Posted by Dr. Jim Joyner
OnsolisTM: A New Fentanyl Dosage Form
OnsolisTM is a new short-acting dosage-form of fentanyl supplied as a soluble film. It consists of a small, dissolvable, polymer film formulated with fentanyl for application to the buccal mucosa (inner lining of the cheek). The film is about the size of a dime and it completely dissolves within 15-30 minutes after administration. It is indicated for treating episodes of severe breakthrough pain in patients who are already being treated with routine opioids.
OnsolisTM joins a couple of close cousins already on the market for management of severe breakthrough pain: the fentanyl lozenge (Actiq) and the fentanyl buccal tablet (Fentora). OnsolisTM is not a generic version of these products and it should not be substituted for any other fentanyl product. Substantial differences exist in how OnsolisTM is absorbed compared to other oral transmucosal fentanyl products. Substitution of OnsolisTM for any other oral transmucosal fentanyl product may result in fatal overdose.
OnsolisTM is available in 5 strengths: 200mcg, 400mcg, 600mcg, 800mcg, and 1200mcg. Strict initial dose titration guidelines are provided in the manufacturer's package insert in order to achieve an effective dose while minimizing the risk for toxicity. All patients must begin treatment using 1 OnsolisTM 200mcg film. The effective dose of OnsolisTM is not predictable from the daily maintenance dose of opioid that the patient is using to manage persistent pain and must be determined by titration. If adequate relief is not achieved after 1 OnsolisTM 200mcg dose, titrate using multiples of the 200mcg film. Increase the dose by 200mcg in each subsequent episode until the patient reaches a dose that provides relief with tolerable adverse effects.
Do not use more than 4 of the OnsolisTM 200mcg films simultaneously. When multiple films are used, they should not be placed on top of each other and may be placed on both sides of the mouth. Single doses should be separated by at least 2 hours. Single doses above 1200mcg should not be used. OnsolisTM film should be limited to 4 or fewer doses per day. The need for more frequent dosing of breakthrough pain medication should indicate that the routine opioid medication dose needs to be increased.
The black-box warning on OnsolisTM stresses the importance of beginning therapy with the 200mcg strength and following the strict dose titration guidelines. The warning also states that OnsolisTM film cannot be substituted in place of the other transmucosal fentanyl products (Actiq and Fentora) due to substantial differences in the extent of absorption of fentanyl among these products.
Lastly, the warning reflects the initial impact of the FDA's new REMS authority upon opioid therapy. Specifically, because of the risk for misuse, abuse and overdose, this product is available only through a restricted distribution program, called the FOCUS Program (Full Ongoing Commitment to User Safety Program). Under the FOCUS Program, only physicians, pharmacists, and patients registered with the program are able to prescribe, dispense, and receive OnsolisTM. Participating pharmacists and physicians are required to receive training on the FOCUS program.
Practitioners and patients may enroll in the program at http://www.onsolisfocus.com/.
OnsolisTM (fentanyl buccal soluble film)
For the management of breakthrough cancer pain in hospice and palliative care patients who are already receiving and are tolerant of opioid therapy
Available Strengths: 200mcg per film 400mcg per film 600mcg per film 800mcg per film 1200mcg per film
Link to FDA Questions & Answers about OnsolisTM
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
Hospice patients may report allergies to opioids, but often these are pseudoallergies consisting of symptoms of itching, flushing and sweating. Pseudoallergy type reactions are relatively common.
True allergy to opioids is rare. (1) Pseudoallergy is caused by release of histamine from the mast cells in the skin, a non-immunologic event. (2) True allergy is believed to be IgE mediated or T-cell mediated. (3) If the reaction is only flushing, itching, or sweating the opioid can often be continued with the addition of an antihistamine or dose reduction. (4) If the true nature of the reaction to an opioid is not clarified, the hospice patient may be incorrectly "labeled" as allergic to opioids and opioid drugs may be withheld unnecessarily.
If the reaction consists of hives, increased heart rate, severe hypotension, or bronchospasm the patient should be assumed to be exhibiting a true allergic reaction and the clinician will need to decide which, if any, opioid is safe for the hospice patient.
Codeine, Morphine, and Meperidine are associated with the most allergictype reactions. (1) It has been suggested that hospice patients allergic to one opioid are less likely to react to an opioid in a different structural class.
It is reasonable to consider rotating from an opioid from one class to one from another distinct class in some situations. The 3 main structural classes are as follows:
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Morphine group: morphine, codeine hydrocodone, oxycodone, oxymorphone, hydromorphone, levorphanol
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Diphenylheptanes: methadone, propoxyphene
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Phenylpiperidines: fentanyl, meperidine
Some patients may experience localized itching and redness underneath the Fentanyl patch. Patch site rotation is very important to reduce this risk. This reaction can be managed by topical application of a steroid, such as triamcinolone spray prior to application of the patch.
Although many hospice patients may report a history of allergy to opioids, most have only experienced a side effect . Proper selection of an opioid medication based upon past history can result in significantly improved outcomes in pain management for the hospice patient.
(1) J Oncol Pharm Practice 2004;10: 177-82 (2) Immunol Allergy Clin North Am 1991;111: 635-44 (3) Anesthesiology 1989; 71: 489-94 (4) Applied Therapeutics: The Clinical Use of Drugs 8th ed. 2005