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10 Articles in Volume 17, Issue #6
A Plea for Proper Opioid Tapering
Centers of Excellence in Pain Management: Past, Present, and Future Trends
Comorbid Pain and Childhood Obesity
Discussing Migraine With Your Patients: A Common Sense Guide for Clinicians
Justification of Morphine Equivalent Opioid Dosage Above 90 mg
Letters to the Editor: Dependence vs Addiction, Opioid Metabolism
Opioid Rotation From Opana ER Following FDA Call for Removal
Psoriatic Arthritis: Established, Newer, and Emerging Therapies
Sleep-Wake Disorders and Chronic Pain: Reciprocal and Interactive Effects
What are Nav1.7 inhibitors and how are they used in the treatment of neuropathic pain?

Opioid Rotation From Opana ER Following FDA Call for Removal

Switching from one opioid to another is never easy, but when the FDA pulls a product from the market, the urgency to find a replacement may make the process that much more difficult. A review of what products may be an appropriate substitute for Opana ER and why is provided.

The US Food and Drug Administration (FDA) asked Endo Pharmaceuticals to voluntarily remove Opana ER from the market in June 2017.1 A month later, Endo announced their compliance with the request to remove the product. Shipments of Opana ER will end on September 1, 2017 to enable patients to convert to an appropriate alternative treatment, noted the company.

As experienced pain clinicians, we are concerned with the potential ramifications that may follow the removal of any opioid product from the marketplace, particularly one used in the treatment of thousands of patients suffering with chronic pain. This removal threatens to, at least temporarily, disrupt treatment, worsening patient discomfort (or far worse) and leaving many clinicians scrambling to figure out what to do next.

We do not wish to debate the merits (or lack thereof) of the FDA’s decision. However, we also recognize that the thousands of patients who had been prescribed Opana ER each month and the thousands of clinicians doing the prescribing may view this as a potential emergency. Opana ER is formulated with abuse-deterrent technology. Although Opana ER was never approved by the FDA as an abuse-deterrent formulation (ADF), if someone attempts to crush and dissolve the tablets, they turn into a gel that is difficult to inject.2 Crushing Opana ER into a fine powder for snorting also is difficult.2 Prescribers will need to make an educated and safe rotation to an alternative opioid based on the best therapeutic decisions and clinical evidence available. Patients treated with the branded Opana ER are matched by thousands taking generic oxymorphone ER, which has no abuse-deterrent properties, is more easily abused, and has not been affected by the FDA request.

Knowing how to accomplish an opioid rotation safely is an important, but often atrophied, skill in the prescriber community. It has become increasingly important, with clinicians now encouraged to stay within sanctioned morphine milligram equivalent (MME) limits set forth in various guidelines (and in certain circumstances, in 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.

In the earlier days of expanded opioid prescribing, the fact that there was no pharmacologic ceiling was taken to mean that prescribing high doses reached slowly and methodically over time was a legitimate way to dose opioids. One consequence might have been that clinicians did not learn all they needed to about rotating these drugs. Now that the mores of practices, or at least the approach to prescribing, have changed, it has become particularly crucial to revisit the critical concepts behind opioid rotation.

One final point to remember before we delve into the thought process of deciding which drug to target and the challenges of switching medications is 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 a smooth and easy transition for patients, especially those who had been treated with Opana ER for a long time.3,4 As we used to tell patients, “Your liver and kidneys don’t know how to add.”

Clinicians should be prepared to change practice patterns to get this done right. It will likely require the patient following up weekly, not monthly. Opioid rotation has its origins in cancer pain management, which means it was often done in semi-emergent situations. For example, 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; this often was done all at once, generally in an institutional setting.5 In outpatient practice, this should be done more slowly and methodically to avoid catastrophic, idiosyncratic reactions.

Targeting a Medication to Try in Lieu of Opana

Marketing Initiatives Likely

Fortunately, there are numerous available options for clinicians to consider, with several branded, proprietary products available, as well as generic alternatives that may be effective (Table 1). Moreover, it is a certainty that other pharmaceutical companies are preparing to capitalize on the withdrawal of Opana ER as an opportunity to invite switches to their product. In so doing, they will offer reasons for clinicians to consider their product. Considering the idiosyncrasies of various opioids and variable response, no one product will suffice.

Our experience tells us that most companies are ethical. More to the point, they will likely be practical enough to recognize that their extended-release opioid (ERO) will not be the right product for 100% of the patients who had been taking Opana ER. Although companies would love to see patients switched to their respective product, they are likely to recognize that for some prescribers, the switch away from Opana ER might represent the first real opportunity for their drug to be considered as an appropriate ERO replacement.

We believe any respectable company would like to avoid the “one-trial learning” that accompanies a treatment failure, or worse, on the first occasion a prescriber uses their product. Thus, we believe that they too would like to see only those patients who have the highest likelihood of a reasonable tolerability and response switched to their product.  

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, per market analyses.6 Many patients started on Opana ER after trying another long-acting opioid (perhaps generic long-acting products such as morphine ER or fentanyl patches with or without the most commonly prescribed branded long-acting opioid, OxyContin). Given that Opana ER had 1 of the highest levels of persistence of therapy over all the long-acting opioid products, clinicians might need to review the medical record to be reminded of how the patient initially came to be on Opana ER.6

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 underdosing, with attention to the 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.

The Easy Approach

Generic oxymorphone ER is the easiest rotation. After all, it is the same drug in the same long-acting form. However, some clinicians may be surprised to learn that the generic product is not an official FDA abuse-deterrent formulation, as previously discussed. Although it may be tempting to make this an easy, 1:1 switch, the clinician must first consider whether the patient is best served with an ADF. This can be based on 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). Perhaps the patient initially was switched to Opana ER for 1 of these reasons, but after uneventful months or years taking the product, with the patient now in a solid and active recovery, the switch can be made to the nonabuse-deterrent generic. But use caution; the generic has been noted to be abused in every way more than Opana ER was (ie, nasally and intravenously) and with the branded product disappearing, the street value of the generic may increase.7 If any of these abuse- or diversion-related concerns are still pertinent, it is worth the time and trouble to consider switching to another abuse-deterrent product.

Abuse-Deterrent Products

There are several products with abuse deterrent features that deter crushing, snorting, or injecting through either physical barriers that harden the tablet, newer microsphere technologies, or sequestered antagonist approaches that are released upon tampering. Not all products have ADF labeling.

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 antifungals, 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 who 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.8

Considering Drug Metabolism and Absorption

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 even though 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. For example, if a patient is on a pGP inducer, the levels of morphine entering the systemic circulation will be lower, which could result in severe withdrawal or an incorrect assumption that their opioid tolerance is exceedingly higher than it really is, or in the case of a pGP inhibitor, an overdose. Therefore, 3 potential options to replace Opana ER that have ADF properties that are morphine products (Morphabond, Embeda, and Arymo ER) need to be titrated with caution. Nevertheless, 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.

A conversion to the hydromorphone product (Exalgo) may also be an easy transition because both hydromorphone and oxymorphone are dehydroxylated phenanthrenes and, therefore, are similarly tolerated. Figure 1, includes a list of various opioids and their chemical structures, including cross-reactivity. 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. Additionally, Exalgo is not an ADF.

Tapentadol (Nucynta ER), as outlined in Figure 1, could be a plausible replacement for Opana ER, but note that it is a phenylpropylamine, which chemically is very different from 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 who require very high doses of Opana ER.

Other Non-ADF Options

Opioids that could also be used include generic morphine ER and transdermal fentanyl. Fentanyl is a phenylpiperidine and generally is very well tolerated, but it is not in the same chemical class as oxymorphone. Due to fentanyl’s potency, at low doses of Opana ER, even the smallest dose, fentanyl transdermal of 12.5 mcg/hour, might be too high.

A final thought: payers may argue for the use of methadone as a substitute for ERO, based 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% to 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.9  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.

A summary of the recommendations can be found in Table 1. A decision tree has also been constructed as a tool for providers in Figure 2.

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, as outlined in Figure 1.10  The exception here is that hydroxylated phenanthrenes (morphine, diacetyl-morphine, and codeine) may not be tolerated as well as their dehydroxylated counterparts. 

Special Considerations

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.11

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 equivalents.4  Some providers may cut the dose by 50%, some providers may do a 1:1 conversion, and some may elect to use 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 underdosing. The following variables, in addition to what has already been discussed, need 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 the patient on 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?

Conclusion

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 or 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.

Last updated on: August 16, 2017
Continue Reading:
Sleep-Wake Disorders and Chronic Pain: Reciprocal and Interactive Effects

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