The Hospice Clinician Blog

In a step towards simplifying opioid Risk Evaluation and Mitigation Strategies (REMS), the FDA has approved a single, shared system REMS for the whole class of transmucosal immediate-release fentanyl (TIRF) drugs. The shared REMS system, called the TIRF REMS Access Program, will replace individual REMS for these agents, allowing prescribers and pharmacies to enroll into a single system. This is the first approved class REMS for any opioid drugs.

TIRF opioid agents include Abstral (sublingual tablet), Actiq (oral transmucosal lozenge), Fentora (buccal tablet), Lazanda (nasal spray) and Onsolis (buccal soluble film). The newly approved immediate-release fentanyl product SUBSYS sublingual spray (see the previous blog article) will also fall under the TIRF class REMS.

With the exception of SUBSYS, all of these products currently fall under individual REMS, with the exception of Fentora and Actiq, which are combined into one. That gives a total of 4 separate REMS in which prescribers, pharmacies and patients must enroll to be able to use these medications. When the new TIRF REMS Access Program launches in March of this year, there will be only one program in which healthcare providers and patients will have to enroll to use any TIRF product. This will ease some of the burden on the healthcare team, and will allow prescribers to decide which product is best for their patient without having to be concerned about which program they, or their patient, are enrolled in.

Until the TIRF REMS Access Program launches in March, the FDA has instructed that prescribers, patients, and pharmacies continue to enroll in the individual REMS programs. Then, prescribers and pharmacies already enrolled in an individual REMS program for at least 1 TIRF medication will automatically be transitioned to the shared TIRF REMS Access Program. Prescribers not yet enrolled in any TIRF REMS can enroll in the new program by reviewing an education program, successfully completing a knowledge assessment, and completing an enrollment form. All of this, and additional information about the enrollment process, will be available on the TIRF REMS Access Program website when the program launches in March.

The TIRF REMS Access Program will only apply to TIRF medications used on an outpatient basis. Healthcare professionals who prescribe TIRF medications that will only be used in an inpatient setting, including hospitals, hospices, or long-term care facilities, will not be required to enroll in the TIRF REMS Access Program, nor will patients who receive TIRF medications in an inpatient setting.

INSYS Therapeutics has announced FDA approval of SUBSYS fentanyl sublingual spray for the treatment of breakthrough cancer pain. SUBSYS is a single-dose sublingually-administered formulation of fentanyl that joins five other rapid-acting fentanyl products already on the market (Abstral, Actiq, Fentora, Lazanda and Onsolis). INSYS Therapeutics claims SUBSYS is the only transmucosal fentanyl product to show statistically significant pain relief when measuring the sum of pain intensity difference at five minutes in a Phase 3 clinical trial of breakthrough cancer pain.

SUBSYS will be launched under the recently approved Transmucosal Immediate-Release Fentanyl (TIRF) REMS Access Program, which we will be discussing further on the blog next week. SUBSYS is expected to be available in the early part of this year.

The US Food and Drug Administration has approved Lazanda, a fentanyl  nasal spray, for management of severe breakthrough pain in adult patients with cancer.  Fentanyl nasal spray has been available in Europe under the brand name PecFent, however, Lazanda is the first fentanyl nasal spray available in the US.    Like other fentanyl products, Lazanda, is a schedule II controlled substance and it is should not be used in patients who are opioid naïve.

The nasal spray device delivers fentanyl as a fine mist which forms a gel when it comes in contact with the nasal mucosa.  The fentanyl  is rapidly absorbed  through the mucus membrane into the systemic circulation.  Analgesic effects have been demonstrated from 5 minutes after dosing, reaching clinically meaningful levels in 10 minutes.  Phase 3, double-blind studies demonstrated superior pain relief within a significantly shorter time frame with fentanyl nasal spray than with oral immediate release morphine.  There were no comparisons with the oral-transmucosal fentanyl products (Actiq, Fentora, Onsolis) reported.

As with the other fentanyl dosage-forms, there is a potential for serious adverse reactions including, respiratory depression, circulatory depression, hypotension and shock.  More common side effects may include: nausea, vomiting, constipation, somnolence, dizziness, and rhinorrhea.

The initial dose of Lazanda for all patients is 100mcg.  If the breakthrough pain episode is not relieved, patients must wait at least 2 hours before taking another dose of Lazanda.  Do Not convert patients on a mcg per mcg basis from any other fentanyl product to Lazanda because significant differences in bioavailability exist among the various dosage-forms.   

Because of the risk for misuse, abuse, addiction, and overdose, Lazanda is available only through a restricted program, required by the Food and Drug Administration, called the Lazanda REMS (Risk Evaluation and Mitigation Strategy) program. Under the Lazanda REMS program, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program to prescribe, receive, dispense, and distribute Lazanda, respectively.

The cost of Lazanda is not been provided as of the date of this article. 

Full Prescribing Information

Photo Credit 

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Onsolis^TM: A New Fentanyl Dosage Form

Onsolis^TM 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.

Onsolis^TM 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). Onsolis^TM is not a generic version of these products and it should not be substituted for any other fentanyl product. Substantial differences exist in how Onsolis^TM is absorbed compared to other oral transmucosal fentanyl products. Substitution of Onsolis^TM for any other oral transmucosal fentanyl product may result in fatal overdose.

Onsolis^TM 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 Onsolis^TM 200mcg film. The effective dose of Onsolis^TM 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 Onsolis^TM 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 Onsolis^TM 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. Onsolis^TM 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 Onsolis^TM stresses the importance of beginning therapy with the 200mcg strength and following the strict dose titration guidelines. The warning also states that Onsolis^TM 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 Onsolis^TM. 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/.

Onsolis^TM (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 Onsolis^TM  

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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.

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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:

• Morphine group: morphine, codeine hydrocodone, oxycodone, oxymorphone, hydromorphone, levorphanol

• Diphenylheptanes: methadone, propoxyphene

• 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

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