Posted by Dr. Jim Joyner
The FDA has recently approved Butrans, a new transdermal opioid patch. The opioid in Butrans, buprenorphine, has been available in the U.S . for several years in the form of Suboxone and Subutex sublingual tablets. The buprenorphine patch has been used for the management of chronic pain in Europe for years under the brand name of Norspan, but it is new to the U.S. market.
The transdermal patch is available in three strengths, 5mcg/hr, 10mcghr, and 20mcg/hr and provides continuous release of the medication for seven days. It is classified as a DEA schedule III controlled substance, similar to moderate-strength opioids such as Vicodin or Norco. Butrans is indicated for chronic severe non-malignant pain when lower doses of strong opioids are indicated. The highest strength Butrans patch (20mcg/hr) is approximately equivalent to 50mg of oral morphine per day. Doses greater than 20mcg/hr are not recommended due to the potential for adverse cardiac effects (QTc prolongation).
Buprenorphine is a partial mu opioid agonist. This means that, even though buprenorphine is an opioid that can produce typical opioid agonist effects (analgesia) and side effects (euphoria and respiratory depression) in hospice patients, its maximal effects are less than those of full agonists such as morphine and methadone. The agonist effects of buprenorphine increase linearly with increasing doses of the drug until at moderate doses they reach a plateau and no longer continue to increase with further increases in dose—the “ceiling effect.” For this reason, buprenorphine is believed to have a lower risk of abuse, addiction, and side effects compared to full opioid agonists. In high doses, buprenorphine may actually trigger some opioid withdrawal symptoms in persons who have been receiving other opioids and have developed some physical dependence, however, this effect may not be clinically significant at the lower doses employed with the transdermal patch.
The Butrans patch is not indicated for management of short-term post-operative pain, but may be beneficial for management of chronic severe pain in hospice patients who are vomiting or have swallowing difficulties. The eventual role of the Butrans patch in chronic pain management is still being established. Cost for the new drug was not available at the time of this post, however, as with all new branded medications, we can expect a hefty price-tag.
http://www.purduepharma.com/PI/prescription/ButransPI.pdf
Posted by Dr. Jim Joyner
Jim Joyner, Pharm.D, our Director of Clinical Operations, recently presented an informative 90 minute program about Methadone use in hospice at the Minnesota Hospice and Palliative Care Conference on April 12th. The program was titled "Methadone: Is This Old Drug in Your Future?" This well received program was presented again this month in California's beautiful Napa Valley for the San Francisco Bay Area Chapter of the Hospice and Palliative Nurses Association on May 1st. Outcome Resources specializes in assisting hospices with increasing utilization of Methadone as a long-acting opioid. While Methadone has clinically significant advantages in the palliative care setting, it is also cost effective. Our team of PharmDs can assist your hospice with education programs for nurses and prescribing physicians, consultation for specific patients, protocols and guidelines for use. Check back soon for a link to a video of Dr. Joyner's presentation. Also, see the previous articles on our Blog regarding Methadone for more information.
Posted by Dr. Jim Joyner
Introduction to Opioid Induced Pain in Hospice Patients
Howard Hughes, the famous aviation pioneer, film-maker, and billionaire business- man became notorious in his later years for bizarre behaviors that were supposedly related to his addiction to opioids that he used for chronic intractable pain following a serious airplane crash decades earlier. It has been reported that he refused to cut his hair, trim his nails or brush his teeth for years. According to a recent book by Forest Tennant, MD; Howard Hughes & Pseudoaddiction (A brief medical tutorial on a saga of intractable pain) Mr. Hughes' avoidance behaviors were probably related to the severe pain that he experienced from performing these daily activities. The author suggests that he suffered from opioid induced allodynia.
Opioids have been implicated as a possible cause of paradoxical, exaggerated pain responses including allodynia and hyperalgesia. Allodynia is a significant painful response to a stimulus that is normally not painful such as light touch. Hyperalgesia is hypersensitive severe pain response to a stimulus that would normally produce only a very mild pain response. These conditions have been described as opioid induced neurotoxicity, a term that has also encompassed symptoms of myoclonus, seizures, and delirium associated with opioid use.
Hughes died in 1976. In his time these conditions were not recognized as possible opioid induced neurotoxicity, however, in the past several years more reports of the neuroexcitatory side effects of opioids have surfaced as health care providers have become more aggressive at pain management with opioids. Awareness of this unusual phenomenon has increased with the increasing use of opioids for chronic severe pain. These conditions are characterized by generalized, non-specific pain in patients who are receiving rapidly increasing doses of opioids, such as hospice patients. The pain will worsen despite increasing doses of the opioid drug. One of the hallmarks is that the pain becomes more diffuse, with a non-specific location, spreading well beyond the pre-existing sites of pain for which drug therapy was initiated. The patient's pain presentation changes to "pain all over" that doesn't make sense in terms of the underlying disease. The increase in pain is unexplained by increased cancer progression. Allodynia and hyperalgesia have been associated with other neurological symptoms such as myoclonus, seizures, and delirium although hypersensitive pain responses to opioids may occur without these additional symptoms.
Possible Mechanisms
There have been a number of possible mechanisms proposed as to how opioids may cause this paradoxical response. One important proposed mechanism is central nervous system sensitization due to opioid activation of the N-methyl-D-aspartate (NMDA) receptors and activation of intracellular messenger protein kinase C. These two changes result in increased excitability of the nerve cells. Another potential mechanism involves neuronal circuits in the brainstem where opioids may activate pathways that amplify pain signals at the level of the spinal cord.
The accumulation of specific opioid toxic metabolites has also been linked to these conditions. Evidence suggests that both morphine and hydromorphone have active metabolites that are responsible for allodynia and hyperalgesia (morphine-3-glucuronide and hydromorphone-3-glucuronide). Both of these active metabolites are eliminated by the kidneys and usually do not accumulate to produce toxicity, however, in the presence of renal impairment, or rapidly escalating high doses, the metabolites can accumulate and result in allodynia and hyperalgesia. Morphine and hydromorphone induced hyperalgesia is often accompanied by myoclonus, seizures, and/or delirium.
Management of Opioid Induced Pain in Hospice Patients
Although it may seem to be counterintuitive in the face of increasing severe pain, the appropriate intervention in the management of suspected opioid related hyperalgesia and allodynia is to reduce or discontinue the current opioid. Rotation to another opioid with less risk of neurotoxic effects is often an effective remedy. Methadone or fentanyl are appropriate choices for hospice patients who exhibit opioid induced pain on morphine or hydromorphone. Methadone and fentanyl do not have any active metabolites that can accumulate and contribute to neurotoxicity.
Methadone oral is much more cost-effective than the fentanyl patch since oral methadone is priced at approximately one-20th of the cost of an equivalent dose of the patch. Other interventions may include adding a non-opioid adjuvant analgesic medication such as dexamethasone (Decadron), gabapentin (Neurontin), or nortriptyline (Pamelor). Benzodiazepines such as lorazepam (Ativan) or midazolam (Versed) may be helpful in managing myoclonus or muscle rigidity which may accompany opioid induced pain.
Conclusion
The problem of opioid induced allodynia and hyperalgesia is difficult to recognize and interpret, especially in hospice patients. There are no estimates as to the frequency with which opioid induced allodynia or hyperalgesia occurs. It still may be a relatively rare side-effect; however, as hospice and health care providers aggressively manage severe chronic pain with strong opioids we will see an increase in the number of these cases. Any opioid may lead to a paradoxical increase in pain, although the majority of reports are due to morphine and hydromorphone.
Opioid induced pain should be considered in any hospice patient that exhibits increasing pain that does not respond to increasing doses of opioid, especially when the pain complaints become more diffuse, with a non-specific location, spreading well beyond the pre-existing sites of pain for which drug therapy was initiated. Hyperalgesia should be suspected whenever there is need for rapid escalation of opioid doses that is unexplained by disease progression. Opioid dose reduction or rotation to methadone or fentanyl should be considered as the primary method for management for hospice patients.
Posted by Dr. Jim Joyner
The Food and Drug Administration Amendments Act (FDAA) passed by congress in September of 2007 provides the FDA with new expanded authority to require Risk Evaluation and Mitigation Strategies (REMS) for drugs and biologicals.
Essentially the FDA can now require the manufacturer of any drug to develop and submit a REMS if the FDA determines that it is necessary to ensure that the benefits of the drug outweigh the risks of drug.
This applies not only to applications for new drugs, but also to drugs that have previously been approved by the FDA and are currently in use by patients. The decision to require REMS for an existing preapproved drug may be triggered at any time if the FDA becomes aware of new safety information that makes the determination necessary in the opinion of the agency.
The REMS are required to contain one or more of the following elements; a patient medication guide, communication plan to healthcare providers, and more complex components to assure safe use (such as a restrictive distribution plan, special training for prescribers and pharmacists, and patient, pharmacy, and prescriber registries). The law states that a REMS should not have "unduly burdensome" effects on patient access to medication, however there are no guidelines or examples offered as to what would constitute an undue burden.
Letters were sent to all of the opioid drug manufacturers on February 6th 2009 to inform them that the FDA has determined that they would be required to develop a comprehensive REMS plan. The purpose of the REMS, according to the FDA, is to ensure that the benefits of the opioids continue to outweigh the risks of misuse, abuse, and accidental overdose and to manage any known or potential serious risk associated with an opioid. The FDA's rationale for this approach is that despite numerous efforts taken by the agency, drug manufacturers, and others in the past, the rates of misuse, abuse, and accidental overdose of opioids has continued to rise over the past decade. The FDA believes that establishing REMS for opioids will reduce these risks, while still ensuring that patients with legitimate need will continue to have appropriate access. All of us in the hospice industry are aware of the need for the use of opioids for pain management in end of life care.
The FDA has specifically targeted all of the long-acting opioids, with heavy utilization in hospice care, including the following: morphine extended release tablets and capsules, oxycodone extended release tablets, oxymorphone extended release tablets, methadone, and the fentanyl transdermal patch.
A meeting between the FDA and the opioid drug manufacturers was held on March 3, 2009 as a follow-up to the FDA letter regarding REMS development. At this meeting Dr. Bob Rappaport, Division of Analgesics, Anesthetics, and Rheumatology Products Director (FDA) stated, "We expect all companies marketing these products to work with us to get this done expeditiously . If not, we cannot guarantee that these products will remain on the market." (The Pain Practitioner vol 1, no 2).
In subsequent meetings with the various stakeholders (including professional societies, consumer groups, industry representatives, providers, patients, and pharmacists), the FDA again indicated that long-acting opioids could be removed from the market if the benefits of the medications are not demonstrated to outweigh the risks.
Dr. John Jenkins, Director of the Office of New Drugs (FDA) stated: "We recognize this is going to be a relatively massive new program... the 21 million prescriptions is orders of magnitude greater than any other program now in place. It's likely that legitimate patients will see new procedures that will be in place for obtaining these drugs, but we hope to make those procedures not so intrusive that it impacts their ability to receive the products while still meeting the second goal of having an impact on safe use."
The recent actions and public comments from FDA regarding opioid medications should give all of us who serve hospice patients great concern. There is a real possibility of serious unintended consequences if the FDA doesn't get this right. If opioid REMS is not developed carefully, so as not to interfere with the appropriate medical care of legitimate patients, another layer of barriers will emerge resulting in even greater problems with under-treatment of pain than we already have today. Some of these unintended consequences may include:
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More pharmacies refusing to stock opioid medications
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Less physicians who are willing to prescribe opioids
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Increased cost of opioid prescriptions for hospice patients
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Increased use of short-acting opioids in cases where the long-acting opioid is more appropriate
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Delayed response in prescribing and dispensing of opioids to hospice patients due to bureaucratic barriers
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Increased pain in our hospice patients
A variety of groups and professional organizations are providing input to the FDA regarding REMS. One among many that has taken an aggressive approach is the American Academy of Pain Management. They have provided some concrete recommendations to help ensure an effective REMS plan that does not lead to unintended adverse consequences.
Continue to support the efforts of your local, state and national organizations to ensure that your hospice patients will continue to have appropriate access to these critical medications without formidable bureaucratic barriers.
If your hospice is in need of hospice pharmacy services, Sign up for a Free Hospice Pharmacy Consultation or Contact Us today!
Photo Credit: Erix!