, University Of Pennsylvania School Of Medicine

There is an increased methadone use for pain therapy; there is a marked increase in methadone related deaths. Are they related?

According to one of my pain therapy sources, methadone, which is longer acting and does not cause euphoria compared to other narcotics, is increasingly being used for the treatment of chronic pain.”  However there now appears to be an increase death associated with methadone use.  According to a recent Philadelphia Inquirer article (April 18, 2008), death of people taking methadone is increasing at a very rapid rate.  According to the National Center for Health Statistics the number of methadone deaths across the United States rose from 786 in 1999 to 4,462 in 2005.The Inquirer notes that the drug is easily diverted to the black market.  They state that even though methadone does not produce a “high” it is often combined with other drugs.

            Methadone has been recently associated with cardiac death in patients using this drug.  Chugh et al (1) over a four year period prospectively evaluated all patients who had sudden cardiac death and underwent investigation by the medical examiner in the metropolitan area of Portland.  Case subjects had a therapeutic blood level of methadone and these were compared to patients with no identified methadone.  Patients with recreational drug use or any drug overdose were excluded.  They found a total of 22 sudden cardiac death cases with therapeutic levels of methadone.  The most common indication for methadone use was pain control.  They found that significantly fewer of the patients taking methadone had a structural abnormality that would explain the cardiac death compared to the non methadone group.  They speculated that death in the methadone cases may have been related to an arrhythmia.  Others (2) have suggested that methadone may produce potassium ion channel blockade, prolonged QT interval and the potential for a Torsade de Pointes arrhythmia.

            The UPENN chief of pain medicine provides the following additional information: most experts believe that methadone-related deaths are attributable to 2 main issues.  First, methadone is used by relatively inexperienced clinicians who do not understand proper dosing.  In these patients, either the initial dose is too high, or dose changes are made too frequently, and the patient "over shoots" the proper dose and then experiences opioid-induced respiratory compromise.  Second is the rarer risk of Torsade de Pointes.  This appears to be an adverse event unique to methadone among the potent opioids.  Methadone appears to block the rapid component of the delayed rectifier potassium current in a dose-dependent fashion, and as a result may prolong the QT interval.  This effect is most commonly observed in patients taking high-dose methadone (> 100 mg/day), but has been reported at lower doses.  The good news is that QTc intervals of 500 msec or more are predictive of an increased risk for Torsade de Pointes.  One of our pain doctors obtains an ECG on patients on methadone if their daily dose is > 80 mg.

            With respect to methadone there is a large inter-individual variability and that reaching a steady state can take 7 days or more.

1)      Chugh SS et al: A community based evaluation of sudden death associated with therapeutic levels of methadone.  Am J Med 2008;121:66-71

2)      Maremmani I et al: QTc interval prolongation in patients on long-term methadone maintenance therapy.  Eur Addict Res 2005;11:44-49

David S. Smith, M.D., Ph.D.

Postoperative analgesia – a multimodality approach

Myles and Power discuss their approach to post operative analgesia. Acetaminophen (oral or intravenous) at fixed dosing intervals forms the base of their post operative analgesic regimen to which is added a narcotic such as morphine for major surgery or oral oxycodone for “minor” procedures.  They emphasize that “simple standardized analgesic regimens can lead to better pain control and reduced post operative complications.”  They also note that in addition to pain scores to titrate narcotic needs, sedation scores may provide an early warning of opioid overdose.  They note the benefits of PCA compared to intermittent nurse provided doses and the use of local anesthetic blocks of various kinds to reduce narcotic use.  They feel strongly that multimodality approaches provide the best route to good pain relief while minimizing the risk of complications (Clinical update: post operative analgesia.  The Lancet 2007;369:810-812)

David S. Smith, M.D., Ph.D.

A novel approach to analgesia

Hot peppers make it hurt less – Binshtok and colleagues reported one of those very clever experiments that creates envy from those less imaginative.  They used capsaicin to selectively open TRPV1 channels allowing an otherwise impermeant local anesthetic (QX-314) to enter and block the sensory channel with absolutely no motor blockade.  QX-314 is a charged lidocaine derivative that will not penetrate neuronal membranes and thus has no local anesthetic activity when applied to small sensory nerves.  Capsaicin is a selective agonist for the noxious heat sensitive channel TRPV1 but not for motor channels.  The effect of capsaicin on the channel allowed QX-314 access to the local anesthetic site of action and thus blocked further sodium influx though these channels.  Hind paw injection of QX-314 together with capsaicin produced a long acting (> 2h) increase in mechanical and thermal nociceptive thresholds.  When applied near the sciatic nerve there was a long acting decrease in pain sensitivity without motor blockade in contrast to application of lidocaine which produced both sensory and motor block (Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers.  Nature 2007;449:607-610).

David S. Smith, M.D., Ph.D.

Pain relief after colorectal surgery

Epidural analgesia after colorectal surgery was examined via a meta-analysis of 16 trials published between 1987 and 2005.  Epidural analgesia compared to parenteral opioid analgesia provided significantly reduced pains scores and decreased duration of ileus.  There was an increase in the incidence of pruritus, urinary retention and hypotension with epidural analgesia.  There was no difference in duration of hospital stay (Marret E et al: Meta-analysis of epidural analgesia versus parenteral opioid analgesia after colorectal surgery.  B J Surg 2007;94:665-673.

David S. Smith, M.D., Ph.D.

Narcotic Related Adverse Events

As presented in Moore TJ (1) and discussed in Med Page Today (September 10, 2007) reports to the FDA of drug related injury, disability and death nearly tripled during the period of 1998 – 2005.  Analgesics and immune system modulators accounted for the majority of adverse events.  Oxycodone was suspected in 5548 of 15107 reported deaths.  Michael Ashburn (our new director of pain medicine) has published three papers investigating aspects of opioid analgesia related adverse events.  In 1990 he and his colleagues (2) determined the frequency of hypoxemia and apnea after sedation with midazolam and fentanyl.  Using volunteers they found that midazolam alone (0.05 mg/kg) had no effect.  Fentanyl alone (2 mcg/kg) produced hypoxemia (oxygen saturation less than 90%) in half the subjects but no apnea.  However, the combination of midazolam and fentanyl produced hypoxemia in 11 of 12 subjects and apnea in 6 of 12 subjects.  In 1994, Ashburn, Love and Pace (3) reported on respiratory related critical events associated with patient controlled analgesia.  They evaluated 3785 patients who received PCA for a total of 11521 patient care days.  Fourteen critical events occurred and four of these led to increased patient care requirements. More recently (2003) he and his associates (4) determined that opioid related adverse events had an incidence of 2.7% in a population of 60,722 surgical patients who received opioids and these were associated with a longer length of stay and an increased median cost of $840.  The commonest adverse events were nausea and vomiting (67%) followed by rash, hives or itching (33.5%).  White and Kehlet (5) caution about the reliance on opioids alone for the control of acute perioperative or for chronic pain.  They cite reports of rapidly emerging opioid tolerance and hyperalgesia in cancer patients receiving oral morphine.  They summarize a number of studies suggesting that since the Joint Commission standards for pain control there has been in increase in opioid-induced adverse events which include respiratory depression.  The dangers of opioids are now being reflected in the FDA data which confirms the findings of earlier studies.  Though opioids are important analgesics they also have significant risks.  References: 1) Moore TJ: Serious adverse drug events reported to the Food and Drug Administration, 1998 – 2005. Arch Intern Med 2007;167:1752; 2) Bailey PL et al: Frequent hypoxemia and apnea after sedation with midazolam and fentanyl. Anesthesiology 1990;73:826-30; 3) Ashburn MA et al: Respiratory-related critical incidents with intravenous patient-controlled analgesia.  Clin J Pain 1994;10:52-6; 4) Oderda GM et al: Cost of opioid-related adverse drug events in surgical patients.  J Pain Symptom Management 2003;25:276-83. 5) White PF, Kehlet H: Improving pain management: Are we jumping from the frying pan into the fire? Anesth Analg 2007;105:10 – 12.

David S. Smith, M.D., Ph.D.

Opiods for the treatment of chronic pain: is there a risk to the physician?

            Dr Ashburn writes, in the June 17, 2007 edition of The New York Times Magazine, Tina Rosenberg wrote the cover story entitled "When is a pain doctor a drug pusher? (http://www.nytimes.com/2007/06/17/magazine/17pain-t.html?ex=1185508800&en=96ed7956679244fb&ei=5070) The focus of this article includes a discussion of the upsurge in the use of potent opioids for the treatment of chronic pain.  The article points out that as opioids have become more widely used, so has the investigation and prosecution of some of the physicians who prescribe these drugs.  In addition, several states have developed or are in the process of developing guidelines that place limits on the amounts of opioids that can be prescribed.  A summary of pain management guidelines by state can be found at http://www.fsmb.org/pdf/grpol_pain_management.pdf.  These guidelines often require patients who receive high doses of opioids (as defined by the governmental authority) be seen by a pain expert.

            The article reports on the recent prosecution and conviction of Dr. McIver.  McIver was convicted in federal court of 1 count of conspiracy to distribute controlled substances, 8 counts of distribution of controlled substances, and 1 count of dispensing drugs that resulted in a death of a patient.  He is serving concurrent sentences of 20 years for 1 of these counts and 30 years for another of these counts.  His appeals of the convictions and sentencing have failed.

            Dr. McIver appears to have prescribed very high doses of opioids to some patients.  In addition, he kept very poor records.  One investigator described his records by stating “His patient records were manila envelopes stuffed with receipts.”  In addition, it appears that McIver continued to prescribe potent opioids even when he became concerned that patients were abusing or diverting the opioids he was prescribing.

            Dr. McIver's conviction points out the importance of using common sense when prescribing opioids as a part of patient care.  Model guidelines for the use of opioids for the treatment of chronic pain have been published by the Federation of State Medical Boards of the United States.  A copy of these guidelines can be found at http://www.fsmb.org/pdf/2004_grpol_Controlled_Substances.pdf .  However, the big question is when does physician behavior stop being an issue to be addressed by the state medical board and start being a criminal offense?  Clearly, physicians who prescribe opioids need to do so in accordance with current medical practice and must be diligent with their medical records.

            This article raises several issues that anesthesiologists will be dealing with for some time.  How strong are the data supporting the assumption that opioids are beneficial for the long-term treatment of chronic pain?  How well do we understand the risks of harm associated with this practice, which may include fundamental changes in endocrine function, hyperalgesia, changes in sexual function, and addiction, as well as the commonly-described opioid-induced adverse effects?  What is the appropriate role of governmental agencies in establishing rules for medical practice?  Do pain physicians have the interest or resources to be responsible for the care of patients requiring high-dose chronic opioid therapy?  What are the risks to the physician who prescribes opioids, and what measures can reasonably be taken to avoid investigation and possible prosecution for this aspect of medical care?

     Michael Ashburn, M.D. is Director of Pain Medicine and Palliative Care in the Department of Anesthesiology and Critical Care, University of Pennsylvania