The flip side of the pill
Medicines prolong life, and we know that. But every pill has a flip side: side effects, dependence, dangerous combinations and the prescribing cascade, when a side effect is treated with a new drug. This is rarely discussed at an appointment. Here is what is written in studies and official warnings, each claim with a source.
“Look to the root!”
“Many things are incomprehensible to us not because our concepts are weak, but because those things lie outside the range of our concepts.”
Kozma Prutkov
Tap a part of the pill or choose a section below. The red centre is the prescribing cascade.
How to read side effects
Before fearing or not fearing a pill, it helps to understand how its harm is counted. In the package leaflet, the frequency of side effects is written on a single European scale.
The scale comes from the European guideline on drug leaflets. European Commission, SmPC guideline ↗
Three questions worth asking
Relative or absolute?
“The risk is 37% higher” and “1.3 more people per 100 per year” can describe the same thing. Ask for absolute numbers: out of 100 people like me, how many benefit and how many are harmed.
Secondary or primary prevention?
After a heart attack, the benefit of many drugs is large. For a healthy person taking a drug “just in case”, the benefit is smaller, and the harm can outweigh it. This is the key question for statins and aspirin.
Nocebo
Expecting harm itself causes symptoms. In the SAMSON trial about 90% of complaints on a statin also appeared on a dummy pill. That does not mean there are no side effects, but it does mean they need to be checked.
SAMSON, NEJM 2020 ↗What a pill actually does
It binds to a target in the body. Knowing the target is useful because it lets you predict both the benefit and the side effect.
The molecule itself acts. It binds to a “target” (a receptor, an enzyme, a pump in a membrane) like a key in a lock. Change the molecule and the effect changes; change the dose and its strength changes.
Where side effects come from. The target a pill blocks is often found not only where it is needed. A painkiller blocks the COX enzyme both at the site of inflammation and in the stomach lining. Hence the ulcer. A blood pressure pill widens blood vessels everywhere, hence the swollen ankles. This is general pharmacology, found in any textbook.
Where the cascade comes from. The side effect of the first pill looks like a new disease. The doctor prescribes a second. The second has its own side effects, and a third appears. The table below shows what each drug group does, how it usually ends and which chains are described in the literature.
| Group | What it does | Typical side effect | Possible next link in the chain |
|---|---|---|---|
| Statinsatorvastatin, rosuvastatin | Block the enzyme HMG-CoA reductase in the liver: less cholesterol is made | Muscle complaints (but more often from expectation), slightly higher blood sugar | Painkillers for “muscle pain”, although the statin may have had nothing to do with it |
| ACE inhibitorsenalapril, lisinopril | Block an enzyme that narrows blood vessels: blood pressure falls | Dry cough (in about one in ten), rarely swelling of the face and throat | Cough tablets and syrups, antibiotics “for bronchitis” |
| Calcium channel blockersamlodipine | Relax the walls of blood vessels | Swollen ankles | A diuretic, then loss of potassium and dizziness |
| NSAIDsibuprofen, diclofenac | Block COX: less pain and inflammation | Stomach, blood pressure, kidneys, heart | Omeprazole “for the stomach”, a blood pressure drug |
| PPIsomeprazole, pantoprazole | Switch off the stomach's “acid pump” | Low B12 and magnesium, fractures, intestinal infections with long use | Magnesium and B12 supplements, treatment of the infection |
| Benzodiazepinesdiazepam, phenazepam | Boost the calming neurotransmitter GABA: they soothe and induce sleep | Dependence, falls, memory gaps | The dose grows, an antidepressant or another sleeping pill is added |
| Antidepressants (SSRIs)sertraline, paroxetine | Keep serotonin in the gaps between nerve cells | Sexual problems, withdrawal syndrome, anxiety in the first weeks | A sleeping pill or sedative “for anxiety” |
| Metformin | Reduces glucose production by the liver | Stomach upset, lower B12 | Numb feet are mistaken for a diabetic complication |
| Opioidsoxycodone, tramadol | Sit on opioid receptors: relieve pain and give euphoria | Constipation, drowsiness, dependence, slowed breathing | Laxatives, sleeping pills, a rising dose |
| Tamsulosin | Relaxes the muscles of the bladder neck and prostate | Dizziness, problems during eye surgery | A second blood pressure pill |
| Finasteride | Blocks the conversion of testosterone into a more active form (5-alpha reductase) | Sexual problems, mood | An antidepressant or an erectile-dysfunction drug |
| Fluoroquinolonesciprofloxacin | Stop bacteria from copying their DNA | Tendons, nerves, mental state | Painkillers, treatment of tendinitis |
| Chemotherapy | Damages rapidly dividing cells: the tumour, but also hair roots, mucous membranes and bone marrow | Nausea, hair loss, weakened immunity, neuropathy | Anti-sickness drugs, growth factors, painkillers |
| Contraceptives | Hormones suppress ovulation | Blood clots, mood, a small rise in breast cancer risk | An antidepressant for mood changes |
| Semaglutide and similar drugs | Mimic the gut hormone GLP-1: slow stomach emptying and reduce appetite | Nausea, vomiting, diarrhoea, gallstones | Anti-sickness drugs, gallbladder treatment |
The “What it does” column is standard pharmacology. The “Possible next link” column gives typical examples to think about: each chain depends on the particular person. For confirmed figures on amlodipine and diuretics, SSRIs and other groups, see the sections below. Definition of the cascade: Rochon, Gurwitz, BMJ 1997 ↗
Acidosis: what it really is
In intensive care it is fought, and that is true. Let us see what follows from that fact and what does not.
Normal blood holds a pH of about 7.35–7.45. If the pH falls below that, it is acidosis, and it is life-threatening. In intensive care, blood gases and pH are checked often, and a baking soda solution (sodium bicarbonate) is sometimes given.
Acidosis occurs in shock, sepsis, kidney failure, diabetic ketoacidosis and lactic acidosis. These are real and serious conditions.
Soda in intensive care does not help everyone
BICAR-ICU: 389 adults with severe acidaemia. The overall result (organ failure on day 7 or death by day 28) did not improve. In the subgroup with acute kidney injury the difference did not reach statistical significance, but dialysis was needed less often: 35% versus 52%. In intensive care, acidosis is more often a consequence of severe illness, and the cause is treated first.
BICAR-ICU analysis ↗Bicarbonate in chronic kidney disease
BiCARB: about 300 people over 60 with severe chronic kidney disease. Bicarbonate did not improve physical performance after 12 months. This is one area where acidosis is treated with bicarbonate, but the results are mixed.
NHS, BiCARB review ↗Food barely moves blood pH
In healthy people, a rise of 1.02 units in urine pH was accompanied by a shift in blood pH of only 0.014. The authors of the review write that the logic of the “alkaline diet” is flawed and the data are lacking, although the diet itself (more vegetables and fruit) is sensible for other reasons.
Cancer Network ↗Bottom line. Severe illnesses can be accompanied by acidosis, but most diseases occur with a normal blood pH: hypertension, type 2 diabetes, asthma, allergy, osteoporosis. A person whose pH is below 7.35 is, as a rule, already in hospital. Acidosis in intensive care is a sign of how severe the condition is; it does not mean that it is the cause of all diseases.
Statins: the number and the root
A statin lowers LDL cholesterol in the blood. It does not remove the root of why cholesterol is high: diet, excess weight, little movement, smoking, insulin resistance, heredity.
LDL accumulates in the vessel wall for years and causes atherosclerosis. This is confirmed by more than 200 studies with over 2 million people, including genetic ones. EAS, 2017 ↗
For every 1 mmol/L reduction in LDL, heart attacks, strokes and vascular operations fall by 22% and deaths by 10%. 26 trials, 170,000 people. CTT, Lancet 2010 ↗
Muscle pain
23 trials, 155,000 people. On a statin 27.1% reported muscle complaints, on a dummy pill 26.6%. A statin adds a few complaints, mainly in the first year and at high doses: 3% more at usual doses, 8% at high doses. About 14 of 15 complaints are not caused by the statin.
CTT, Lancet 2022 ↗Blood sugar and diabetes
High-dose statins: new diabetes in 4.8% a year versus 3.5% on a dummy pill. Usual doses: 1.3% versus 1.2%. Most often in those whose blood sugar was already at the upper limit. The authors believe the benefit outweighs the risk, but for people at low risk the calculation is finer.
CTT, Lancet Diabetes Endocrinol 2024 ↗Can a statin be stopped after 75?
France, about 1,160 people over 75 taking a statin only for primary prevention, without a previous heart attack or stroke. After 3 years, 7.9% of those who continued and 7.2% of those who stopped had died: the difference was within the pre-set margin. LDL in those who stopped rose from 114.6 to 170.6 mg/dL. The trial was open-label, and the participants were already tolerating the statin well. The conclusion does not apply to those who have already had a heart attack or stroke.
SAGA/SITE, Lancet Healthy Longevity, 2026 ↗ US Pharmacist ↗A pill instead of lifestyle
A statin works as long as it is taken. Diet, exercise, weight and quitting smoking also lower risk, and they are worth discussing with a doctor before the pill or together with it, not instead of it.
- What is my 10-year risk of heart attack and stroke, and by how much will a statin reduce it?
- Is this treatment after a heart attack or “just in case”?
- What changes in diet and exercise would give me a comparable effect?
- If my muscles hurt: can the dose be lowered or the drug changed instead of stopping?
- I am over 75 and have never had a heart attack: should we review the statin together?
Do not stop on your ownAfter a heart attack, stroke or stent, stopping a statin on your own raises the risk of another event. Make any change only together with a doctor.
Blood pressure pills
High blood pressure damages vessels, heart, brain and kidneys for years, and it needs treatment. But every drug group has its own side effects, and in older people the more pills, the higher the risk of dizziness and falls.
Lowering blood pressure reduces the risk of stroke, heart attack and heart failure. Usually not one drug is needed but a combination, and it is chosen gradually.
Cough from ACE inhibitors
A dry, persistent cough affects about one in ten people on enalapril, lisinopril and similar drugs. Rarely there is swelling of the lips, tongue and throat; this is dangerous and needs urgent help.
Cleve Clin J Med, 2001 ↗Swollen legs and an extra diuretic
Amlodipine and similar drugs (calcium channel blockers) often cause swollen ankles. In Ontario, among 41,086 older adults who started such a drug, 9.5% received some diuretic within a year (7.3% on other blood pressure pills, 3% in the control group), and a loop diuretic 3.5% versus 1.8% and 1.4%. The authors advise first checking whether the drug is needed, lowering the dose or switching.
Savage et al., JAMA Intern Med 2020 ↗Mild hypertension with no other risks
A Cochrane review of 4 trials (8,912 people, 4–5 years) in people with mildly raised blood pressure and no cardiovascular disease: the drugs did not reduce overall mortality or the number of heart attacks and strokes, and about 9% of participants had to stop because of side effects. This does not apply to high blood pressure or to people after a heart attack or stroke. The authors call for new trials.
Cochrane, 2012 ↗Can one pill be removed?
569 people over 80. One blood pressure pill was removed: after 12 weeks blood pressure was in the normal range in 86.4% versus 87.7% with no change. But there were more adverse events, and the authors ask that no conclusions be drawn without a doctor.
OPTIMISE, JAMA 2020 ↗- I developed swelling or a cough after a new pill: could it be a side effect?
- What blood pressure do I need at my age?
- I feel dizzy when I stand up: is my blood pressure too low?
Aspirin “for the heart”
Millions of people take aspirin every day just for prevention. Studies from 2018 showed that it does not help healthy older people, and bleeding becomes more frequent.
A structural diagram, not a photograph. Aspirin differs from salicylic acid in one detail: an acetyl group has been added (highlighted in pink). Oxygen is labelled in red; carbon at the corners of the rings is not labelled. KEGG ↗
After a heart attack, stroke or stent, aspirin lowers the risk of another event. Here it is needed, and you must not stop it on your own.
Not needed by healthy older people
19,114 people aged 65 and over, about 5 years. Aspirin did not prolong disability-free life, and serious bleeding occurred in 3.8% versus 2.8% on a dummy pill.
ASPREE, NEJM 2018 ↗The Beers criteria
A panel of experts recommends avoiding aspirin for primary prevention of cardiovascular disease, that is, without a previous heart attack or stroke. This is a guide for the doctor, not a ban; the decision is individual.
AGS Beers Criteria, 2023 (AAFP) ↗Stomach bleeding
Of 18,820 hospital admissions, 6.5% were due to drug side effects. Aspirin and painkillers were most often to blame, and the most common problem was bleeding from the stomach.
Pirmohamed et al., BMJ 2004 ↗- Was aspirin prescribed to me after an event or “for prevention”?
- Isn't it time to review it in view of my age and bleeding risk?
Blood sugar pills
Diabetes drugs protect vessels, eyes and kidneys. But they too have a quiet side effect, which is discovered years later.
Structural diagram: metformin. The molecule contains only carbon, nitrogen (labelled in blue) and hydrogen. In many guidelines it is the first-choice drug for type 2 diabetes; its side effect, B12 deficiency, is described below.
Blood sugar control reduces the risk of diabetes complications. Metformin is the first-choice drug in many guidelines.
Metformin and vitamin B12
Metformin often lowers B12. The risk is higher at large doses and with long use. Signs: marked fatigue, a red sore tongue, tingling in the hands and feet. The UK regulator advises checking B12, and metformin can usually be continued.
MHRA, 2022 ↗Avandia: hidden data
GSK admitted guilt for failing, from 2001 to 2007, to report to the FDA safety data on the diabetes drug Avandia. This was part of a $3 billion settlement.
US Department of Justice, 2012 ↗- I have been on metformin for a long time: has my B12 been checked?
- Are my numb feet from diabetes or from a lack of B12?
Omeprazole for years
Omeprazole, pantoprazole and similar drugs are prescribed for a few weeks but taken for years, often with no review. The FDA has issued several warnings about them.
Ulcer, reflux, stomach protection when taking aspirin and painkillers. As a course and with a clear indication they are very useful.
Fractures
The risk of hip, wrist and spine fractures may rise, mainly at high doses and with use for a year or more.
FDA ↗Low magnesium
With use for more than a year, blood magnesium may fall. This matters particularly for those taking diuretics or digoxin.
FDA ↗Intestinal infection
The risk of diarrhoea caused by the bacterium Clostridioides difficile may rise. If diarrhoea does not go away, see a doctor.
FDA ↗A dangerous combination
Omeprazole weakens clopidogrel (Plavix), taken after a stent. Spacing the doses apart does not help.
FDA ↗- How much longer do I need to take this drug, and can the dose be lowered?
- How should it be stopped properly so that heartburn does not come back?
Over-the-counter painkillers
Ibuprofen, diclofenac and naproxen are sold freely, and they seem safe. Yet together with aspirin they most often bring people to hospital because of side effects.
Structural diagram: two different molecules with different side effects. Ibuprofen is an NSAID and can cause stomach ulcers and bleeding as well as kidney problems, especially at a high dose and with long use. Paracetamol is not an NSAID, but above the safe dose it can damage the liver. Nitrogen is labelled in blue. NHS: ibuprofen ↗ NHS: paracetamol ↗
Pain and inflammation: joints, back, injuries, teeth. A short course at the lowest dose is a sensible decision.
Heart attack and stroke
The risk rises within the first weeks of use, by 10–50% or more depending on the drug and dose. The risk of heart failure is higher. After a heart attack such painkillers raise the risk of death.
FDA, 2015 ↗Bleeding and kidneys
The main cause of hospital admissions from side effects is stomach bleeding from aspirin and painkillers. Kidney failure and lithium poisoning when combined with them have also been noted.
BMJ, 2004 ↗The Vioxx story
Merck withdrew the painkiller Vioxx in 2004: it roughly doubled the risk of heart attacks and strokes. In 2007 the company paid $4.85 billion to settle lawsuits, without admitting fault.
NPR, 2007 ↗- Are painkillers safe for me with my blood pressure, heart and kidneys?
- For how many days in a row can I take them?
Dependence: opioids, oxycodone, methadone, Subutex
Dependence on medicines and drugs often begins in the pharmacy: with a painkiller, a sedative, a “pill for energy”. Opioid painkillers save people from severe pain, but tolerance develops quickly. Methadone and buprenorphine (Subutex) are opioids too. They are prescribed to people dependent on heroin, and here the pill has two sides at once.
Oxycodone and morphine: for severe acute pain and in cancer. Methadone and buprenorphine: substitution therapy; the person receives a controlled dose instead of street heroin.
A review of 72 studies (15 trials with 3,852 people and 36 cohort studies with 749,634 people): mortality on substitution therapy is about half, roughly 11 versus 24 deaths per 1,000 person-years. Santo et al., JAMA Psychiatry 2021 ↗
Scale
According to a report by the UN Office on Drugs and Crime, about 331 million people used drugs in 2024, 34% more than ten years ago. The authors attribute the rise both to population growth and better data, and to rising prevalence.
UNODC, World Drug Report 2026 ↗Gabapentin and pregabalin: breathing
These drugs for pain and seizures are not opioids, but in 2019 the FDA warned of serious breathing problems in the presence of risk factors: taking opioids and other substances that depress the brain, lung disease (COPD), older age. The FDA review found 49 cases in 2012–2017; 12 people died, and all had at least one risk factor.
FDA, 2019 (NeurologyLive) ↗Other roads to dependence
For benzodiazepines and sleeping pills, see the section “Insomnia”; for heroin, cocaine, amphetamines, codeine and “krokodil”, see the section “From pharmacy to street”.
How people get hooked
38 studies. On average about a quarter (21–29%) of people with chronic pain take opioids not as prescribed, and 8–12% become dependent. The range is huge, from under 1% to 81%, because definitions differ between studies.
Vowles et al., Pain 2015 ↗OxyContin and Purdue Pharma
The maker of OxyContin pleaded guilty to three criminal counts: misleading regulators and paying doctors to prescribe the drug. The settlement was about $8 billion.
NBC News, 2020 ↗After a break, the dose is dangerous
After a break or leaving a programme, tolerance to opioids falls, and the former dose can become dangerous. That is why leaving is planned with a doctor, and naloxone is kept at home.
Teeth on Subutex
Buprenorphine tablets dissolved in the mouth can destroy teeth: cavities, infections, tooth loss, even in people who had no dental problems before.
FDA, 2022 ↗- For how many days do I need this opioid, and how will it be stopped afterwards?
- Do I have naloxone at home in case of an overdose?
- How can I protect my teeth on buprenorphine?
DangerousStopping opioids abruptly on your own, or leaving a substitution programme, is dangerous. After a break tolerance falls, and the former dose can become fatal.
Insomnia and sleeping pills
Insomnia is one of the most common complaints, and the first advice is not a pill. Phenazepam, diazepam, alprazolam and zolpidem are recommended for weeks but taken for years.
Short-term relief of severe insomnia or anxiety. In that mode they help. If insomnia lasts for months, doctors first offer behavioural therapy, and pills are added together with the doctor.
What is advised first
American College of Physicians: cognitive behavioural therapy for insomnia (CBT-I) is first-line treatment for chronic insomnia. It probably does less harm than pills. Sleeping pills ideally for no more than 4–5 weeks, and if they have not helped within 7–10 days, the prescription should be reviewed.
ACP, Ann Intern Med 2016 ↗Dependence within weeks
Since 1988 the UK Committee on Safety of Medicines has recommended no longer than 2–4 weeks. Dependence can appear after just a few weeks. Stopping abruptly is dangerous, up to seizures; the dose must be reduced gradually, sometimes over months.
Patient.info ↗Falls and memory in older people
Benzodiazepines and “Z-drugs” raise the risk of confusion, falls, fractures and driving accidents. For older people they are generally advised to be avoided.
AGS Beers Criteria, 2023 ↗Walking and driving in sleep
Zolpidem, zopiclone and zaleplon received a boxed warning: people walked, drove and did other things without waking. 66 cases of serious injury and 20 deaths.
FDA, 2019 ↗Over-the-counter “sleeping pills”
Many non-prescription “night-time” products are old antihistamines (diphenhydramine and the like). For older people they are on the list of undesirable drugs; details in the section “Allergy and asthma”.
Melatonin: poisonings in children
In the USA melatonin is sold as a supplement, and parents consider it safe. Calls to poison centres about children rose by 530%: from 8,337 in 2012 to 52,563 in 2021. Of 260,435 cases, 83.8% were children under 5. Most children had no symptoms, but 4,097 of the 27,795 treated in hospital were admitted, five were put on a ventilator and two died. Store melatonin like a medicine.
CDC, MMWR 2022 ↗What it blocks and what is prescribed next
| Group | What it does | Typical side effect | Possible next link in the chain |
|---|---|---|---|
| Benzodiazepinesdiazepam, phenazepam, alprazolam | Boost the calming neurotransmitter GABA: they soothe and induce sleep | Dependence, falls, memory gaps, severe withdrawal | The dose grows, another sleeping pill or an antidepressant is added |
| Z-drugszolpidem, zopiclone | Act on the same GABA receptors, more selectively | Sleep with unconscious actions, memory gaps, morning drowsiness | A switch to another sleeping pill |
| Old night-time antihistaminesdiphenhydramine, doxylamine | Block histamine and acetylcholine | Dry mouth, constipation, a “fog” in the head in the morning, confusion in older people | A laxative, remedies for dry mouth |
| Melatoninsupplement | The hormone signal “night has come” | Daytime drowsiness, headache; poisonings in children | Usually not needed |
The “What it does” column is standard pharmacology. The “Possible next link” column gives typical examples to think about.
- For how many weeks can I take this sleeping pill?
- Can I start with cognitive behavioural therapy for insomnia, and where can I get it?
- What in my habits affects sleep: coffee, alcohol, screens, routine?
- Could one of my medicines be causing the insomnia?
Do not stop abruptlyAfter long use, sleeping pills and sedatives are withdrawn slowly and only according to a doctor's plan.
Antidepressants
Antidepressants help many people with severe depression. But withdrawal, sexual side effects and risks in young people are often not mentioned when they are prescribed.
Depression, anxiety disorders, obsessive-compulsive disorder. Untreated severe depression is dangerous in itself.
Suicidal thoughts in young people
Since 2004 antidepressants in the USA carry a boxed warning about increased suicidal thoughts in children and adolescents; later it was extended to young adults up to 25. In the first weeks the person needs to be watched closely.
J Clin Psychiatry ↗Withdrawal syndrome
The Royal College of Psychiatrists in the UK acknowledged that stopping over 4 weeks is too fast for some people; withdrawal symptoms can be severe and long-lasting. The dose is reduced slowly, at a pace proportionate to how long the drug was taken.
RCPsych, 2019 ↗Sexual side effects after stopping
The European Medicines Agency added a warning to the leaflets of 10 antidepressants: there are reports of sexual dysfunction that persists after the drug is stopped.
EMA, 2019 ↗Paxil for teenagers
GSK admitted guilt for the unlawful promotion of Paxil for depression in children and adolescents, for whom it was not approved.
US Department of Justice, 2012 ↗- For how long should I take the antidepressant, and how will we stop it?
- Which sexual side effects are possible, and what should I do if they appear?
Do not stop abruptlyReduce the antidepressant dose gradually, together with your doctor. If thoughts of suicide appear, contact a doctor or emergency help immediately.
Prostate pills
For benign prostate enlargement tamsulosin and finasteride are prescribed. Men are rarely told what these pills can do to the eyes, potency and mood.
To ease urination and shrink the prostate, to postpone surgery.
Finasteride: mind and potency
In 2022 the FDA required depression and suicidal thoughts and behaviour to be added to the finasteride (Propecia) leaflet. In May 2026 the UK regulator MHRA reported 170 cases of suicidal thoughts and 19 suicides in reports on finasteride from 1994 to 2025, and introduced new measures: a warning that sexual dysfunction may contribute to mood disorders, and a conversation with the patient at prescribing. Case reports do not prove causation, but the regulators judged the signal sufficient.
FDA, 2022 ↗ MHRA, 2026 ↗Tamsulosin and eye surgery
Tamsulosin is linked to a “floppy iris” during cataract surgery (IFIS syndrome), which complicates the surgeon's work. In a Canadian cohort of men aged 66 and over, rupture of the posterior lens capsule occurred in 0.76% on tamsulosin versus 0.58% without it. Before eye surgery, tell the surgeon that you take tamsulosin.
AAO EyeNet, 2019 ↗- If I am facing eye surgery, should I warn the surgeon about tamsulosin?
- Which side effects of finasteride do I need to watch for?
Fluoroquinolone antibiotics
Ciprofloxacin, levofloxacin and moxifloxacin are often prescribed even for simple bronchitis or cystitis. Their side effects can last a lifetime.
Severe bacterial infections when other antibiotics do not fit. In such cases they save lives.
Tendons, nerves, mind, blood sugar
On 12 May 2016 the FDA warned of “disabling and potentially permanent” side effects of fluoroquinolones, which can occur together, and for acute sinusitis, acute bronchitis and uncomplicated urinary tract infection advises using them only when there are no other options. In July 2018 the requirements were tightened: the risk of hypoglycaemic coma (especially in older people and people with diabetes) and mental disturbances were added.
FDA, 2016 ↗ FDA, 2018 (AAFP) ↗- Do I need this particular antibiotic, or will another do?
- A tendon started to hurt on an antibiotic: what should I do?
Oncology and chemotherapy: the benefit and the price
Chemotherapy cures some kinds of cancer and gives months in others. In both cases it has severe side effects, and you need to know them in advance.
Chemotherapy is a set of drugs that kill rapidly dividing cells. There are three goals: to cure, to prolong life or to relieve symptoms. The decision always rests with the oncologist, and it is worth knowing the goal of treatment in advance.
There are tumours that chemotherapy really does cure: metastatic testicular cancer (overall survival rose from 5% in the early 1970s to about 80%), lymphomas, acute lymphoblastic leukaemia in children, childhood sarcomas. Review, PMC ↗
Chemotherapy's contribution to 5-year survival
An Australian analysis estimated the contribution of chemotherapy to the survival of adult cancer patients at 2.3% (Australia) and 2.1% (USA), with overall 5-year survival of about 63%. Limitations: data from 1998, rare curable tumours and leukaemias not counted, quality of life not assessed. Critics say that among those who actually received chemotherapy the contribution is higher, about 5–6%.
Morgan et al., Australian Prescriber review ↗New cancer drugs: what was known at approval
Of 68 indications for drugs approved in Europe in 2009–2013, 39 (57%) had no evidence of improved survival or quality of life at the time of approval. After 5.9 years only 6 of those 39 had shown such an improvement. Of 23 drugs that prolonged life, 11 (48%) did not reach the threshold of “clinically meaningful” benefit. Average survival gain in another analysis of 71 drugs for solid tumours: 2.1 months.
Davis et al., BMJ 2017 ↗Mortality in the first 30 days
England, 2014. After palliative chemotherapy 10% of lung cancer patients and 7.5% of breast cancer patients died within 30 days; after radical (curative-intent) chemotherapy 2.9% and 0.26%. These are usually seriously ill patients, and the figures show the price of treatment in advanced disease.
Lancet Oncol, 2016 (eCancer) ↗Typical side effect
Fatigue; nausea and vomiting; mouth sores; diarrhoea; hair loss (usually regrows in 3–6 months); low white blood cells and risk of infection; bruising and bleeding; numbness and tingling in hands and feet; “chemo brain” (difficulty with memory and attention, recovery can take years); impaired fertility. Rare but serious: heart damage and secondary cancer, for example leukaemia.
Kaiser Permanente ↗The heart and doxorubicin
The risk of heart failure grows with the cumulative dose: by classic estimates about 3% at 400 mg/m², 7% at 550, 18% at 700. Figures differ between studies. That is why the dose is limited and the heart is monitored by ultrasound.
Numb hands and feet
31 studies, 4,179 patients. One month after chemotherapy neuropathy was present in 68%, at three months in 60%, at six months and beyond in 30%.
Seretny et al., Pain 2014 ↗- What is the goal of treatment: to cure, to prolong life or to relieve symptoms?
- In numbers, how much does this regimen improve survival for my particular diagnosis and stage?
- What happens if I delay or decline? And if I choose a less toxic regimen?
- How will my heart, kidneys and blood be checked before and during treatment?
- What if my fingers go numb, and can the regimen be adjusted?
A decision with your oncologistFor curable tumours (for example lymphoma, testicular cancer, leukaemia in children) delay or refusal sharply reduces the chances. In advanced disease you are entitled to discuss openly the choice between treatment and supportive care.
Anabolic steroids
Anabolics are prescription hormone drugs that people take in gyms without a doctor for muscle. The consequences show up years later.
In medicine: for certain hormonal disorders and wasting, strictly under a doctor's supervision.
Mortality almost three times higher
Denmark: 1,189 young men caught using anabolics, average age 27, followed for 11 years. 2.8% died versus 1% of their peers. Deaths from disease were higher, and so were deaths from accidents, violence and suicide. The study is observational.
Windfeld-Mathiasen et al., JAMA 2024 ↗- Tell your doctor honestly: that way they can check your heart, liver and hormones.
- Do not stop or change a course without the supervision of a specialist.
Hormonal contraceptives
These are among the most prescribed pills in the world, and the benefit is real: reliable protection against unwanted pregnancy. But hormones have a price.
Hormones suppress ovulation and prevent pregnancy. The choice of contraception is always a balance between benefit and risk for the particular woman.
Blood clots in veins
A British study: on combined pills the risk of venous thromboembolism is 2.4–4.3 times higher depending on the progestogen. In absolute numbers: per 10,000 women a year about 6 extra cases with levonorgestrel and about 14 with desogestrel and cyproterone. This is an odds ratio, not an exact risk.
Vinogradova et al., BMJ 2015 ↗Mood
Denmark, over a million women with no previous mental disorders. In girls aged 15–19 the risk of a first antidepressant prescription was 1.8 times higher on combined pills and 2.2 times higher on progestogen-only pills. Absolute numbers are not given in the summary. Experts ask that no sharp conclusions be drawn from this.
Skovlund et al., JAMA Psychiatry 2016 ↗Breast cancer
Denmark: relative risk 1.20 with current or recent use. That is about 13 extra cases per 100,000 women a year, that is, one extra case per 7,690 women per year of use. The risk rises with duration (from 1.09 to 1.38 for use over 10 years) and persisted in those who took them for 5 years or more and then stopped.
Mørch et al., NEJM 2017 ↗The root of the problem
If the pills were prescribed “to regulate the cycle”, they only manage the cycle while they are taken. The cause of an irregular cycle (for example polycystic ovary syndrome) is worth finding out separately.
- Which progestogen is in my pill, and what is the clot risk with it?
- Do I have risk factors: smoking, clots in the family, migraine with aura, excess weight?
- If your mood changes, discuss it without stopping the pill on your own.
- Are there other methods of contraception for me?
Do not stop suddenlyIf you do not want a pregnancy, choose another method of protection before stopping.
New weight-loss drugs
Semaglutide and tirzepatide are the most talked-about drugs of recent years. They really do reduce weight. The question is what happens afterwards and along the way.
In the STEP-1 trial semaglutide 2.4 mg reduced weight by an average of 17.3% over a year. In SURMOUNT-1 tirzepatide gave about 22% in people without diabetes. The Hospitalist ↗
Stomach and gut
Gastrointestinal events occurred in 30.8% on semaglutide versus 12.7% on a dummy pill and in 79.8% on tirzepatide versus 25%. Gallbladder disease occurred more than 2.5 times as often on semaglutide.
EMJ, review ↗What happens after stopping
In the extension of STEP-1, within a year after the drug and the lifestyle programme were stopped, people regained about two thirds of the weight they had lost, and blood pressure and blood sugar returned to their starting values. That is, this is a treatment that has to be continued for as long as it works.
The Hospitalist ↗The root of the problem
The drug reduces appetite, but the causes of weight gain (diet, sleep, stress, inactivity, genetics) remain. It makes sense to agree on changing them in advance.
- For how long will I have to take the drug, and what will happen after I stop?
- How should I eat and do strength training to lose fat rather than muscle?
- Which abdominal symptoms require urgent attention?
- Is there a history of gallstones or pancreatitis in my case?
Osteoporosis pills
Fractures of the hip and spine are severe and dangerous, and osteoporosis treatment prevents them. But here it is important to know what happens when treatment is stopped.
Bisphosphonates and denosumab slow the breakdown of bone or reduce the risk of fractures in people with osteoporosis and a high risk of fracture.
Stopping denosumab
A Swiss clinic described nine patients who had multiple vertebral fractures 9–16 months after the last denosumab injection (a “rebound” effect). In 32 women who switched to bisphosphonates before or after, there were no such fractures. After bisphosphonates there is no rebound. The series is small, and the conclusions are cautious.
The Rheumatologist ↗The root of the problem
Bone depends on protein in the diet, vitamin D, calcium and load. Strength and balance exercises reduce the risk of falls, and that too is fracture prevention. Discuss a plan with your doctor.
- What is my 10-year fracture risk and how was it calculated?
- If I start denosumab, what is our plan for when it has to be stopped?
- What exercise, food and vitamin D should I add?
Do not skip injectionsDenosumab must be given on schedule, and stopping it should follow the doctor's plan, usually with a switch to another drug.
Allergy and asthma: pills, sprays and inhalers
Allergy and asthma often go together: many people with asthma also have allergic rhinitis. Medicines for them are sold both on prescription and over the counter, and some of their side effects are more serious than they seem.
Aspirin-induced asthma is not a classic allergy. The reaction does not go through IgE antibodies (so allergy tests do not show it); it comes from a disturbance in arachidonic acid metabolism when the COX-1 enzyme is blocked. But it looks like an allergy: runny nose, nasal polyps, attacks of breathlessness after aspirin and similar painkillers. That is why the sections are combined. Medicine Today, 2019 ↗
Antihistamines block histamine receptors and relieve itching, runny nose, watering eyes and hives. Hormone sprays reduce inflammation in the nose. Inhaled hormones reduce inflammation in the bronchi and prevent asthma attacks; fast bronchodilators relieve an attack. In anaphylaxis, emergency adrenaline saves life.
Allergy
Old antihistamines and dementia
A study of about 3,500 people over 65, followed for 7 years on average, with about 800 cases of dementia. The higher the cumulative dose of anticholinergic drugs (including diphenhydramine), the higher the risk. For diphenhydramine the risk was higher at 50 mg a day for longer than 3 years or 25 mg a day for longer than 6 years. This is an association, not a proven cause. Newer-generation antihistamines exist.
Gray et al., JAMA Intern Med 2015 ↗Old antihistamines in older people
The American Geriatrics Society puts first-generation antihistamines (diphenhydramine, chlorphenamine) on its list of “potentially inappropriate” drugs for older adults. As alternatives for allergy it names cetirizine, fexofenadine and loratadine, steroid sprays and rinsing the nose with saline. Discuss any switch with your doctor.
Health in Aging, Beers 2023 ↗Montelukast: the “black box”
In March 2020 the FDA required the strictest warning on the packaging: agitation, depression, sleep disturbances, suicidal thoughts and actions are possible. For allergic rhinitis the drug is advised only if other treatments have failed, and to be avoided for mild symptoms, especially hay fever. How often such events occur is unknown. The same drug is prescribed for asthma.
FDA, 2020 ↗Decongestant spray: rebound
Drops and sprays with oxymetazoline (Nasivin, Afrin) must not be used for more than three days in a row: after that the blockage can return stronger (“rebound”), and the person keeps using the spray. Medicine calls this condition rhinitis medicamentosa.
Cleveland Clinic ↗Pseudoephedrine: a risk to the brain
In November 2023 the European medicines safety committee recommended measures against two rare conditions that disturb the blood supply to the brain (PRES and RCVS). Products with pseudoephedrine, found in many “cold and blocked nose” remedies, must not be used in severe or uncontrolled hypertension or severe kidney disease. With a sudden severe headache, nausea, vomiting, confusion, seizures or visual disturbances, stop taking it and seek help urgently.
EMA PRAC, 2023 ↗Asthma
Too many “fast” inhalers
The nationwide SABINA study: 365,324 people with asthma. Compared with those who collected no more than two canisters of reliever inhaler (salbutamol and similar) a year, with 3–5 canisters the risk of an exacerbation was 1.26 times higher and of death 1.26 times; with 6–10 canisters 1.44 and 1.67 times; with 11 or more 1.77 and 2.35 times. This is an association: a frequent need for a reliever inhaler signals poor asthma control. But it is a reason to discuss baseline treatment with the doctor, rather than keep treating only the attacks.
Regulator lifted the “black box”
In December 2017 the FDA removed the strictest warning from combinations of an inhaled hormone and a long-acting beta-agonist. The decision relied on four manufacturer trials: serious asthma events were 0.60% with the hormone alone and 0.66% with the combination (the difference was not significant), and exacerbations were 17% fewer. The trials were sponsored by the companies themselves. The lesson: safety assessments change over time.
The Hospitalist, 2018 ↗Aspirin-induced asthma
Aspirin-exacerbated respiratory disease (the triad: asthma, nasal polyps, reaction to aspirin) affects about 8% of people with asthma and about 15% of those with severe asthma. The reaction starts 20 minutes to 3 hours after aspirin and other NSAIDs; ketorolac (an injection) can cause it within 15 minutes. Selective COX-2 inhibitors are safe. Aspirin and similar NSAIDs should be avoided; if needed, desensitisation is possible in a specialist centre.
Medicine Today, 2019 ↗Oral steroids in asthma
24,117 matched pairs of adults with asthma. Starting courses of oral corticosteroids was accompanied by a higher risk of: osteoporosis and fractures 3.1 times, pneumonia 2.7 times, cataract 1.5 times, depression and anxiety 1.3 times, type 2 diabetes 1.3 times. The risk is noticeable from about 1 gram of cumulative dose, roughly four short courses. The study is observational and was funded by AstraZeneca.
Price et al., J Asthma Allergy 2018 ↗Hormones in an inhaler
Common side effects: thrush in the mouth, a dry or sore throat, hoarseness. Rinsing the mouth with water or brushing the teeth after inhaling helps; for thrush a doctor or pharmacist can suggest an antifungal gel. Serious effects are unusual and more likely with high doses over many months. In children, high doses over a long time can slow growth, so the doctor monitors growth; according to the NHS, a temporary slowing has little effect on final height.
NHS ↗Breathing
Buteyko breathing
90 adults with asthma, 6 months. The Buteyko group felt better (symptoms −3 points versus −1 and 0) and cut their use of a bronchodilator by about 2 puffs a day. But lung function, bronchial reactivity, exacerbations and the ability to reduce inhaled steroids did not change. A device imitating pranayama did not differ from a dummy.
Cooper et al., Thorax 2003 ↗Holotropic and other forms of forced breathing
A review of forced-breathing practices describes unusual changes in states of consciousness and “suggested” benefits in stress- and trauma-related disorders, and calls for rigorous clinical trials. The review contains no data that it treats asthma or allergy. Rapid deep breathing causes hypocapnia and alkalosis and in some people with asthma can provoke attacks.
Fincham et al., 2023 ↗The root of the problem
Find out exactly what you react to (allergy testing) and reduce contact with the allergen: mites, mould, pollen, animals, smoke, cold air. Rinse the nose with saline, treat chronic rhinitis, stop smoking, work with the doctor on baseline asthma treatment. For some allergies an allergist may offer immunotherapy with the allergen. All this gives a chance to cut the need for both pills and fast inhalers.
What it blocks and what is prescribed next
| Group | What it does | Typical side effect | Possible next link in the chain |
|---|---|---|---|
| First-generation antihistaminesdiphenhydramine, chlorphenamine | Block histamine receptors and, at the same time, acetylcholine receptors | Drowsiness, dry mouth, constipation, urinary retention, confusion in older people | A laxative, remedies for dry mouth, sometimes a bladder drug |
| Newer-generation antihistaminescetirizine, loratadine, fexofenadine | The same histamine receptors, but with less effect on the brain | In some people drowsiness (more often with cetirizine), dry mouth | Usually not needed: the drug can be changed |
| Hormone nasal spraysfluticasone, mometasone | Reduce inflammation of the nasal lining | Dryness, irritation, nosebleeds | Moisturising sprays and gels |
| Decongestant drops and tabletsoxymetazoline, pseudoephedrine | Narrow the blood vessels of the lining, the nose “opens” | Rebound congestion after three days; pseudoephedrine: rise in blood pressure and pulse, insomnia | Another spray, a blood pressure drug or a sleeping pill |
| MontelukastSingulair | Blocks leukotrienes, which narrow the bronchi and swell the lining | Agitation, depression, sleep disturbances, thoughts of suicide | A sleeping pill or an antidepressant, if the side effect is not recognised |
| Fast inhalerssalbutamol | Relax the bronchial muscles (beta-2 agonists) | Tremor, palpitations, low potassium | If tremor and palpitations are mistaken for anxiety, a sedative |
| Hormones in an inhalerbudesonide, fluticasone | Reduce inflammation in the bronchi | Thrush, hoarseness | Antifungal gel |
| Hormones in tabletsprednisolone | Suppress inflammation throughout the body | Rise in blood sugar and blood pressure, weak bones, insomnia, mood swings | Drugs for osteoporosis, for sugar, for blood pressure, a sleeping pill |
The “What it does” column is standard pharmacology. The “Possible next link” column gives typical examples to think about: every chain depends on the individual person and on the doctor's decision.
- Which antihistamine suits me if I drive or am over 65?
- Why was I prescribed montelukast and are there alternatives?
- For how many days can I use drops or a spray for a blocked nose?
- How many canisters of fast inhaler do I use a year, and is it time to strengthen the baseline treatment?
- Could aspirin or the painkillers I take be triggering my asthma?
- How many courses of hormone tablets have I had, and should I have my bones, sugar and eyes checked?
- How can breathing exercises complement my inhaler?
An attack and anaphylaxis are an emergencyBreathing exercises do not replace the rescue inhaler. In an attack, with difficulty breathing, blue lips, or swelling of the lips, tongue or throat, use your prescribed inhaler or adrenaline auto-injector at once and call an ambulance (112). Do not wait for it to pass on its own.
The prescribing cascade
The side effect of the first pill is mistaken for a new disease and a second pill is prescribed. Then a third. The term was introduced by Canadian doctors in 1997, and since then it has been one of the main topics of drug safety in older people.
Where the term comes from
Rochon and Gurwitz described the prescribing cascade in the British Medical Journal: a side effect is mistaken for a new condition and treated with yet another drug.
Rochon, Gurwitz. BMJ 1997 ↗Almost one in ten
After a year, 9.5% of older people who started a drug like amlodipine had received some diuretic (3% in the control group). By the authors' estimate, this could mean 500 thousand to 1.3 million unnecessary diuretic prescriptions a year.
Savage et al., JAMA Intern Med 2020 ↗The topic is growing
A review of studies of cascades: they are found with a very wide range of drugs, and most often in people who take many drugs at once.
Front Pharmacol, 2023 ↗- Once a year, bring your doctor or pharmacist all your pills, including supplements and anything bought without a prescription.
- With every new symptom, ask: “Could this be a side effect of what I already take?”
- Ask which of the drugs can be removed or reduced.
The imaginary patient and overdiagnosis
Two different phenomena that are often confused: when a healthy person is turned into a patient, and when a person feels unwell while the tests are “normal”.
1. Overdiagnosis. When the boundaries of disease are widened (blood pressure, cholesterol, sugar, bone density) or something is found that would never have shown itself, healthy people become patients and receive drugs with side effects. This is described in the literature on “disease mongering” and in the article on how to stop harm to healthy people. Moynihan et al., BMJ 2012 ↗
2. “The tests are normal, but I feel bad.” The symptoms are real. The causes vary: lack of sleep, diet, stress, deficiencies (for example B12 with metformin), and often the side effects of drugs already being taken. So the first question with a new symptom is: “Could this be a side effect of what I already take?” This is exactly the prescribing cascade.
3. Expectation of harm. In the SAMSON trial, about 90% of complaints about a statin also occurred on a dummy pill. This does not mean the side effect is absent: the symptoms are real, and the cause can be complex. The method: try, record and check together with the doctor. SAMSON, NEJM 2020 ↗
- Keep a diary: the date the drug was started, the date the symptom appeared, the dose.
- Bring your doctor or pharmacist all your pills, including supplements, and ask which one could be linked to the symptom.
- Do not stop a drug on your own; discuss a replacement or a lower dose.
How to support immunity
The words “boost immunity” sell for the most, and reliable remedies are few. What is really confirmed is rather boring.
Sleep
Chronic lack of sleep weakens the body's defences. It is the cheapest way to support immunity.
Movement
Moderate daily activity is considered the basis of general health, immunity included.
Diet
Vegetables, fruit, whole grains. A deficiency of vitamins A, C, D, E, zinc and selenium raises the risk of infection. An excess does not strengthen immunity, and an excess of zinc can weaken it.
No single food and no single supplement boosts immunity “as a whole”; there is no convincing evidence for herbs and supplements, and the contents of supplements can differ from the label. Community Cancer Center ↗ Questions about vaccination and recovery after chemotherapy or antibiotics are worth discussing with a doctor.
From the pharmacy to the street
Many substances now called narcotics began as pharmacy medicines. Here is how that looked, and what these stories taught.
How we learned to test medicines
The Scottish doctor James Lind described a comparison of six treatments for scurvy in 12 patients. In 1948 the streptomycin trial in tuberculosis by the British Medical Research Council already concealed the allocation order of patients from the researchers (sealed envelopes). It is considered one of the first modern controlled trials.
Chalmers, J R Soc Med 2011 ↗Sulfanilamide elixir: a hundred deaths
The manufacturer dissolved sulfanilamide in diethylene glycol (antifreeze) and did not test it for toxicity. In autumn 1937 more than 100 people died in 15 US states. In response, a law passed in 1938 required the safety of new drugs to be tested before sale.
FDA ↗Heroin: Bayer's “safe” cough remedy
Heroin was synthesised in 1897 and from 1898 sold as a cough remedy: it was believed to give the benefit of morphine with almost no side effects and no habituation. In the first year 45 kg were produced, by 1913 970 kg. Warnings from doctors (for example the 1899 article “On the danger of heroin”) were in the minority. Bayer stopped production in 1940.
ChemistryViews ↗Cocaine in pharmacies, tonics and drinks
Cocaine was isolated in 1859. Doctors recommended it for fatigue, toothache, headache and even morphine addiction. It was an ingredient of tonics and hay fever remedies, and in Coca-Cola it was replaced by caffeine only in 1903. By some estimates, Americans consumed as much cocaine in 1906 as in 1976, with half the population. The first federal law was the Harrison Act of 1914.
US Department of Justice, history of cocaine ↗Benzedrine and Pervitin: amphetamines
Benzedrine appeared as an inhaler for blocked noses; from 1936 its tablets were prescribed for narcolepsy, obesity, chronic pain, low blood pressure and “for mood”. After the war housewives used them to slim. The company Temmler brought Pervitin (methamphetamine) to market in 1938 as a “magic pill”; under an April 1940 order more than 35 million tablets of Pervitin and Isophan (the name of a slightly altered version from the company Knoll) were sent to the front.
Museum of Health Care ↗ History.com ↗Thalidomide: a sedative for pregnant women
A sedative that was also prescribed for morning sickness caused severe birth defects in children: an estimated 10,000 or so worldwide. In the USA it was not approved: the FDA reviewer Frances Kelsey demanded stricter data. In 1962 the Kefauver–Harris Amendment required proof not only of safety but also of effectiveness, and informed consent.
Smithsonian ↗Methaqualone (Quaalude): “a good sleeping pill”
Synthesised in India in 1951 in research on antimalarial drugs; its sleep-inducing properties were found in 1955. By 1965 it had become the most prescribed sedative in Britain. Dependence developed, from the early 1980s it was withdrawn from the market, and in the USA it became a Schedule I substance in 1984. John Eckman, chairman of the company Rorer (maker of Quaalude), said the drug brought in less than 2% of sales and 98% of the headaches.
Wikipedia ↗Valium: “mother's little helper”
Diazepam was approved in 1963. In 1978 more than two billion tablets were sold in the USA, and in the 1970s it was the most prescribed drug in the world. Women took it noticeably more often than men. After the patent expired in 1985 it was sold under more than 500 generic names.
Royal Society of Chemistry ↗Phenazepam
The benzodiazepine phenazepam was developed in the USSR in the mid-to-late 1970s. It is still among the most prescribed benzodiazepines in Russia and the CIS countries, but is not licensed in the rest of the world. Outside the CIS its appearance has raised concerns about misuse.
Dundee, 2013 ↗OxyContin
A drug that was advertised as less likely to cause dependence. In 2007 Purdue pleaded guilty to misbranding (a fine of over $600 million, another $34.5 million from three executives), and in 2020 it pleaded guilty to three criminal charges.
NPR, 2007 ↗ NBC News, 2020 ↗Over-the-counter codeine and “krokodil”
Codeine-containing tablets were sold in pharmacies without a prescription, and desomorphine (“krokodil”) was made from them. In 2007 desomorphine was used occasionally in 19 regions of Russia; by 2009 regularly in 60. In the first quarter of 2010 the police seized desomorphine worth 65 million average single doses, made from medicines bought in pharmacies. In 2011 the Ministry of Health and Social Development planned to introduce prescription-only sale of codeine from June 2012.
Pharmvestnik, 2010 ↗ Interfax, 2011 ↗About mephedrone (a correction). Mephedrone did not come from pharma: it is a chemical compound synthesised in 1929 and forgotten. It was “rediscovered” in the early 2000s, and in 2007–2010 it spread as a “legal” street substitute for amphetamines and ecstasy, often sold as “plant food” or “bath salts”. Countries banned it quickly: Israel in January 2008, Sweden in December 2008, the United Kingdom in April 2010, the EU in December 2010. Users described euphoria and sociability, and some had cravings and a wish to take more. Among the severe consequences described are seizures, serotonin syndrome and myocarditis, but many cases involve a mixture of substances. We did not find a reliable share of people who developed dependence. Wikipedia, mephedrone ↗
The market, the price of a pill and generics
Medicines are not only medicine but also an enormous industry. Understanding the money helps explain why side effects are talked about less than benefits.
The best-selling medicines
| № | Drug | Company | For what | Sales 2024, $ bn |
|---|---|---|---|---|
| 1 | Keytrudapembrolizumab | Merck | cancer (immunotherapy) | 29,5 |
| 2 | Eliquisapixaban | BMS / Pfizer | anticoagulant | 20,7 |
| 3 | Ozempicsemaglutide | Novo Nordisk | type 2 diabetes | 17,5 |
| 4 | Dupixentdupilumab | Sanofi / Regeneron | dermatitis, asthma | 14,2 |
| 5 | Biktarvybictegravir and others | Gilead | HIV | 13,4 |
| 6 | Jardianceempagliflozin | Boehringer / Lilly | diabetes, heart, kidneys | 12,4 |
| 7 | Skyrizirisankizumab | AbbVie | psoriasis, Crohn's disease | 11,7 |
| 8 | Darzalexdaratumumab | Johnson & Johnson | multiple myeloma | 11,7 |
| 9 | Mounjarotirzepatide | Eli Lilly | type 2 diabetes | 11,5 |
| 10 | Stelaraustekinumab | Johnson & Johnson | psoriasis, Crohn's disease | 10,4 |
Sales data for 2024. Xtalks ↗ Note that the most common pills, taken by millions of people (statins, amlodipine, metformin, omeprazole), are absent from this list. They are cheap generics. The top of the sales is expensive drugs for cancer and immune diseases, diabetes and obesity.
How much they earn: the margin
The estimated production cost of a 12-week course of sofosbuvir at large volumes is $68–136, the US price is $84,000. This is the estimate of the analysis's authors, not company data, and it does not include development costs. Scientific American ↗
An estimate of a profitable price of insulin glargine for a year of treatment under competition, and the price that governments pay (UK $532, USA $1,251). BMJ Global Health, 2018 ↗
In 2015 the company Turing raised the price of a tablet from $13.50 to $750 (the rise was put at about 5000%, more precisely 5,456% by our calculation); in 2018 many pharmacies were still asking more than $800 a tablet. Healio ↗
1000%, 2000%? For an individual new patented drug the gap between cost and price can be hundreds of times or more. But this is not pure profit: the price pays for failed developments, trials, promotion and taxes. Net profit after tax and all expenses at the 25 largest pharma companies in 2015 averaged 20.1% of revenue, at all pharma companies in the sample 17.1%, at the other companies in the sample 8.6% (Bloomberg's calculation for a GAO report, 403 companies, averages weighted by revenue). This is data for a single year; the conclusion about what counts as a fair profit margin for a risky industry remains disputed. GAO, 2017 (Stanford) ↗
How much it costs to create a new drug
Median across 38 drugs
A RAND study of 38 drugs approved by the FDA in 2019, taking into account the cost of capital and failed projects. The mean is $1.31 billion, and the direct costs without adjustments: median $150 million, mean $369 million. Mulcahy et al., JAMA Netw Open, 2025 ↗
The average Big Pharma “asset”
According to a Deloitte estimate for 20 large companies in 2024 (the cost per drug brought to market). The expected return on R&D is 5.9% (3.8% without GLP-1 drugs such as semaglutide). Fierce Biotech ↗
Promotion versus science
An estimate by two researchers at the University of York (2008): the American pharmaceutical industry spends almost twice as much on promotion as on research. This is an estimate, not the companies' reporting, and the industry claims the opposite. BioSpace ↗
The spread is huge, because most candidates never reach the market, and the price of one success includes the price of many failures. We did not find a reliable source for this site on how much all the companies in the world together spend on research in a year, and we do not give a figure.
What a generic is
The original (brand-name) drug is created and patented by a company. A generic is the same active ingredient, made by other manufacturers after the patent expires. Regulators require it to be shown to be absorbed in the same way as the original; a small spread is allowed (usually within 80–125%). The excipients may differ, and people with an allergy to dyes or fillers should read the composition. A biosimilar is a copy of a complex biological drug (for example insulin or antibodies); it is similar but not identical.
The generic manufacturers' association reports that in 2024 in the USA generics and biosimilars made up 90% of prescriptions but only 12% of spending on medicines, and saved the system $467 billion. Meanwhile, of 118 biological drugs whose patents expire in the next ten years, biosimilars are being developed for only 12. The source is the organisation of the generic manufacturers themselves, which is worth remembering. AAM, 2025 ↗
Why medicines are “chemical” and not “natural”
What can be patented
The principle confirmed by the US Supreme Court in the Myriad case (2013): an isolated natural object (there, a gene) cannot be patented as a “product of nature”, while a human-made one (cDNA) can. For medicines this means: a plant or substance “as it is” is hard to protect, but a modified molecule, a method of production, a dosage form and a new use can be. This is one of the reasons why companies invest in altered molecules.
Goodwin Law, 2013 ↗But “there are no natural medicines” is wrong
Of 185 small-molecule anticancer drugs approved in 1981–2019, 62 (33.5%) are natural products or their direct derivatives, and with synthetic compounds created on the basis of natural structures, 64.9%. Aspirin grew out of willow bark, lovastatin from a fungus, paclitaxel from yew. Natural compounds remain the basis of many medicines; they are often modified, and that, among other things, makes the product patentable.
Newman, Cragg, J Nat Prod 2020 ↗Why herbs are not studied in the same way
Full clinical trials of herbal remedies cost as much as trials of a chemical drug, and there is no patent-protected revenue. This is an economic argument, not proof that herbs do not work or do work. Every remedy needs its own trials.
When the harm was kept quiet
We do not say that all doctors and all companies are dishonest. But there are cases proven in court. They show why you need to ask about side effects yourself.
12345678- Illness. A person falls ill or feels unwell.
- Doctor. Examination, tests, recommendations.
- Medicine. A prescription and pills.
- Pharma company. Development, research, marketing.
- Advertising. Television and the internet create demand.
- Factory. Production and packaging.
- Warehouse. Delivery to pharmacies.
- A new illness. A side effect or a new diagnosis, and the circle goes on.
- At the centre is money, which moves around the circle together with the pills.
The author's view. The diagram shows how the interests of money can feed the circle “disease → drug → new disease”. It is an illustration, not proof: it simplifies. Most doctors treat in good faith, and medicines save lives. Only the cases below are confirmed in court.
In 2007 the company pleaded guilty to fraudulent misbranding of OxyContin: fines of over $600 million and another $34.5 million from three executives. In 2020 it pleaded guilty to three criminal charges: deceiving regulators and paying doctors to prescribe the drug.
NPR, 2007 ↗ NBC News, 2020 ↗Illegal promotion of Paxil for teenagers and Wellbutrin for weight loss, and hidden safety data on Avandia.
US Department of Justice ↗The painkiller Vioxx was withdrawn because of a twofold rise in heart attacks and strokes. Payments on lawsuits without an admission of guilt.
NPR ↗Ask about any drug
The side effects of all drugs cannot be described on one page. Ask in plain language: the assistant answers briefly, distinguishes “proven / observation / hypothesis” and suggests what to ask the doctor. It can be wrong and does not make diagnoses.
The assistant works when the page is opened in Claude. It is not available here right now. Use the links to the official instructions below.
Official instructions for any drug
How to report a side effect
Regulators learned of many dangers of drugs from reports by ordinary patients. Anyone can report, not only a doctor.
The State Agency of Medicines (Zāļu valsts aģentūra) accepts reports of adverse reactions on its website zva.gov.lv.
zva.gov.lv ↗The Yellow Card scheme of the British regulator MHRA.
yellowcard.mhra.gov.uk ↗The MedWatch programme of the Food and Drug Administration.
FDA MedWatch ↗What to include: the name and dose of the medicine, when you started it, what happened and when, and what other medicines you take.
How to reduce medicines
Doctors call this deprescribing: planned withdrawal or reduction of medicines that are no longer needed or that harm more than they help. It is a normal part of treatment, which you can and should ask for.
Make a list
All pills, drops, injections, supplements and whatever you bought without a prescription. With doses, and with who prescribed each and when.
Ask about each one
Why am I taking this? What will happen if I stop? What can be reduced first?
Reduce to a plan
Sleeping pills, antidepressants, opioids, hormones and blood pressure pills are withdrawn gradually and under supervision.
OPTIMISE ↗ Benzodiazepines ↗The main ruleThis site does not urge you to give up medicines. It helps you ask your doctor the right questions. Any changes only together with your doctor.
Andrey Petrovich
Born in 1976. The author of information sites about living water and the gifts of the forest. He built this site so that everyone would know not only the benefits of medicines but also their flip side, and could calmly discuss it with their doctor.
TikTok · @amanita_latvijaAll sources
- Pirmohamed M et al. Adverse drug reactions as cause of admission to hospital: 18 820 patients. BMJ, 2004
- WHO. Medication Without Harm, 2017
- European Commission. Guideline on Summary of Product Characteristics
- SAMSON: statin vs placebo symptoms. NEJM, 2020 (BHF)
- Ference BA et al. LDL causes atherosclerotic cardiovascular disease. EAS consensus, Eur Heart J 2017
- CTT Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol. Lancet, 2010
- CTT Collaboration. Statins and muscle symptoms. Lancet, 2022
- CTT Collaboration. Statins and new-onset diabetes. Lancet Diabetes Endocrinol, 2024
- Vidt DG. ACE inhibitor cough and angioedema. Cleve Clin J Med, 2001
- Savage RD et al. Calcium channel blockers and loop diuretics prescribing cascade. JAMA Intern Med, 2020 (CMAJ)
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