Preventing and treating acute gout attacks across the clinical spectrum: A roundtable discussion
COLCHICINE: SPECIAL CONSIDERATIONS FOR USE
Dr. Mandell: Let’s move to colchicine, which represents a unique class of anti-inflammatory agent. It has been available and widely used for many years, but it had not been formally licensed by the FDA until last year. Without corporate imperative and funding, data on its clinical use have been limited. As we mentioned, an IV form of colchicine was withdrawn from the market a few years ago after being associated with multisystem organ failure and death. Low-dose short-term colchicine doesn’t have those risks, and its efficacy in treating gout has been accepted for many years despite the dearth of clinical trial data until recently. How has colchicine been used in the past, and do the new data guide us on how it should be used differently, specifically for treating acute gout attacks?
Dr. Simkin: The so-called traditional regimen of starting with a pair of colchicine tablets and then giving another tablet every 1 or 2 hours until relief (or until GI toxicity developed) is one of the great embarrassments in the history of our field. The more recent trial evidence clearly indicates in the short term that there is no additional benefit beyond a very low dose. As we noted, this has been in the wind anecdotally for quite a few years, and it was confirmed by the recent AGREE trial.11 I find it interesting that the dosage used in AGREE—three 0.6-mg tablets—is very close to what we use for prophylaxis. We may well wind up concluding that any patient we’re seeing for the first time with an acute attack should be treated with that dose of colchicine, as an adjunct to another anti-inflammatory drug.
The use of colchicine as an adjunct for acute gout attacks was advanced in a review by Cronstein and Terkeltaub several years ago.32 Since we know that the mechanisms of action of the various drugs for acute gout are sufficiently different from each other, it makes sense to consider hitting the process at more than one spot. Having said that, one of the most crucial concerns in using colchicine is what other medications the patient is taking, given colchicine’s multiple drug interactions (Table 3). These include interactions with most statins, some antibiotics, and some calcium channel blockers, which share drug transporters with colchicine. So we have to be cautious about using colchicine with those other therapies.
Dr. Mandell: That’s also important in patients on chronic prophylactic colchicine therapy, as we know from recent pharmacokinetic studies and anecdotal case reports of colchicine and some of these other drugs.16–23 Do you think it’s as important in a patient on, say, chronic statin therapy who’s not on baseline colchicine, in whom you use a colchicine regimen of just two tablets followed by one tablet and then stop the colchicine right there? Is the potential for meaningful drug interactions as important in that setting?
Dr. Simkin: Probably not. One of the key issues is to educate patients about what to look for. Tell patients that if they notice numbness, weakness, or myalgia, you want to know about it. The evidence I’ve seen is that people who go into colchicine-induced rhabdomyolysis, for instance, develop it over a period of days, not hours, and if they stop the drug early, they probably will be okay. That’s the biggest concern. Neutropenia is the second concern.
Dr. Mandell: But fortunately, assuming no chronic kidney disease, those are generally patients taking colchicine chronically, not just acutely. We talked a bit before about our panel’s concerns about the efficacy of colchicine. Say you have a patient who has no history of prior colchicine use. How comfortable are you that treating such a patient with just the three-tablet colchicine regimen is likely to give the desired effect of rapid pain control and resolution of the attack?
Dr. Edwards: I’d expect that there wouldn’t be a profound or rapid improvement on that regimen, although the patient would certainly do better than if he or she were on nothing. I think that’s what the AGREE trial showed—that patients improve but still have significant morbidity days after initiating therapy.
Dr. Mandell: I think the AGREE trial did what it was intended to do: it showed that a low-dose colchicine regimen was as effective as and better tolerated than a high-dose colchicine regimen. This was something most of us believed, but it had never been demonstrated in a trial, and now there are good data to show it. And AGREE was consistent with the 1987 Ahern study10 in showing that the high-dose regimen is better than placebo. However, it in no way convinced me that colchicine in this dosing regimen is a monotherapy I’d be comfortable using to treat a severe acute attack. AGREE also didn’t give me any information as to how likely this approach would be to resolve an attack. For all the reasons we discussed, continued anti-inflammatory therapy is likely necessary beyond three pills, and I can’t be confident that a course of three colchicine pills is sufficient to maintain a drug level inside white cells to prevent other attacks from happening or a rebound attack once the regimen is over. I’m sure this approach will work for some patients; I just don’t know at the outset which ones or what percentage of patients will respond completely.
Dr. Edwards: I like the idea of combination therapy, of using colchicine as an adjunct. We’ve been talking up to now about monotherapies for acute gout because monotherapy is simple and patients and physicians alike prefer things that are fairly simple to use. But there is good theoretical reason to support using colchicine in combination with either NSAIDs or steroids, though there are probably no experimental data. I can’t imagine a reason for using corticosteroids and NSAIDs together, but pairing up colchicine with a steroid or an NSAID might allow you to keep the dose of the other agent lower and perhaps reduce the overall toxicity of your therapy. I’ve occasionally put patients on that type of combination therapy, and it’s probably a helpful way to go.
Dr. Mandell: For years my approach has been one of cotherapy, counting on either NSAIDs or corticosteroids to treat the acute attack by rapidly relieving the pain and inflammation and using colchicine in low doses—at a prophylactic dose, as Peter said—and extending it over a much longer period. I’m counting on the colchicine not to treat the acute attack but to prevent the next one and hopefully, for all the reasons we talked about, shorten the duration of therapy with the steroid or NSAID.
Dr. Edwards: Sure. The way I use colchicine is mostly for maintenance and for prophylaxis while I’m initiating urate-lowering therapy. I use it for a bit longer than most others might—I draw it out to at least 6 months after a complete resolution of symptoms, sometimes to 9 or 12 months. When a patient has a flare, I certainly have them maintain the colchicine if I’m going to treat them with something else, as I almost always do, and I believe that lets me get by with lower doses of the other agent I’m using for the acute attack.
Dr. Sundy: When I use colchicine as monotherapy for an acute flare, it’s because the patient has concluded from experience that it has worked effectively for him or her. But that’s not very common.
Dr. Mandell: There are times when the patient’s comorbidities lead me to conclude that colchicine may be the best drug to try for acute treatment. But I’m not comfortable assuming that three pills will do it all.
Dr. Pile: From the perspective of the generalist, who typically treats a simpler gout population than you do, what is the recommended treatment duration if colchicine is used as monotherapy for an acute attack? We now have this recommendation to use a single day’s worth of therapy, but you’re all expressing reservations with that.
Dr. Edwards: The recommendation in the drug’s current labeling is to take two 0.6-mg tablets at the first sign of a flare and a third 0.6-mg tablet 1 hour later. That was the low-dose regimen in AGREE, and I think it’s a good one, as only a very small percentage of patients will get the GI side effects with this regimen that occur with more prolonged therapy. The real question is what you do on day 2 and day 3 on out to day 7 or 10. If I were to use colchicine monotherapy, after that first day I’d prescribe one tablet three times daily for another 3 or 4 days and then drop down to one tablet twice daily for the rest of whatever duration of therapy I felt was justified. Of course, this is highly individualized and depends on how the drug is tolerated; probably more than 25% or 30% of patients can’t tolerate a three-times-daily regimen even for 3 or 4 days. But the total duration would be at least 7 days and up to 10 or even 14 days.
Dr. Simkin: Or months, because you’ve established a diagnosis.
Dr. Edwards: Yes—as prophylaxis, for which the dosage is one tablet once or twice daily. And then you’d leave the patient on prophylaxis and start urate-lowering therapy, if it hadn’t been started already.
Dr. Mandell: We’re now way past having trial data to support this, and this approach may negate the purported safety advantages of the low-dose regimen supported by AGREE.
Dr. Edwards: Yes, this is rank speculation.
Dr. Simkin: But there is evidence of the value of prophylaxis.
Dr. Mandell: There is certainly evidence for the value of prophylaxis, from a number of studies. We’ll get to that shortly. However, if we think just about treating the acute attack and the AGREE findings, I don’t think we can extend those results with confidence to a setting where we switch immediately from acute therapy into a prophylactic mode. Not that we shouldn’t consider doing that—it’s similar to my practice as well, though I tend to use lower doses as I extend out—but the existing trial data are limited to that very short window of acute treatment. Anything we do beyond that is an extension from our belief that the inflammatory response to crystals in a joint lasts longer. I believe it generally requires longer anti-inflammatory therapy, but we need to expect some frequency of side effects and drug interactions as we put patients on chronic colchicine therapy.
The other factor that used to be an advantage of this type of regimen was its low cost. For a long time colchicine was available from multiple manufacturers and was exceedingly inexpensive, although with less FDA guidance on its use and less oversight of its manufacturing. This enabled even patients with no insurance to go on a prophylactic therapy and remain on it. The environment is now quite different with the introduction of a single FDA-approved and -regulated branded product. So how do we deal with cost in the current environment?
Dr. Edwards: In terms of specific numbers, once-daily and twice-daily doses of unbranded colchicine used to cost about $6 and $12 a month, respectively, based on the average wholesale price. Now the cost of branded colchicine (Colcrys) is about $175 a month for the once-daily dose and $350 a month for the twice-daily dose, again based on the average wholesale price.
Dr. Simkin: I think all of us are deeply troubled by the high cost of this preparation and hope that the alternatives will still remain available to us.
Dr. Edwards: Yes, especially since it sounds like most of us consider colchicine our go-to drug for maintenance. It used to be that patients might be on maintenance colchicine therapy for 5 or 10 years without any addition of urate-lowering therapy. Today, however, when most of us put a patient on prophylactic therapy with colchicine, it’s with the intent of also addressing the hyperuricemia that’s at the heart of the disease process. In that case we still cover patients with colchicine prophylaxis during the initial months of urate-lowering therapy because of the elevated rate of gout flares—so-called mobilization flares—that occur during the process of uric acid reduction.
Dr. Mandell: The manufacturer of branded colchicine has introduced a patient assistance program to ease the drug’s cost for the financially needy. We will have to see how practical it is and how it affects our patients’ use of this medication.
