Since we started this blog, we’ve been discussing about writing something about metamizole (dipyrone, a.k.a Novalgin). Mostly because it’s probably the most sold drug in Brazil, because it’s banned in several countries, like US and Sweden, and because there is a funny history, which is probably not true, behind the US withdrawal in the 70s. Furthermore, acetaminophen sucks as antipyretic and analgesic, and metamizole seems to be a good alternative, however, things might not be so crystal clear.
So, here we go. For those who never prescribed the bone marrow killer drug metamizole, I’ll give you a summary. It is a NSAID, with both analgesic and antipyretic activity. It exerts its analgesic effect through inhibition of cyclooxygenase (COX) and it also acts in the central and peripheral nervous system, an effect somehow related to the endogenous opioid system. The mechanism of its antipyretic effect is not fully understood, maybe it inhibits some prostaglandin synthesis or has a direct effect on the hypothalamic heat-regulating center . The anti-inflammatory effect of metamizole is weak, compared to other NSAIDs. It can be administered IV, IM or PO, and the usual dose is 1g q.6h. Ok, now if you can smuggle some metamizole you know what to do with it. Also, when you run out of stamp ink, some drops of metamizole will give you an extra mile.
Show me the data!
There are few trials evaluating the analgesic and antipyretic effect of metamizole, some of them comparing it against acetaminophen, which is very interesting, some against placebo, and some against other NSAIDs. A Chochrane review published last year  evaluated the effect of a single dose metamizole (500mg) for acute postoperative pain, a total of 8 studies were included, all of them with small sample size and done in the 80s or 90s. Metamizole was able to provide effective pain relief in 70% of the participants, compared to 30% in the placebo group. In 1973, a study published in Anaesthesia  compared metamizole vs pethidine vs placebo for postoperative pain, both metamizole and pethidine were superior to placebo, with no statistical difference between metamizole and pethidine. A systematic review of metamizole for the relief of cancer pain was published recently , showing that metamizole significantly decreased pain compared to placebo and was equally effective as 60mg oral morphine/day, with the advantage of a better side effect profile (short term use).
Before we continue, I have some conflict of interest to declare: I think acetaminophen is a scam! Is a shitty drug, with no real benefits, for both pain and fever control. And I’m not even gonna throw you the statistics about acute liver failure, at least not now. But, unfortunately, nobody is paying me to say this. A trial comparing metamizole vs acetaminophen in post-episiotomy pain  showed that metamizole was superior to placebo and acetaminophen (figure below). A brief report comparing metamizole vs acetaminophen for postoperative pain after breast cancer surgery showed clinical equivalence between both drugs .
Good old times when we had lot of patients with typhoid fever to study. The antipyretic effect of metamizole was compared to acetaminophen in a double blind study in typhoid fever . The onset of antipyretic effect was shorter in metamizole than acetaminophen, also the area under time-temperature curve was greater for metamizole.
A more interesting study was published in 2013 , comparing the antipyretic effect of metamizole vs acetaminophen vs dexketoprofen in ICU patients. After 180 minutes, 76% of patients treated with dexketoprofen had a decrease of at least 1℃ in temperature, compared to 72% in metamizole group and 40% (yeah, F-O-R-T-Y) in acetaminophen group. This study also evaluated the hemodynamic effect of these drugs, but we’ll come back to this later.
There are also studies of metamizole for colic pain. One review showed similar efficacy when comparing metamizole vs indomethacin or diclofenac , and one showed that metamizole was better than hyoscine alone , with the combination of metamizole + hyoscine showing no additional benefit to metamizole alone. The information contained in this last sentence is very interesting, specially for my Brazilian friends, since the combination of metamizole + hyoscine is widely used in our country.
In summary, although we have studies showing that metamizole is effective for both fever and pain control, which is consistent with what we see on daily basis, the quality of these studies is, at best, moderate. Most of them are small studies, some observational and some we’re made before I was born. And since metamizole is banned from several “first world countries” and is a cheap drug, we should not expect new trials in the near future.
The literature about the fearful side effects of metamizole is far more abundant, but let’s not mistake abundance with good evidence. United States, United Kingdom, Sweden and India have banned metamizole due its increased risk of agranulocytosis. But, as the poet once said: “is this real life? or it’s just fantasy?” In 2014 the incidence of metamizole induced agranulocytosis (MIA) was evaluated using data from the Berlin Case-Control Study , the authors identified 26 cases of MIA, giving an incidence of 0.96 (CI 0.95–0.97) cases per million per year. A PLOS ONE systematic review and meta-analysis  showed fewer adverse events for metamizole when compared to opioids, but no difference when compared to placebo, aspirin or acetaminophen. No agranulocytosis were reported. The reported incidence of MIA in Sweden, based on spontaneous reports, was estimated to be around 1:1439 prescriptions . If we look at some Swiss data, the crude number of deaths related to MIA between 1991 and 2012 was 7 .
Time and again we see a little old lady saying she is “allergic” to metamizole, and when you look at her and say: “Tell me about it”, the usual answer is: “metamizole drops my pressure”. And I gotta tell you, for a long time I thought this was bullshit, yet, life is funny. We have few articles discussing the hemodynamic effect of IV metamizole. A recent published article  studied the effect of metamizole on human artery and vein tone in an ex vivo model. Metamizole caused sustained and dose-dependent relaxation of saphenous vein. The mammary arteries showed a transient contraction followed by a time-dependent relaxation. Of course this wasn’t new, in 1983 a study  showed that metamizole decreased blood pressure in about 0.34% of studied patients. In the trial by Vera et al  we already discussed, all three drugs (metamizole, acetaminophen and dexketoprofen) reduced the MAP, as shown below.
Another potential downside of metamizole, which I wasn’t aware since few weeks ago, is the potential impairment on the pharmacodynamic response to aspirin  . However, although this might have a physiological background, the evidence of worse outcomes is weak.
Give’em acetaminophen instead
Well, if you don’t wanna be part of our mental masturbation, you might think acetaminophen is the answer. Not so fast, baby! Regarding pain control, metamizole consistently showed to be superior to acetaminophen. And in my humble opinion, when we talk about fever control, the HEAT trial  nailed the acetaminophen’s coffin on this matter. I’ll quote: “Patients assigned to receive acetaminophen had a lower mean daily peak body temperature than those assigned to placebo (38.4±1.0°C vs. 38.6±0.8°C; absolute difference, −0.25°C; 95% CI, −0.38 to −0.11; P<0.001) and a lower mean daily average body temperature (37.0±0.6°C vs. 37.3±0.6°C; absolute difference, −0.28°C; 95% CI, −0.37 to −0.19; P<0.001)”! Really? −0.25°C/−0.28°C absolute difference?? I can decrease my body temperature in −0.28°C just by expelling a hot fart!
How about acetaminophen induced acute liver failure (ALF)? I bet my wife’s wedding ring that every time you see a previously healthy patient with ALF, acetaminophen overdose comes to your mind. Am I wrong? A population based survey published in 2007  estimated an anual incidence of ALF 5.5 (95% CI 4.3-7.0) per million in US, in which 41% was related to acetaminophen. From 1998 to 2003, acetaminophen was the leading cause of acute liver failure in the US .
Therefore, why not ban acetaminophen from US, UK, Sweden, or India? It seems to be useless for both pain and fever control, and it is associated with an adverse effect far worse than agranulocytosis. There are rumors that metamizole was banned from US because it was a German drug, since it was first sold in Germany in 1922 under the name Novalgin (Bayer). Damn Krauts! I still can remember an ER episode where some guy is diagnosed with agranulocytosis caused by smuggled metamizole injections from Mexico!
Ok, probably the FDA don’t read my blog and some of you guys will never be able to prescribe metamizole. But it seems a bit nonsense to ban a drug based on a pretty rare adverse effect while more harmful drugs are bought over the counter. Of course metamizole is not 100% safe, but neither Holy water is . I once knew a guy at the hot dog stand that told me his cousin’s baby died after drowning at the Holy water sink while he was baptized. Anyhow, I was also intrigued by the potential interaction of metamizole in aspirin efficacy, and I really think this is a interesting study field. For now, I’ll keep doing what my daddy once told me: A gram of metamizole and a pinch of beer can kill any hangover.
1. Nikolova I, Tencheva J, Voinikov J, et al. Metamizole: A Review Profile of a Well-Known “Forgotten” Drug. Part I: Pharmaceutical and Nonclinical Profile. Biotechnology & Biotechnological Equipment. Vol. 26 , Iss. 6,2012
2. Hearn L, Derry S, Moore RA. Single dose dipyrone (metamizole) for acute postoperative pain in adults. Cochrane Database Syst Rev. 2016;4:CD011421.
3. Lal A, Pandey K, Chandra P, et al. Dypirone for tratamento of post-operative pain. Anaesthesia. Volume 28, pages 43-47, 1973.
4. Gaertner J, Stamer UM, Remi C, et al. Metamizole/dipyrone for the relief of cancer pain: A systematic review and evidence-based recommendations for clinical practice. Palliat Med. 2017;31(1):26-34.
5. Daftary SN, Mehta AC, Nanavati M. A controlled comparison of dipyrone and paracetamol in post-episiotomy pain. Current Medical Research And Opinion. Vol. 6 , Iss. 9,1980.
6. Kampe S, Warm M, Landwehr S, et al. Clinical equivalence of IV paracetamol compared to IV dipyrone for postoperative analgesia after surgery for breast cancer. Curr Med Res Opin. 2006;22(10):1949-1954.
7. Ajgaonkar VS, Marathe SN, Viran AR, et al. Dipyrone versus Paracetamol: A Double-Blind Study in Typhoid Fever. Journal of International Medical Research. Vol 16, Issue 3, pp. 225 – 230
8. Vera P, Zapata L, Gich I, et al. Efectos hemodinámicos y antipiréticos del paracetamol, metamizol y dexketoprofeno en pacientes críticos. Med. Intensiva, v. 36, n. 9, p. 619-625, 2012.
9. Brogden RN. Pyrazolone derivatives. 1986; Drugs 32 [Suppl 4]: 6O-70.
10. Lloret J, Mufioz J, Monmany J, et al. Treatment of renal colic with dipyrone. A double-blind comparison trial with hyoscine alone or combined with dipyrone. 1987; Curt Ther Res 42:1119-1128
11. Huber M, Andersohn F, Sarganas G, et al. Metamizole-induced agranulocytosis revisited: results from the prospective Berlin Case-Control Surveillance Study. Eur J Clin Pharmacol. 2015;71(2):219-227.
12. Kötter T, da Costa BR, Fässler M, et al. Metamizole-associated adverse events: a systematic review and meta-analysis. PLoS One. 2015;10(4):e0122918.
13. Hedenmalm K, Spigset O. Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole). Eur J Clin Pharmacol. 2002;58(4):265-274.
14. Blaser LS, Tramonti A, Egger P, Haschke M, Krähenbühl S, Rätz Bravo AE. Hematological safety of metamizole: retrospective analysis of WHO and Swiss spontaneous safety reports. Eur J Clin Pharmacol. 2015;71(2):209-217.
15. Hoenicka M, Gorki H, Traeger K, Liebold A. Selective venous vasodilator properties of the analgesic metamizole (dipyrone) in a human ex vivo model-implications for postoperative pain management. Naunyn Schmiedebergs Arch Pharmacol. 2017.
16. Zoppi M, Hoigné R, Keller MF, et al. Reducing blood pressure with Dipyron (novaminsulfone sodium). 1983; Schweiz Med Wochenschr 113:1768–1770
17. Dannenberg L, Erschoff V, Bönner F, et al. Dipyrone comedication in aspirin treated stroke patients impairs outcome. Vascul Pharmacol. 2016;87:66-69.
18. Polzin A, Zeus T, Schrör K, et al. Dipyrone (metamizole) can nullify the antiplatelet effect of aspirin in patients with coronary artery disease. J Am Coll Cardiol. 2013 Oct 29;62(18):1725-6.
19. Young P, Saxena M, Bellomo R, et al. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. N Engl J Med. 2015;373(23):2215-2224.
20. Bower WA, Johns M, Margolis HS, Williams IT, Bell BP. Population-based surveillance for acute liver failure. Am J Gastroenterol. 2007;102(11):2459-2463.
21. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology, 2005 Dec; 42(6):1364-72.
22. Michel M, Entenmann A, Wiemann T, van Baalen A, Krause M. Holy water associated pulmonary infection with a multiresistant Acinetobacter baumanii in an 11-year-old child. Klin Padiatr. 2013;225(1):43-44.