Opioid Rotation From Opana ER Following FDA Call for Removal – July 7, 2017
Endo Pharmaceuticals has announced that they have complied with the US Food and Drug Administration (FDA) order to voluntarily remove Opana ER from the market.
As experienced pain clinicians, we are concerned with the potential ramifications that may follow the removal of an opioid product from the marketplace, particularly one used in the treatment of thousands of patients suffering with chronic pain.
This removal threatens at least a temporary disruption in treatment, worsening discomfort to patients, and will leave clinicians scrambling as to what to do next.
Fortunately, there are numerous available options for clinicians to consider, with several being branded, proprietary products, as well as generic alternatives that may be effective. Considering the idiosyncrasies of various opioids and variable response, no one product will suffice.
Will The Alternatives Be Right for Your Patient?
Patients treated with the branded Opana ER are matched by thousands of generic oxymorphone ER, which has no abuse deterrent properties, is more easily abused, and has not been affected by the FDA request.
This makes no sense, but I guess we have to get used to all these senseless edicts arising from pseudo-medical statistical manipulation to show that they are “doing something” about the “opioid crisis”.
Knowing how to accomplish an opioid rotation safely is an important but often atrophied skill in the prescriber community. It has become increasingly important in the present day where clinicians are encouraged to stay within sanctioned morphine milligram equivalents (MME) set forth in various guidelines (and, in certain circumstances, state laws). The ability to switch nimbly but safely between opioids may even capitalize on incomplete cross tolerance, and might be a way to maintain response and decrease total daily doses, even to within acceptable limits
Let us remember that this can and should be done slowly and carefully. Just because the mathematics of a switch seems straightforward does not mean it will be smooth and easy transition for patients, especially those who had been treated with Opana ER for a long time.
Clinicians should be prepared to change practice patterns to get this done right. It will likely require the patient returning or following up weekly, not monthly.
Opioid rotation has its origins in cancer pain management, which means it was often done in semi-emergent situations (ie, a patient with new disease progression has a dramatic increase in pain, and has their opioid dose rapidly escalated). In the process, they develop delirium and need to be rotated to a new drug; often done all at once though generally in an institutional setting.5 In outpatient practice this should be done more slowly and methodically to avoid catastrophic, idiosyncratic reactions occur.
Targeting a Medication to Switch to
To begin the process, it might be helpful for clinicians to remind themselves why the patient was receiving Opana ER in the first place.
For many years, Opana ER was the second most commonly prescribed branded long acting opioid on the market. Many patients started on Opana ER after trying another long acting opioid (perhaps generic long acting products such as morphine ER or fentanyl patches +/- the most commonly prescribed branded long acting opioid, OxyContin)
Selecting a replacement product is more complex than one might think, if it is done correctly, carefully, and methodically to mitigate risks of over or under dose with attention to likelihood of tolerability based on the patient’s history. If all of these items are considered appropriately, the pharmacotherapeutic selection should fall into place nicely.
One approach: generic oxymorphone ER is the easiest “rotation.”
After all, it is the same drug in the same long-acting form. As noted, however, the generic product is not an official FDA abuse deterrent formulation, as previously discussed.
While it may be tempting to make this easy, 1:1 switch, the clinician must first consider whether the patient is best served with an ADF.
This can be based on either the patient’s own level of risk for misuse and/or diversion, indifference to the instability, and risk in their home environment (ie, the need to make the drug less appealing to others who might divert it for abuse).
Oxycodone Products: OxyContin and Xtampza ER
Neither of these products is an option if the patient has a history of intolerance to oxycodone, or known cytochrome (CYP)450 3A4 or 2D6 abnormalities, or if a patient frequently but intermittently requires a potent CYP3A4 inhibitor. Examples of 3A4 inhibitors include certain macrolide antibiotics, various anti-fungals, and several other commonly prescribed medications. Within 48 hours, the inhibition of the CYP3A4 enzyme by these drugs and reduced metabolism could be fatal
The very same argument can be made for both ER hydrocodones, Hysingla ER and Zohydro ER
Oxycodone and hydrocodone rely specifically on CYP3A4 to convert their active parent compound to the inactive metabolites noroxycodone and norhydrocodone respectively.
Both rely on CYP2D6 as well to convert to the more potent active metabolites oxymorphone and hydromorphone respectively. A patient that has an unknown rapid CYP2D6 phenotype could overdose if switching from oxymorphone to oxycodone without careful titration, especially if they are also a poor metabolic CYP3A4 phenotype which would slow the metabolism of active parent compounds oxycodone and hydrocodone
It is especially important to understand that oxymorphone undergoes Phase II metabolism only and thereby avoids CYP metabolism altogether.
Moreover, there are 5 such opioids in total that avoid Phase I metabolism similarly to oxymorphone: hydromorphone, morphine, levorphanol, and tapentadol.
But just because CYP metabolism is not an issue with these drugs, there still is risk when converting between products. In particular, morphine relies heavily on p-glycoprotein (pGP) for oral absorption. So, even though CYP inhibitors or inducers are not problematic, there are several drugs that are inducers or inhibitors of pGP.
morphine is an excellent choice if the patient previously tolerated it or it’s prodrug, codeine, since morphine avoids CYP metabolism. However, morphine is not an option in a patient with compromised renal function due to potential accumulation of the 3 and 6 glucuronide metabolites, as the former can result in neurotoxicity and the latter, opioid overdose
Moreover, they both undergo Phase II metabolism only thereby avoiding CYP interactions. But, hydromorphone is in general more sedating than oxymorphone, so this too needs to be titrated with caution
Tapentadol, available as the brand Nucynta ER, could be a plausible replacement for Opana ER, but note that it is a phenylpropylamine, which chemically is very different than oxymorphone. Tapentadol does not undergo CYP metabolism as noted above, so it could be a very good option if tolerated especially in the patient with compromised kidney function.
It is important to note, however that Nucynta ER has a ceiling dose so it may or may not be a viable option in patients that required very high doses of Opana ER.
A final thought: payers may argue for the use of methadone as a substitute for ERO, basing on cost as primary factor.
However, Methadone is a unique opioid and as such must be treated differently by clinicians.
And, although treated as an “ER opioid” by FDA REMS guidelines, it is not an ER product; instead it has a very long and potentially dangerous variable half-life.
CDC suggests that although methadone comprises 3-5% of prescribed opioid analgesics, up to 30% to 50% of unintentional overdoses involve methadone.
Methadone analgesia is extremely complex due to the
- variable half-life,
- genetic polymorphisms,
- high volume of distribution,
- involvement with sic CYP enzymes, and
- risk for widened Qtc.
The result is a drug with inconsistent effects across patients. There is no adequate conversion table, so initiating is always done as low dose. Also, based on interpatient variability of effects slow titration with infrequent dosing is potentially safer than more traditional rotations
Various opioids have unique chemical structures and many share the same nucleus.
Generally speaking, those that fall into the same chemical class are tolerated or not tolerated similarly in patients. The exception here is that hydroxylated phenanthrenes (morphine, diacetyl-morphine, and codeine) may not be tolerated as well as their dehydroxylated counterparts.
Once an opioid selection is made, the next clinical consideration is whether or not to use an ER vs IR (immediate release opioid). Given the recent release of the CDC opioid prescribing guidelines for primary care providers, this question is again not always easy to answer
The final step for the clinician is to settle on a safe and equivalent dose. There is an incredibly wide range and variety of opioid conversion charts in addition to the debated concept of morphine equivalents4. Some providers may cut the dose by 50%, some providers may do a 1:1 conversion, and some may elect to use both ER and IR opioids to find the preferred dose. Conversions between these medications discussed above can lead to both death from opioid overdose or withdrawal due to opioid under dosing. The following variables, in addition to what has already been discussed, needs to be considered:
Is the patient elderly or frail?
What is the patient’s psychological state? How does this play out in their drug taking and following of instructions? Do they need a referral for support during the change
Will an ER product help for uncontrolled insomnia?
How anxious is the patient and how will anxiety affect their pain is worse on their drug taking?
Concomitant CNS depressant medications?
Does the patient use illicit drugs, alcohol or cannabis and how will this be monitored during the switch?
Should the patient be hospitalized for the switch?
In conclusion, the FDA request to remove Opana ER from the market seems simple; however, the announcement is riddled with complexities and challenges for both patients and providers. A flow chart has been provided in Figure 2 to help circumvent some of the potential issues. The singling out of one product, despite its ADF properties, could contribute to additional discomfort or deaths when transitioning from one on more opioids to another. Combating the opioid abuse epidemic while also treating appropriate patients with chronic pain, unfortunately is more complex than one opioid product.
We would like to acknowledge Steven D. Passik, PhD, VP, Scientific Affairs, Education and Policy for Collegium Pharmaceuticals.