Physicians’ current literature review.
New routes of opiate administration Gary A. Johanson, MD
In an attempt to maximize the relief of physical pain in many settings including that of chronic cancer pain, a number of new routes of administration are currently being more actively explored. Someof the current problem areas in pain management that may be addressed by alternate delivery systems include the following:
Of these, the system now seeing widespread application is the Transdermal Fentanyl Patch. Currently available in four strengths, it is designed to be placed continuously for 72 hours at which point it is replaced by a new patch. A recent supplement issue to the Journal of Pain and Symptom Management describes the results of many small field trials in which the safety, effectiveness In an attempt to and acceptance of the patches was • Patient or family lack of underdemonstrated.’-7 Initial doses ranged from maximize the relief standing or inability to dose pain 25-325 mcg/hr with a median initial dose ofphysical pain in meds regularly; in the 50-130 mcg/hr range. Final doses many settings including • Cost of administration, especially of were usually in the 200-300 mcg/hr range. that of chronic cancer parenteral drugs; Onset of action has been shown to be 4-8 hours after application with peak effect at pain, a number of new • Peak/trough effects; 14-24 hours. Plasma half-life then after routes of administration • Nausea, vomiting and GI tract obremoval is 14-34 hours. are currently being more struction, especially esophageal; Despite its simple ease of administraactively explored. tion and its proven safety and effective• Side effects of orally or parenterally ness, there are some drawbacks to the use administered drugs; of the Fentanyl patch, however, which precludes it from replacing oral morphine as the drug of • Need for high level of technical support for some pain choice in the management of severe cancer pain. These drawrelief systems (IV, epidural, intrathecal). backs include: Newer delivery systems being explored include the following: • Difficulty in titration due to long half-life; ______________
______________
• Transdermal therapeutic systems (TTS); • Oral-transmucosal; • Intranasal transmucosal; • Electrotransport or iontophoresis. GaryA. Johanson, MD, is Medical Directorof the Home HospiceofSonoma County, Santa Rosa, California. He is author of Physician’s Handbook of Symptom Relief in Terminal Care.
• May need frequent bolus with an alternate agent for breakthrough pain which would be prior to reaching the steady-state; • Dosing tables are based on 6:1 oral to parenteral morphine ratio. This results in under-shooting dose when going from oral morphine (OMS) to fentanyl patch, and, conversely, over-shooting when going back from patch to OMS;
The AmericanJournal of Hospice & Palliative Care July/August 1992
Downloaded from ajh.sagepub.com at UNIV OF MASSACHUSETTS on April 9, 2015
• Variability in absorpiton can make dose selection difficult. High lipophilicity contributes to this problem; • Patches can come off; • Skin irritation; • Cost similar to long-acting preparations but considerably more than immediate-release oral morphine. Of course, it is less costly than parenteral delivery. —
Some practical considerations in the use of the Fentanyl patch include the following: • It is best suited to patients with persistent daily pain and a minimal incident component to the pain; • Will need supplement short-acting opiateat least the first 48-72 hours while approaching steady-state, and for breakthrough pain thereafter; • Titrate dose upward every three days pm; • Titrate downward by stopping patch for 12-24 hours, then starting new smaller patch; • Cannot re-attachpatch if it falls off; • Use trunk of body only;
demonstrated the analgesic effect of sublingual morphine in patients who are no longer swallowing. Although not available in the U.S., buprenorphine is well absorbed sublingually and is used in Europe in the treatment of cancer pain. The article also noted the recent study of a fentanyl lollipop called fentanyl oralete which is undergoing trials as a rapid-acting analgesic for both acute pain and chronic cancer pain. Transdermal patches are now coming intouse for a variety of drugs. The technique of electrotransport or iontophoresis is a tool by which drugs can be delivered in a more efficient manner via the transdermal route.’°In this technique, ionic solutes are driven across biologic membranes utilizing electric currents. Experiments utilizing hydromorphone and morphine have been done showing implications for palliative care is that a greater variety of drugs may become deliverable by the transdermal route. It also seems apparent that more control over the rapidity of the rise and fall of serum concentrations will be possible than by the simple passive transdermal route as with the current fentanyl patch. In conclusion, it is hoped that research into alternate drug delivery systems will continue to provide new tools by which we in palliative care will be able to better deliver costeffective, non-invasive symptom relief to our patients with terminal illness.~
References
• Try to avoid particularly obese areas. • In chronic steady-state, use the following approximate equivalencies: 25 mcgfhr patch = 10mg OMS q4h 50 mcgfhr patch = 20mg OMS q4h 75 mcgfhr patch = 30mg OMS q4h 100 mcg/hr patch = 40mg OMSs q4h. Ripamonti et al.8 recently reviewed the use of inhaled morphine in the treatment of surgical pain and dyspnea associated with advanced chronic lung disease. Limited studies showed significant subjective response in the relief of both post-operative pain and the dyspnea associated with advanced chronic lung disease. Bioavailability was quite variablewhere documented with a mean in the 17 percent range. Intranasal sufentanyl has also been shown torapidly (within 10 minutes) induce sedation in both children and adults.9 Further study and refinement of the intranasal technique should result in a very useful alternative to the oral route of delivery especially for instances of breakthrough or incident pain. The oral transmucosal administration of opiates has also recently been reviewed by Stanley et al.9 Their findings led to the conclusion that the sublingual route is significantly more effective than the buccal or gingival route and that the more highly lipid soluble agents are better absorbed and therefore more logical for use. Nevertheless, clinical experience has
1. Simmonds MA, RichenbacherJ: Transdermal fentanyl: Long-term analgesic studies. J Pain Symptom Manage 1992;7:S36-S39
2. Lehmann KA, Zeck D: Transdermal Fentanyl: Clinical pharmacology. J Pain Symptom Manage 1992;7:S8-S16 3. Payne R: TransdermalFentanyl: Suggested recommendationsforclinical use, J Pain Symptom Manage 19972;7:S40-S44 4. Slover R: Transdermal Fentanyl: Clinical trial at the University of Colorado Health Sciences Center. J Pain Symptom Manage l992;7:S45S47 5. Levy MH, Rosen SM, Kedziera P: Transdermal Fentanyl: Seeding trial in patients with chronic cancer pain. JPain Symptom Manage 1992;7:S48S50
6. Herbst LH, Strause LG: Transdermal Fentanyl use in hospice home-care patients with chronic cancer pain. J Pain Symptom Manage 1992;7:S54S57
7. Mayes TJ, Barcellos WA: Management of cancer pain with Transdermal Fentanyl: Phase IV trial, University of Iowa. J Pain Symptom Manage 1992;7:S58-S62
8. Ripamonti C, Bruera E: Transdermal and inhalatory routes of opioid administration: The potential application in cancer pain. Palliative Medicine 1992;6:98-104 9. Stanley TH, Ashbum MA: Novel delivery systems: Oral transmucosal and intranasal mucosal. J Pain Symptom Manage 1992;7:163-171 10. NimmoWS: Novel delivery systems: Electrotransport. J Pain Symptom Manage 1992;7:160-162
The American Journal of Hospice & Palliative Care July/August 1992 Downloaded from ajh.sagepub.com at UNIV OF MASSACHUSETTS on April 9, 2015
5
New routes of opiate administration Gary A. Johanson, MD
In an attempt to maximize the relief of physical pain in many settings including that of chronic cancer pain, a number of new routes of administration are currently being more actively explored. Someof the current problem areas in pain management that may be addressed by alternate delivery systems include the following:
Of these, the system now seeing widespread application is the Transdermal Fentanyl Patch. Currently available in four strengths, it is designed to be placed continuously for 72 hours at which point it is replaced by a new patch. A recent supplement issue to the Journal of Pain and Symptom Management describes the results of many small field trials in which the safety, effectiveness In an attempt to and acceptance of the patches was • Patient or family lack of underdemonstrated.’-7 Initial doses ranged from maximize the relief standing or inability to dose pain 25-325 mcg/hr with a median initial dose ofphysical pain in meds regularly; in the 50-130 mcg/hr range. Final doses many settings including • Cost of administration, especially of were usually in the 200-300 mcg/hr range. that of chronic cancer parenteral drugs; Onset of action has been shown to be 4-8 hours after application with peak effect at pain, a number of new • Peak/trough effects; 14-24 hours. Plasma half-life then after routes of administration • Nausea, vomiting and GI tract obremoval is 14-34 hours. are currently being more struction, especially esophageal; Despite its simple ease of administraactively explored. tion and its proven safety and effective• Side effects of orally or parenterally ness, there are some drawbacks to the use administered drugs; of the Fentanyl patch, however, which precludes it from replacing oral morphine as the drug of • Need for high level of technical support for some pain choice in the management of severe cancer pain. These drawrelief systems (IV, epidural, intrathecal). backs include: Newer delivery systems being explored include the following: • Difficulty in titration due to long half-life; ______________
______________
• Transdermal therapeutic systems (TTS); • Oral-transmucosal; • Intranasal transmucosal; • Electrotransport or iontophoresis. GaryA. Johanson, MD, is Medical Directorof the Home HospiceofSonoma County, Santa Rosa, California. He is author of Physician’s Handbook of Symptom Relief in Terminal Care.
• May need frequent bolus with an alternate agent for breakthrough pain which would be prior to reaching the steady-state; • Dosing tables are based on 6:1 oral to parenteral morphine ratio. This results in under-shooting dose when going from oral morphine (OMS) to fentanyl patch, and, conversely, over-shooting when going back from patch to OMS;
The AmericanJournal of Hospice & Palliative Care July/August 1992
Downloaded from ajh.sagepub.com at UNIV OF MASSACHUSETTS on April 9, 2015
• Variability in absorpiton can make dose selection difficult. High lipophilicity contributes to this problem; • Patches can come off; • Skin irritation; • Cost similar to long-acting preparations but considerably more than immediate-release oral morphine. Of course, it is less costly than parenteral delivery. —
Some practical considerations in the use of the Fentanyl patch include the following: • It is best suited to patients with persistent daily pain and a minimal incident component to the pain; • Will need supplement short-acting opiateat least the first 48-72 hours while approaching steady-state, and for breakthrough pain thereafter; • Titrate dose upward every three days pm; • Titrate downward by stopping patch for 12-24 hours, then starting new smaller patch; • Cannot re-attachpatch if it falls off; • Use trunk of body only;
demonstrated the analgesic effect of sublingual morphine in patients who are no longer swallowing. Although not available in the U.S., buprenorphine is well absorbed sublingually and is used in Europe in the treatment of cancer pain. The article also noted the recent study of a fentanyl lollipop called fentanyl oralete which is undergoing trials as a rapid-acting analgesic for both acute pain and chronic cancer pain. Transdermal patches are now coming intouse for a variety of drugs. The technique of electrotransport or iontophoresis is a tool by which drugs can be delivered in a more efficient manner via the transdermal route.’°In this technique, ionic solutes are driven across biologic membranes utilizing electric currents. Experiments utilizing hydromorphone and morphine have been done showing implications for palliative care is that a greater variety of drugs may become deliverable by the transdermal route. It also seems apparent that more control over the rapidity of the rise and fall of serum concentrations will be possible than by the simple passive transdermal route as with the current fentanyl patch. In conclusion, it is hoped that research into alternate drug delivery systems will continue to provide new tools by which we in palliative care will be able to better deliver costeffective, non-invasive symptom relief to our patients with terminal illness.~
References
• Try to avoid particularly obese areas. • In chronic steady-state, use the following approximate equivalencies: 25 mcgfhr patch = 10mg OMS q4h 50 mcgfhr patch = 20mg OMS q4h 75 mcgfhr patch = 30mg OMS q4h 100 mcg/hr patch = 40mg OMSs q4h. Ripamonti et al.8 recently reviewed the use of inhaled morphine in the treatment of surgical pain and dyspnea associated with advanced chronic lung disease. Limited studies showed significant subjective response in the relief of both post-operative pain and the dyspnea associated with advanced chronic lung disease. Bioavailability was quite variablewhere documented with a mean in the 17 percent range. Intranasal sufentanyl has also been shown torapidly (within 10 minutes) induce sedation in both children and adults.9 Further study and refinement of the intranasal technique should result in a very useful alternative to the oral route of delivery especially for instances of breakthrough or incident pain. The oral transmucosal administration of opiates has also recently been reviewed by Stanley et al.9 Their findings led to the conclusion that the sublingual route is significantly more effective than the buccal or gingival route and that the more highly lipid soluble agents are better absorbed and therefore more logical for use. Nevertheless, clinical experience has
1. Simmonds MA, RichenbacherJ: Transdermal fentanyl: Long-term analgesic studies. J Pain Symptom Manage 1992;7:S36-S39
2. Lehmann KA, Zeck D: Transdermal Fentanyl: Clinical pharmacology. J Pain Symptom Manage 1992;7:S8-S16 3. Payne R: TransdermalFentanyl: Suggested recommendationsforclinical use, J Pain Symptom Manage 19972;7:S40-S44 4. Slover R: Transdermal Fentanyl: Clinical trial at the University of Colorado Health Sciences Center. J Pain Symptom Manage l992;7:S45S47 5. Levy MH, Rosen SM, Kedziera P: Transdermal Fentanyl: Seeding trial in patients with chronic cancer pain. JPain Symptom Manage 1992;7:S48S50
6. Herbst LH, Strause LG: Transdermal Fentanyl use in hospice home-care patients with chronic cancer pain. J Pain Symptom Manage 1992;7:S54S57
7. Mayes TJ, Barcellos WA: Management of cancer pain with Transdermal Fentanyl: Phase IV trial, University of Iowa. J Pain Symptom Manage 1992;7:S58-S62
8. Ripamonti C, Bruera E: Transdermal and inhalatory routes of opioid administration: The potential application in cancer pain. Palliative Medicine 1992;6:98-104 9. Stanley TH, Ashbum MA: Novel delivery systems: Oral transmucosal and intranasal mucosal. J Pain Symptom Manage 1992;7:163-171 10. NimmoWS: Novel delivery systems: Electrotransport. J Pain Symptom Manage 1992;7:160-162
The American Journal of Hospice & Palliative Care July/August 1992 Downloaded from ajh.sagepub.com at UNIV OF MASSACHUSETTS on April 9, 2015
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