Posted by Dr. Jim Joyner
Our hospice partners have been telling us about difficulty in obtaining oxycodone oral solution and dramatically increasing cost when available. Several of the generic manufacturers for oxycodone solution have discontinued production recently. This is in response to FDA action starting last year to remove “unapproved drugs” from the market-place. For a variety of mostly historical reasons, some drugs, mostly older products, continue to be marketed in the United States without required FDA approval. The FDA has expressed their concern that the lack of evidence demonstrating that these unapproved drugs are safe and effective is a significant public health concern. Many of these products have been in widespread use in the United States for decades with proven track records of efficacy and safety, however, the FDA considers all of the unapproved products to be marketed illegally and has taken action to force the manufacturers to discontinue them or apply for FDA approval.
FDA sent warning letters to several suppliers of unapproved narcotic medications (including morphine, oxycodone, and hydromorphone) last year. These companies were given a specified time-frame to stop manufacturing new product, until they went through a formal process for approval of their products with FDA. Wholesale distributors were instructed to stop shipping “unapproved” product. The following manufacturers: Mallinckrodt, Lannett, and Glenmark, have stopped production of all oxycodone solutions in accordance with the unapproved drug ruling by FDA. As far as we can tell that leaves only one manufacturer (Xanodyne Pharmaceuticals) that has an “approved” oxycodone solution product on the market. They market their product as the brand name Roxicodone and it is significantly more expensive than the discontinued “unapproved products”.
More detailed information can be found on the FDA website at www.fda.gov.
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. Julia Harder
The FDA has approved a generic version of Fentora (fentanyl) buccal tablets, which will be manufactured by Watson Pharmaceuticals. Fentanyl buccal tablets will be available in 100, 200, 300, 400, 600 and 800 mcg strengths. The tablets are designed to be placed between the upper gum and cheek, near the back teeth. Medication is absorbed transmucosally while the tablet dissolves, which takes 15 to 25 minutes.
The FDA has also approved the first generic version of Effexor XR capsules (venlafaxine hydrochloride) to treat major depressive disorder. Venlafaxine extended-release capsules in 37.5, 75 and 150 mg strengths have been approved to be manufactured by TEVA Pharmaceuticals.
Teva Effexor XR 37.5 mg
Posted by Dr. Jim Joyner
The July issue of The Clinician, our quarterly clinical newsletter, will feature the final article in our three-part series on pediatric palliative care. In the upcoming article, Julia Harder, PharmD, will discuss the management of some of the most common non-pain symptoms encountered in pediatric palliative care. Specific symptom complexes that will be addressed include: anxiety & depression, agitation, insomnia, anorexia-cachexia, nausea-vomiting, constipation, and dyspnea. Specific medication strategies will be presented for managing each of these troubling symptoms in pediatric hospice patients. All clients of Outcome Resources receive complimentary copies of The Clinician each quarter. Previous issues of The Clinician can be obtained by contacting Jim Joyner, PharmD, at jjoyner@outcomeresources.com Be sure to check the Blog for the upcoming Part 3 in the series.
Dowload Part 1 of Pediatric Palliative Care Series: Current Concepts in Drug Therapy
Dowload Part 2 of Pediatric Palliative Care Series: Pain Management
Posted by Dr. Julia Harder
In pediatric palliative care, the first rule of pain management is to always tailor assessment and treatment to the unique needs of the child and his or her family. Many factors will shape a child's pain, including developmental level, emotional and cognitive state, personality traits, physical condition, and past experiences. The meaning of the pain for the child; the child's fears and concerns about illness and death; issues, attitudes, and reactions of the family; cultural background; and the environment are all elements in a child's perception of pain. Getting to know the child and having knowledge of developmental norms and behavioral competencies are important in the assessment and management of pain.
Open communication about pain among the child, the family, and the health care team is critical to successful pain assessment and management. To encourage open communication, determine the language the child uses for pain (e.g., hurt, owie, booboo) and how and to whom the child communicates pain. Often, parents/caregivers are the primary source of information about how the child exhibits and responds to pain and should be encouraged to be active participants in both assessment and management. Parents/caregivers can also contribute important information including prior painful events, previously used methods for pain control and preferences for assessing and treating pain.
Posted by Dr. Jim Joyner
Buprenorphine (Subutex, Suboxone) tablets are now being used to treat severe pain, not just opioid addiction. Since 2002 Buprenorphine has been widely used to treat opioid addiction by preventing the symptoms of opioid withdrawal.
More recently it is being used to treat severe pain, although the tablets only have an FDA approved indication for addiction treatment at this time. Subutex contains buprenorphine alone, and Suboxone contains buprenorphine and naloxone. The naloxone is there to prevent opioid effects if patients try to inject it.
Buprenorphine is a strong opioid with analgesic properties similar to morphine, methadone, oxycodone, hydromorphone, and fentanyl. It has an advantage over these traditional full agonist opioids in that there is less risk for psychological or physical dependence and it results in fewer withdrawal symptoms when it is stopped. There is also less risk for psychotomimetic effects (delusions, hallucinations). The FDA has recognized the lower risk factor for abuse with Buprenorphine and has assigned it a Schedule III controlled drug classification as opposed to the more stringent Schedule II classification seen with other strong opioids.
Some subtle differences in Buprenorphine pharmacology may account for the decreased risks seen when comparing to more traditional strong opioids. Drugs such as Morphine, Methadone, Fentanyl and others are full-agonists at the mu opioid receptor which means they bind tightly to the drug receptor sites in the body. Withdrawal of therapy for drugs with complete and tight binding at their receptor sites is associated with significant withdrawal symptoms. Buprenorphine is a partial-agonist the mu opioid receptor and is actually an antagonist at the kappa opioid receptor. It essentially is loosely bound to the mu receptor. This partial agonist property and the mixed agonist-antagonist activity may result in a decreased potential for abuse, withdrawal, and psychotomimetic effects in patients using Buprenorphine.
Subutex and Suboxone are available in tablets for sublingual administration. They are not effective by the oral route. Strengths are 2mg and 8mg tablets. The dosage range is 2 to 16mg three to four times a day for pain (instead of once a day for addiction treatment). Unlike traditional full-agonist strong opioids (morphine, methadone, fentanyl, oxycodone, and hydromorphone), Buprenorphine seems to have a "ceiling dose" after which increased doses produce no increase in opioid agonist effects.
This was demonstrated in clinical trials at doses of 16 to 32mg. The onset of action of the tablets is about 15 minutes, with peak activity at 60 minutes and a duration of analgesic activity of 6 to 8 hours. There is also an injectable solution available for intramuscular or intravenous administration. This injectable solution carries an FDA approved indication for the treatment of severe pain. The IM/IV dosage is 0.3mg at six hour intervals as necessary. IV doses should be administered slowly over 2 minutes.
The cost of a 15 day supply of a mid-range dose of Subutex (4mg three times per day) is in the range of $360.00. This makes Subutex one of the highest, if not the highest cost opioid drug on the market. The role of Buprenorphine in the management of chronic pain is still being defined. It has some significant advantages including: a lower potential for psychotomimetic side effects, lower abuse potential, reduced potential for severe withdrawal reactions, and no requirement for a schedule II triplicate prescription. Due to the fact that its duration of action is only 6 to 8 hours, Burprenorphine does not have the characteristics of a desirable long acting opioid that one would use for maintenance therapy of severe chronic pain. The greatest negative is the extremely high cost which makes it an unrealistic option for most hospice organizations at this time. The evolving role for Buprenorphine in the management of pain may be one that is targeted at acute severe pain in the hospital and clinic setting.
Posted by Dr. Julia Harder
Intranasal Ketorolac Approved
The FDA has approved Roxro Pharma's Sprix (ketorolac tromethamine) nasal spray for the short-term (up to 5 days) management of acute moderate to moderately severe pain that requires analgesia at the opioid level. Sprix is rapidly absorbed through the nasal mucosa, achieving peak blood levels as quickly as ketoroloac administered as an intramuscular injection, and provides acute pain relief for outpatients with a nonnarcotic and easy-to-administer alternative to other commonly prescribed opioid medications.
Sprix Photo
OTC Pain Relief Patch Approved
The FDA has approved Hisamitsu's Salonpas Pain Relief Patch and Salonpas Arthritis Pain (methyl salicylate 10% and I-menthol 3%) for the temporary relief of mild to moderate muscle and joint aches and pains associated with arthritis, sprains, strains, bruises, and simple backaches. The patches are effective for up to 12 hours and can be used as an alternative for patients who have difficulty swallowing. The product is the only FDA-approved OTC pain relief patch on the market.
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. Julia Harder
New OxyContin Formulation Approved
The FDA has approved a new formulation of OxyContin (Purdue Pharma) designed to discourage medication misuse and abuse. The reformulated OxyContin is intended to prevent the product from being cut, broken, chewed, crushed or dissolved to release more medication. This formulation may result in less risk of overdose due to tampering, likely resulting in less abuse by snorting or injection.
However, according to Dr. Bob Rappaport, director of the FDA's Division of Anesthesia and Analgesia Products, the new formulation provides only an "incremental advantage" over the current version of the drug. "Prescribers and patients need to know that its tamper-resistant properties are limited and need to carefully weigh the benefits and risks of using this medication to treat pain."
Many addiction experts are skeptical about how tamper-resistant the new formulation will prove to be. According to the FDA, Purdue Pharma will be required to conduct post-marketing analysis on how - or if - the new formula reduces abuse of the drug.
FDA News Release on New OxyContin Formulation
Generic Alprazolam Orally Disintegrating Tablets Approved
The FDA has granted market approval to Actavis Group for alprazolam 0.25, 0.5, 1, and 2 mg orally disintegrating tablets, indicated for the management of anxiety disorder and the short-term relief of anxiety symptoms. The medication is generically equivalent to Niravam (Schwarz Pharma). The company will begin distributing the product immediately.
Posted by Dr. Jim Joyner
A group of investigators from a Japanese palliative care unit published an article describing the benefits of Baclofen (Lioresal) for managing cancer pain.
(1) This is significant since Baclofen, an effective muscle relaxant, has not previously been studied for its effect as an adjuvant medication specifically for managing cancer pain. Baclofen has potent antispasmodic activity making it a logical choice for numerous conditions associated with muscle spasm and pain related to muscle spasm. There are also reports in the medical literature that describe the effectiveness of Baclofen for certain neuropathic pain syndromes such as trigeminal neuralgia as well as post herpetic neuralgia.
(2) Baclofen's mechanism for pain relief is thought to be mediated via the GABA receptors in the central nervous system, a mechanism distinctly separate from that of the opioids which are the primary category of drugs used to manage cancer pain in hospice patients.
(3) Adding Baclofen to opioid therapy may make sense from the perspective of attacking the pain from two separate mechanisms of action.
This study was limited to 25 cancer patients who had pain resulting from the following conditions: spinal metastasis, pelvic plexus invasion, thoracic wall invasion, neck invasion, bone metastasis, brachial plexus invasion, celiac plexus invasion, and thalamic pain. The maintenance dosage range was 10mg-40mg per day in 2 to 4 divided doses. Pain was rated by the patient on a numerical rating scale (NRS) of 0 to 10. A 50% or greater reduction in pain according to the NRS was reported by 21 of the 25 patients after the addition of Baclofen. Side effects of sleepiness and GI symptoms were minimized by initiating therapy at a low initial dose of 10mg/day and titrating up to 40mg/day with gradual increases every 2 days depending upon response. Weakness is also a common side effect related to the muscle relaxant properties of Baclofen, however, in this study weakness was only noted in 1 patient. Baclofen was continued for a median duration of 114 days in the 21 patients who reported positive effectiveness.
The effectiveness of Baclofen in a few of the cancerous conditions is not too surprising since these conditions were likely to have a significant neuropathic pain component (ex; pelvic plexus invasion or spinal mets). The interesting finding is that it was also effective for other pain types such as bone metastases. This study suggests that Baclofen can be an effective adjuvant analgesic for managing cancer pain in combination with opioid therapy.
References: (1.) Yomiya, Matsuo, Tomiyasu, et al. Amer.J.Hosp&PalliatCare Med. 2009;Vol26, No2, 112-118. (2.) Fromm, et al. Arch Neurol. 1980;37:768-771 (3.) Chen, Pan . Neuroscience. 2006;142:595-606