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FDA introduces new safety measures for extended-release and long-acting medications

Strategy emphasizes education for prescribers, patients on highly potent pain killers.

The U.S. Food and Drug Administration today approved a risk evaluation and mitigation strategy (REMS) for extended-release (ER) and long-acting (LA) prescription pain killers (opioids), highly potent drugs approved for moderate to severe, persistent pain that requires treatment for an extended period.

The REMS is part of a federal initiative to address the prescription drug abuse, misuse, and overdose epidemic. The REMS introduces new safety measures designed to reduce risks and improve the safe use of ER/LA opioids, while ensuring access to needed medications for patients in pain.

“Misprescribing, misuse, and abuse of extended-release and long-acting opiods are a critical and growing public health challenge,” said FDA Commissioner Margaret A. Hamburg, M.D. “The FDA’s goal with this REMS approval is to ensure that health care professionals are educated on how to safely prescribe opioids and that patients know how to safely use these drugs.”

ER/LA opioid analgesics are associated with serious risks of overuse, abuse, misuse and death and the numbers continue to rise. According to the Centers for Disease Control and Prevention, 14,800 Americans died from overdoses involving opioids in 2008. In 2009, there were 15,597 deaths involving these medications – nearly four times as many deaths compared to 1999.

“Misuse and abuse of prescription opioids is a complex problem and demands a holistic response,” said John Jenkins, M.D., director of CDER’s Office of New Drugs. “The new REMS program is one component of a multi-agency, national strategy to address this important public health issue.”

In my humble opinion – the flawed use of equianalgesic dosing tables along with lack of physicians recognizing the powerful respiratory depressant effects of prescription pain killers are the true culprits in the widespread fatal outcomes involving overdoses.The additive nature of these respiratory depressants reduces the normal respiratory drive. During sleep, apnea events can reduce breathing to the point of death. It is important to consider that when pain is abruptly relieved and the sedative effects of prescription pain killers are no longer opposed by the stimulating effects of pain, substantial respiratory depression can occur.

It has been reported that the majority of deaths (60%) occur in patients that have been prescribed pain killers as recommended by prescribing guidelines approved and endorsed by medical boards and pain management-physician associations. Only approximately 20% of deaths occur in patients on “low dose” opioid therapy and 40% in those receiving moderate doses. In comparison, it is estimated that 40% of deaths occur in individuals abusing drugs obtained through multiple prescriptions, doctor shopping, or drug diversion.

What are the reasons for so many pain killer related deaths

Maybe it is because respiratory depression occurs with many of the medications used for pain management. Think about the patient that has gained weight due to lack of exercise due to an injury. The patient that smokes or has COPD. Sleep Apnea often gets worse and is ignored by patients who believe fatigue is just a consequence of their medications. All of these factors are additive! Opioids severely worsen sleep-related breathing disorders. It appears that opioid analgesics should be used with caution or if possible avoided in patients with obstructive sleep apnea, patients with COPD, or receiving chronic benzodiazepine therapy or Soma.

Anything that sedates, as there are different mechanisms, is additive or synergistic with other drugs that cause respiratory depression. In my experience fatalities occur during the evening in the majority of pain management patient fatalities. With this in mind, extra attention and recognition of the reduction of respiratory drive associated with these commonly utilized agents is required.

Here is a guide that helps to quantify the additive nature of these treatment options. Number of stars indicates the risk of respiratory depression.

Respiratory Depression Index

***** Alcohol or Marijuana combined with any medication listed below.
***** Benzodiazepines or hypnotic agent including Ambien, opioid, Soma (combinations of these drugs)
**** High dose or long acting opioid combined with Benzodiazepine or hypnotic
*** Soma combined with opioid, without benzodiazepine or hypnotic
** Opioid alone in tolerant patient
** Benzodiazepine alone in tolerant patient
** Soma alone in tolerant patient
* Other sedating medications including Lyrica, Neurontin, antihistamines, benadryl, hydroxyzine, tricyclic antidepressants, phenergan

To further compound the problem physicians utilize opioid equianalgesic dosing charts that fail to account for important factors including ethnicity, advanced age, concomitant medication use, or comorbid conditions. Patients have different responses to different pain killers. A response to a short acting medication like Vicodin will not be similar to a response to Methadone. Chronic versus acute users of opioids are faced with different risks as well. Special consideration and warnings exist for most narcotic pain killers if clinical diagnosis or signs and symptoms of sleep apnea, COPD or cardiac impairment exist. Activating selective serotonin reuptake inhibitors (SSRIs), Wellbutrin, Cymbalta and poor timing of therapies may interfere with a patient's sleep cycle, leading to use of sleeping pills or other sedating medications. Basically, lack of sleep may prompt people to start mixing pain medications, sedatives or hypnotics, Lyrica, muscle relaxants, or over-the- counter medications (OTC). Soma (carisoprodol) has a half-life elimination of 2.4 hours and its active metabolite meprobamate has a half-life elimination of 10 hours. With most chronic pain patients receiving concomitant opioids or benzodiazepines, the risk of accumulation and respiratory depression is quite likely.

If a patient is faced with an adverse reaction to one opioid or is just failing to have pain relieved adequately, prescribers often utilize these tables to rotate or switch therapies. I do not believe that any validity exists to attempt to calculate a new dose with conversion factors used in these confusing tables. I would suggest starting with the lowest possible dose and monitoring patients during any titration schedule. Deaths and life-threatening changes in breathing and heart rate in patients newly started on opioids can occur just as patients on chronic long standing therapy can suffer fatal events. Changing to a new pain reliever might be necessary because of a perceived loss of effectiveness or side effects. Published equianalgesic tables (see an example below) have inconsistent and variable conversion ratios and data on the conversion to newer extended-release opioids, are inconsistent and potentially dangerous due to long half-lives.

If the FDA wants to prevent death from narcotic pain killers, risk factors for respiratory depression should be described and education on the topic should be required for prescribers. How many patients are obese, elderly, on illicit medications, or are chronic pain patients that occasionally use alcohol? It is impossible to calculate how many of the recent deaths that have occurred are due to hypoxemia resulting from illogical dose conversion tables or sleep apnea.

Drug | Dose

Morphine 30 mg

Hydrocodone 30 mg

Fentanyl Patch 10 mcg

Methadone 7.5 mg

Oxycodone 20 mg

Oxymorphone 10 mg

Adam M. Kaye Pharm.D. , FASCP,FCPhA
akaye@pacific.edu

References

Pain Physician: Special Opioid Issue. July 2012 Volume 15.

American Society of Interventional Pain Physicians (ASIPP) Guidelines for Responsible Opioid Prescribing in Chronic Non-Cancer Pain: Part I Evidence Assessment. Pain Physician 2012; 15:S1-S66

American Society of Interventional Pain Physicians (ASIPP) Guidelines for Responsible Opioid Prescribing in Chronic Non-Cancer Pain: Part 2 Guidance. Pain Physician 2012; 15:S67-S116

This medication or healthcare article is for information only and is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.