When New Doesn’t Necessarily Mean Better in Pain Medicine

Many new drugs are introduced each year, and there is a clear rationale for their development. Some provide new options for diseases for which there are few, if any, treatments available; others offer alternatives that may be more efficacious or have more benign side effects than currently approved treatments.

However, there are also drugs introduced for which it is difficult to discern the improvement they offer over their predecessors. Three new opioid analgesics-two that recently came on the market and one that an FDA advisory panel unanimously recommended against approving-seem to fit into this category.

The advisory panel opposed approval of Moxduo, a combination of oral morphine and oxycodone intended for treatment of acute pain. As far as I am aware, there are no products containing two opioids currently available, so this one would have been unique.

I’m assuming the members of the advisory panel were just as skeptical as I am as to why this combination would be any more efficacious than either of the opioids taken separately or be less likely to cause adverse events, which its manufacturer claims.

There is nothing to indicate that opioids act synergistically with each other. Furthermore, since analgesia from an opioid may decrease over time and hyperalgesia may also develop in some patients, switching to another opioid when these situations occur may be beneficial. Combining two opioids would seem to simply reduce the options available for doing this.

The two other drugs, both of which are now available, are Zohydro ER, an extended-release/long-acting (ER/LA) form of hydrocodone that I discussed in a previous column, and Xartemis XR, a combination of oxycodone and acetaminophen.

Xartemis is a bit of a hybrid: an ER/LA drug requiring only q12 hour dosing that also has rapid onset of analgesia (reportedly in less than an hour).

Apparently the only thing, apart from this rapid onset of action, which some might consider a benefit of Xartemis is that it also contains acetaminophen. Other currently available ER/LA oxycodone compounds such as OxyContin do not.

I find this an interesting issue, especially because Zohydro contains no other medications (most notably acetaminophen) thus reducing the risk of adverse events that may be related to excessive doses of them. The manufacturer has highlighted this as a benefit in contrast to the other currently available hydrocodone products.

We are left with a dichotomy. One can either view having the opioid and acetaminophen contained in one tablet as beneficial for patients, as the manufacturer of Xartemis would like us to believe, or one can believe that this combination is better avoided, as the manufacturer of Zohydro suggests.

I have concerns about Xartemis. First of all, I have never been a fan of combination opioid drugs, especially those with acetaminophen. Patients can develop tolerance to the analgesic effects of opioids and therefore may require increasing doses over time to attain the same level of analgesia. Since the dose of acetaminophen is increased at the same time in the combination tablet, there is a significant risk of patients ingesting potentially toxic doses of the drug.

The only dosage of Xartemis that the manufacturer recommends is two tablets, each containing 7.5 mg of oxycodone and 325 mg of acetaminophen, q12 hours. If prescribers stick to this recommendation, it is unlikely that acetaminophen toxicity would be a problem. However, I have frequently encountered physicians prescribing dosages of opioids that exceed manufacturers’ recommendations as well as those prescribing ER/LA opioids on much shorter schedules than is indicated. Even more frequently I have encountered patients taking additional doses of these drugs when they are having pain, ignoring the prescribed schedule.

My other major concern about Xartemis is that it is an ER/LA drug only indicated for management of acute pain, which to me seems like an oxymoron. In fact, the advertising for the drug is a bit confusing. Despite the indication, an advertisement for it notes that it is “the first and only FDA-approved oxycodone/acetaminophen combination to provide immediate- and extended-release analgesia,” suggesting that it would be useful to patients who needed an ER/LA opioid.

Since most cases of acute pain are time-limited and it can be very difficult to determine which cases of acute pain will go on to become chronic pain, immediate-release/short-acting (IR/SA) opioids are generally considered to be better choices than the ER/LA preparations.

Even if it has more rapid onset than other ER/LA opioids, Xartemis will still remain in the body longer than IR/SA opioids, so if a patient has an adverse reaction to the medication, it’s probably going to be more problematic.

IR/SA oxycodone is readily available both in combination with acetaminophen and without it, so Xartemis is far from the only option when it comes to using this opioid for acute pain. Also, other oxycodone products are available in generic form, and so are likely less expensive than Xartemis.

The major selling points for Xartemis seem to be the convenience of taking the opioid less often and not having to take separate acetaminophen if it is also indicated.

I have never found the issue of convenience to be of special importance to most patients with pain. From my experience, patients care most about how much pain relief they receive. How often they need to take analgesics is usually a minor issue. For conditions like hypertension, in which patients will not notice immediate onset of symptoms if they forget to take their medications, dosing convenience is important if it helps patients remember to take them. If those suffering from pain don’t take their analgesics, then their discomfort will remind them to do so.

The major reason for using an ER/LA opioid is not patient convenience but the belief that it may provide better analgesia for patients who are expected to have pain that is fairly consistent and marked throughout the course of a day for an extended period of time.

As far as I can ascertain, Zohydro, Xartemis, and Moxduo provide little, if any, advance in the management of pain. They all contain drugs that have been available for many years-hydrocodone, oxycodone, acetaminophen, and morphine-and, except for hydrocodone, have also long been available in both IR/SA and ER/LA formulations.

Sadly, this has been a major problem common to many of the new analgesics introduced over the last 10 to 20 years. When it comes to opioids, the two major changes during this period have been the introduction of more tamper-resistant and ER/LA formulations.

With regard to the purported benefits of the tamper-resistant drugs, they are aimed at reducing prescription opioid abuse rather than improving analgesia. The former may be a laudable goal (although, as of yet, there is little to indicate that the availability of these formulations has had much of an impact on this problem), but putting an existing medication in a tamper-resistant tablet doesn’t make the drug any more effective or make it any more likely that patients who would benefit from opioids will receive them.