ProCare HospiceCare

Fall Edition 2012

On-Demand Clinical News

Clinical Corner Opioid Review: Alternative Routes and Monitoring
Part I: Nebulized Opioids and the Management of Dyspnea
Joelle Potts, Pharm.D., CGP Listed below are three articles ranging in date from 2004 to the present which pertain to nebulized opioids; they are listed in chronological order from oldest to most recent. These articles have been chosen as they are representative of findings from other articles reviewed, and/or are among the most recent. The search is focused on review articles (vs. individual studies or case reports), in order to find the most complete assessment of existing studies on the subject. 1. Foral PA, Malesker MA, Huerta G, Hilleman DE. Nebulized opioids use in COPD. Chest, Feb 2004; 125: 691-4. Discourages use of nebulized opioids because current data do not support their use; reports that most of the studies they reviewed demonstrated no significant difference between nebulized morphine and placebo (nebulized saline). 2. DiSalvo WM, Joyce MM, Tyson LB, Culkin AE, Mackay K. Putting evidence into practice: evidence-based interventions for cancer-related dyspnea. Clinical Journal of Oncology Nursing. Apr 2008, 12(2); 341-52. Reviews a number of studies of nebulized opioids, some of which included non-cancer patients concludes that oral and parenteral opioids are
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Part II: Transdermal Delivery of Opioids

Alexander Jones, Pharm.D. In the field of hospice care it is necessary to try any and all drug delivery options that have the possibility to bring our patients comfort and increase their quality of life; this includes exploring the use of transdermal delivery of topical opioids. Patients frequently require pain relief and many are unable to take oral medication. For these patients, there are a number of factors that need to be reviewed to determine what the best course of action is to get them pain relief. Transdermal delivery of medication is a popular route due to the ease and ability of administering the drug to patients where conventional administration may not be possible. There is a great deal of interest and use of topical morphine in the hospice field currently. The data is lacking, however. There have been studies that show transdermal delivery can be effective when applied to cutaneous lesions but not effective for systemic absorption. In some case reports, morphine has been shown to provide pain relief in wounds when applied topically, however the effect on healing has been controversial and more research is needed to determine if morphine increases or diminishes healing time in these patients wounds. In the studies reviewed, systemic levels of morphine could not be quantified or otherwise detected. Methadone has demonstrated similar efficacy for topical wounds. Ketamine has also been studied and found to provide pain relief when applied topically as a gel to specific areas of neuropathic pain such as post herpetic neuralgia and should only be considered when all primary and secondary options have been exhausted.

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Part I: Nebulized Opioids and the Management of Dyspnea Continued from page 1

more effective than placebo in reducing breathlessness, but that not enough scientific data exists to support the use of nebulized opioids for this purpose. The study includes evaluations of other dyspnea interventions as well. 3. Mahler DA, Selecky PA, Harrod CG, Benditt JO, Crrieri-Kohlman V, et al. American College of Chest Physicians consensus statement on the management of dyspnea in patients with advanced lung or heart disease. Chest, Mar 2010, 137(3); 674-91. States oral and/or parenteral opioids can provide relief of dyspnea, but describes the evidence for use of nebulized opioids as "anecdotal." The article cites two randomized controlled trials that found nebulized morphine is no better than nebulized saline for relieving dyspnea, and another study that concluded nebulized opioids did not relieve breathlessness. The article also discusses other methods of dyspnea management. In general, these articles seem to indicate that current evidence does not clearly demonstrate the effectiveness of nebulized morphine in reducing SOB. There appear to be some anecdotal reports of benefit, but it seems to be unclear whether this is due to the presence of the opioid or due to the process of nebulizer administration (i.e. a placebo effect). Based on the information examined, nebulized morphine is not typically recommended as a first- or second-line therapy for SOB however, there may be cases where it may be appropriate and effective.
Part II: Transdermal Delivery of Opioids Continued from page 1

The authors of all the studies reviewed recommend more research to further understand the use of these topical preparations. Topical morphine and methadone in wound application, and topical ketamine application in peripheral neuralgia are unfavorable options in the hospice setting. Systemic absorption from intact skin is often the desired outcome for pain management and there are very few studies demonstrating these uses. Taking morphine for example; most morphine for topical use is compounded in a matrix, such a pleuronic lecithin organogel (PLO), which is theoretically designed to enhance drug delivery. In a study that used PLO and morphine applied to healthy, intact skin, the researchers found that application ended up providing no quantifiable levels in the blood with detectable limits set to 0.5ng/ml. The fact that the minimum plasma concentration for analgesia is 10ng/ml shows that most compounded preparations of topical morphine may not be delivering the amount of drug needed for analgesia. On the other hand, another study demonstrates that morphine in an aqueous preparation had up to 75% bioavailability after topical application. It is important to note, however, that the authors had to do a lot of work to prepare the skin. The process required removing the epidermis via vacuum chamber and waiting for a blister to form, then removing the blister on the following day so that the dermal surface was finally ready for application. The topical application included gauze soaked with a morphine solution that was placed on the dermis with a plastic containment chamber on top. It is clear that there needs to be more, randomized controlled studies that do not require extensive skin preparation. In vitro morphine does not penetrate the epidermis and the method described above is not practical in the clinical setting. In conclusion, using topical morphine, or other opioids, for patients who need systemic absorption is not the best option for analgesia, nor is it cost-effective.
References: 1. Paice JA, Von Roenn JH, Hudgins JC, Luong L, Krejcie TC, Avram M Morphine bioavailability from a topical gel formulation in volunteers. J Pain Symptom Manage. 2008 Mar;35(3):314-20. Epub 2008 Jan 7. 2. D Westerling, P Hglund, S Lundin, and P Svedman. Transdermal administration of morphine to healthy subjects. Br J Clin Pharmacol. 1994 June; 37(6): 571576. PMCID: PMC1364817 Gammaitoni A, Gallagher RM, Welz-Bosna M. Topical ketamine gel: possible role in treating neuropathic pain. Pain Med. 2000 Mar;1(1):97-100. PubMed PMID:15101968 Farley P. Should topical opioid analgesics be regarded as effective and safe when applied to chronic cutaneous lesions? J Pharm Pharmacol. 2011Jun;63(6):747-56. doi: 10.1111/j.2042-7158.2011.01252.x. Epub 2011 May 3. Review. PubMed PMID: 21585371.5. Gallagher RE, Arndt DR, Hunt KL. Analgesic effects of topical methadone: a report of four cases. Clin J Pain. 2005 Mar-Apr;21(2):190-2. PubMed PMID:15722814.

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II. FDAs Risk Evaluation and Mitigation Strategy for Opioids

Cody Midlam, PharmD, CGP

In 2007, Congress enacted an amendment to the Prescription Drug User Fee Act (PDUFA) which gives the FDA authority to require every pharmaceutical manufacturer to develop a REMS (Risk Evaluation and Mitigation Strategy) for drugs that have value but whose risks could out-weigh benefits if the medications are not used carefully. REMS are programs that may call for requirements such as medication user guides, or other safekeeping processes for drug approval and/or marketing. Recently, on July 9, 2012 the FDA approved a REMS program for extended-release and long-acting (ER/LA) opioids. There are more than 20 companies and more than 30 products affected by the REMS. An overview of the requirements of the new REMS are listed below: ER/LA opioid analgesic companies make available training for health care professionals who prescribe ER/LA opioid analgesics on proper prescribing practices ER/LA opioid analgesic companies required to distribute educational materials to prescribers and patients on the safe use of these powerful pain medications.

REMS within 120 days and describing the elements that needed to be included in the REMS notification letters. The central component of the Opioid REMS program is an education program for prescribers (e.g., physicians, nurse practitioners, physician assistants) and patients. In the REMS notification letters, FDA provided an outline of the required prescriber education. The outline specified that the education must include: information on weighing the risks and benefits of opioid therapy, choosing patients appropriately, managing and monitoring patients, counseling patients on the safe use of these drugs, and learning points to recognize evidence of and potential for opioid misuse, abuse, or addiction. There is no mandatory requirement that prescribers take the REMS course as a precondition to dispensing the medication to patients. However, application holders (drug manufacturers) will be required to establish goals for the number of prescribers trained, collect the information about the number of prescribers who took the courses, and report the information to FDA as part of periodic required assessments. The FDA addresses concern that the REMS program may make it more difficulty for patients to get their pain medications, stating, FDA understands how important it is for patients to get their pain treated and does not expect that this action will affect patient access to their pain medicines. As part of the opioid REMS, FDA will monitor patient access to pain medicines and will continue to talk with the community of pain patients and prescribers to ensure that patients get proper pain management. References: Risk Evaluation and Mitigation Strategy (REMS) for Extended-Release and Long-Acting Opioids. (2012). FDA Drug Safety. Accessed online Sept. 15, 2012 at:
www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm163647.htm

Background: In February of 2009, the FDA sent letters to manufacturers of certain opioid drug products indicating that these drugs will be required to have a REMS to ensure that the benefits of the drugs continue to outweigh the risks. The affected opioid drugs include long-acting and extended-release brand name and generic products and are formulated with the active ingredients buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. In April of 2011, the FDA issued letters to application holders to direct them to submit a

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Editor: Dr. Cody Midlam, PharmD, CGP Executive Editor: Dr. Meri Madison, PharmD, CGP