You’ll see them piled up next to the Advil and Acamol (paracetamol) in any Israeli pharmacy: boxes of Optalgin tablets sold over-the-counter as a household painkiller. Many Israelis barely distinguish among these three medicines and consider Optalgin just another brand name, different packaging of more or less the same thing. This is a misconception. Optalgin is a much stronger medication, and for some consumers it comes with a decided twist.
Six years after moving to Israel, I had never heard of Optalgin until I returned from a trip abroad with food poisoning in February 2018. My physician told me there was a non-steroidal, non-narcotic medication available here over-the-counter I was probably not familiar with that was highly effective against pain. She was right: Optalgin was quite effective against my lingering stomach pain. Strangely, though, it took me a number of weeks to get over the infection fully, surprising her by its unusual length. In retrospect, it is conceivable this may have been the fault of the Optalgin. At the time, my doctor did not make this connection, nor did she offer any cautions on using the drug.
In December 2018, I started taking Optalgin intermittently for muscle pain. I had joined a professional chamber choir in the fall, and the hours of rehearsal and performance while holding the scores at arm’s length were taking a toll on my upper back, which often referred pain to the back of my head. Despite exercise and massage, my pain got worse over the months, and I tended to take more medication, including Optalgin, to control it, especially around concert times. One pharmacist who sold me Optalgin made a vague reference to side effects, but pointedly said this did not apply to our population subgroup (which I took to mean Israelis in general or Ashkenazi Jews).
One morning in late March of this year I awoke with a bad sore throat which progressed with the telltale signs of a streptococcal infection. I confirmed this with a rapid strep test, started the usual course of penicillin, and saw my doctor the next day. Over the course of the following week, my fever and pain seemed to get better but sometimes persisted. Anxious to get well enough to perform in two upcoming Schubert concerts with the choir, I took Optalgin liberally. Each time it eased the symptoms, but when it wore off, they returned, seemingly worse. Unwittingly, I had entered a vicious circle. The concerts went well, but by the end of the weekend, I felt systemically worse, and by Monday morning I was devastated by what felt like a re-infection by the strep. The fever, pain, and malaise were considerably worse than they had been at the height of the infection the week before. Highly puzzled at the apparent failure of the antibiotics to get rid of the infection, my doctor consulted an infectious disease specialist. Within a day, they urged me to go to the hospital emergency room. When in triage I was offered Advil and paracetamol to bring down a 39° fever, I asked for Optalgin instead because I said I knew it worked, and was given it. That was my third dose of the last 24 hours.
Admitted to the ear, nose, and throat department of Shaare Zedek Medical Center, I began a five-day stay of misery. Tonsillitis was evident but did not show unusual pathology. What was highly unusual were the results of blood tests that showed severe neutropenia, very low levels of neutrophils, white blood cells key to fighting infections, which as an acute condition is also termed agranulocytosis. As long as my levels were this low, I was at high risk of further infection, progression of the infection to the blood, and even life-threatening sepsis. My misery from the unremitting high fevers, the pain in my tonsils, a swollen hand from the IV, sleep deprivation, and the psychological pressure was horrendous. In that state, I prepared words of parting for my family members.
A doctor from the hematology ward visited me and asked me a series of questions. What drugs had I been taking? Had I taken Optalgin recently? Did I have a family history of blood diseases or cancers? I told him I had taken Optalgin liberally over the past weeks, especially in the last week. He told me it was long known to cause severe neutropenia as a rare side effect, and I should stop taking it immediately. He instructed the nurses on the ward not to give me any more. In addition to the heavy IV antibiotics and other drugs I would receive, he agreed with my suggestion to administer Neupogen, a drug that I knew raised white blood cell counts. Over the following days, I received or administered myself six Neupogen injections. Ultimately, after five days, my fever began to come down, and I was released in a greatly sickened, weakened, although not precarious state. My long home recovery was about to begin.
Four days later I returned to the hospital hematology department for a scheduled follow-up, which was supposed to include a bone marrow biopsy and other tests to explore additional possible underlying causes for my condition. With a dry mouth from a pre-anesthesia fast, I waited two hours for the results of preparatory blood tests. Finally, to my great relief, the hematologist called me into his office and told me they were going to release me without further tests. My white blood cell count had shot up and was in fact considerably above normal. I was to stop the Neupogen and wait for a normalization. With this they were confident of their hypothesis of drug-induced agranulocytosis. I would wear a red wristband for ‘allergic/hypersensitive to certain drugs’; Optalgin would be listed as strictly off limits in my medical file from now on.
I asked the hematologist why this drug was used in Israel. He said it was banned in many countries such as the US, and for good reason. As I was getting ready to leave the hospital, I met a nurse from the ear, nose, and throat department who had taken care of me in the wards and filled her in. She said, “Yes, the Americans are afraid of this drug (Optalgin) and stay away from it.” What did the Americans know that the Israelis didn’t? What regulatory, corporate, or bureaucratic failure could explain the continued OTC marketing of Optalgin in Israel decades after its ban in the US?
Why had this happened to me? I was plagued by the question of why a drug with such potentially devastating and even fatal side effects should be freely available without prescription or strong warnings in every pharmacy in the country. Granted, the package insert in Teva’s Optalgin includes a warning about agranulocytosis, but how many people carefully read and heed the long lists of every reported side effect of run-of-the-mill OTC pain relievers they buy in drug stores, particularly when no health care professional draws their attention to them?
Turning to the Internet, I found many articles discussing the history of Optalgin (the drug dipyrone, also known as metamizole), the discovery of the side effects of neutropenia/agranulocytosis, and the resulting controversy in many countries over allowing its continued use. It is indeed a highly effective, non-addictive pain reliever, particularly useful for the elderly since it does not carry the risks of narcotics (addiction, overdose), ibuprofen (gastrointestinal bleeding), or paracetamol (liver damage). But because of the potentially life-threatening risk of agranulocytosis– which according to the research is fatal on average 24% of the time – the US FDA banned its further sale in the US in 1977, following Sweden’s ban in 1974, and the UK, Japan, Australia, and most of the EU followed suit. The incidence and severity of this particular adverse effect was considered high enough to warrant taking it off the market. Ibuprofen and paracetamol are on the World Health Organization’s Model List of Essential Medicines; dipyrone is not. Astoundingly, just last year (2018), Spain banned its sale to visiting British and Irish nationals after an inquiry linked dipyrone consumption to the deaths of ten British tourists in Spain who were prescribed the drug while on vacation and subsequently developed fatal agranulocytosis and related infections. (Some data point to greater susceptibility among certain population subgroups such as these.)
In Spain, Portugal, Switzerland, and Germany, dipyrone is a prescription-only drug. In Switzerland it is indicated for severe pain and high fever that do not respond to other medications. Notably, in Germany, dipyrone’s use is closely monitored, and if it is prescribed for more than 10 days, the patient’s blood is regularly screened for abnormalities. In Brazil dipyrone has been a mainstay in treating moderate to severe pain and fever, and partly in view of the lack of alternatives, the ministry of health decided to keep dipyrone on the market, a decision that generated great public debate and controversy. There, however, it carries several warnings about the need for early detection and treatment of any resulting agranulocytosis. Dipyrone remains available over-the-counter in Brazil, Mexico, India (banned in 2013 but reinstated in 2014), Russia, and Israel. In 2012, the Israeli Ministry of Health convened a panel of experts to consider changing the policy after three cases of Optalgin-induced neutropenia but ultimately decided to leave the drug over-the-counter.
It is time to revisit the question of why Optalgin remains a freely available OTC drug in Israel, with scant warnings to patients and physicians of the rare but potentially fatal side effects that induced many other countries to ban or highly regulate it decades ago. Properly regulated, Optalgin may well have a useful place in the arsenal of pain-relieving medications in Israel, and it is not my intention here to adversely affect the quality of medical care by advocating a complete ban. However, it is clear that Optalgin should be a prescription-only medication in Israel, with strict guidelines concerning use and monitoring, and physicians and pharmacists should be better educated on the warning signs in patients prescribed the drug.