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Underappreciated Risks in Pain Management.

Hidden Hazards: Over-the-Counter Painkillers

A recent study published in the British Medical Journal (BMJ) revealed that certain commonly recommended over-the-counter, non-steroidal antiinflammatory drugs (NSAIDs), utilized as painkillers, can significantly increase the odds of heart attack. (1) This can occur within a month (or less) if high doses are ingested. To carry out the study, a team of researchers pooled data from various healthcare databases in countries that included Canada, Finland, and the UK with a total cohort population of nearly 447,000 participants. More than 61,000 of these patients had suffered a heart attack (myocardial infarction). The research team found that use of painkillers was associated with increased risk of heart attack, and more than 90% of the painkillers assessed were associated with that increased risk. Researchers also found that overall risk of heart attack was 20% to 50% higher in NSAID users than non-users. The experts noted that risk varied greatly.

Using ibuprofen or similar drugs at elevated levels for extended periods of time was associated with a 75% higher risk of heart attack, while rofecoxib correlated with greater than 100% increased risk. The research team noted that the risk of a cardiovascular event becomes elevated within a week and persists with longer use and higher doses.

Nonsteroidal anti-inflammatory drugs (NSAIDs) includes medications that provide analgesic and antipyretic effects, and, at higher doses, antiinflammatory effects. Usually, these medications can be acquired over the counter (OTC), and no prescription is obligatory. Overdosing on NSAIDs is dangerously easy. By way of example, a single caplet of ibuprofen is available in a standard dosage of 200 mg. Yet consuming more than six of these caplets within 24 hours for over a month is accompanied by increased heart attack risk. Without knowledge of this risk, patients could exceed safe thresholds (which vary widely from one drug to the next). It is important to remember that with almost any medication some people will be more sensitive than others, given their health history, genetic detoxification capacity, and current liver status. Risks also increase during pregnancy, in childhood, and with aging.

Dr. Michele Bally, researcher at the University of Montreal Hospital Research Centre, and colleagues wrote: "Given that the onset of risk of acute myocardial infarction (heart attack) occurred in the first week and appeared greatest in the first month of treatment with higher doses, prescribers should consider weighing the risks and benefits of NSAIDs before instituting treatment, particularly at higher doses." (1)

Previous studies had also reported that painkillers raise the odds of heart attack. A team of researchers from the University of Bern (Switzerland) analyzed 31 clinical studies with a total cohort population of more than 116,000 patients. (2) According to the analysis, patients who took rofecoxib and lumiracoxib were twice as likely to suffer heart attack compared with those who took a placebo. The researchers also found that ibuprofen was associated with a threefold increased risk of stroke. In addition, the experts noted that patients who took etoricoxib and diclofenac were up to four times as likely to die of heart attack or stroke.

Another study published in the European Heart Journal showed that commonly used painkillers were associated increased likelihood of cardiac arrest. According to a team of researchers at the University of Copenhagen, ibuprofen can raise the odds of cardiac arrest by 31%. (3) The experts also noted that diclofenac was tied to a 50% higher risk of cardiac arrest. In 2015, the US Food and Drug Administration (FDA) issued strong warning labels against painkiller use, after mounting evidence showed that the drugs may indeed increase the risk of heart attack, liver damage, and kidney failure.

Painkillers and the Risk of Liver Failure.

Acute paracetamol (acetaminophen, Tylenol[R]) toxicity can be caused when the recommended dose of three grams per day is doubled to more than six grams daily. When patients ingest 6 grams per day or more over several weeks to months, they are at risk for toxicity and liver failure. (4) Most people with paracetamol toxicity have no symptoms in the first 24 hours following overdose. Others may initially have nonspecific complaints such as vague abdominal pain and nausea. With time, signs of liver injury may develop, such as low blood sugar, low blood pH, a tendency to bleed easily, and eventually hepatic encephalopathy (hepatic coma which can lead to death). Drug-induced liver damage (hepatotoxicity) results from decreases in the liver's natural antioxidant glutathione and directly damages cells in the liver, leading to liver failure, usually requiring liver transplantation. Some cases will spontaneously resolve. However, in the US, the UK, and the EU, ibuprofen toxicity is the most common cause of acute liver failure and worldwide, one of the most common causes of poisoning.

The most prominent members of this group of drugs are aspirin, ibuprofen, diclofenac (Voltaren[R]) and naproxen (Aleve[R], Midol[R]); all available over the counter in most countries. Paracetamol (acetaminophen, Tylenol[R]) is generally not considered an NSAID because it has little anti-inflammatory activity. Most NSAIDs inhibit the activity of COX-1 and COX-2 pathways, which produce analgesic and anti-inflammatory effects. However, chronic use of NSAIDs, particularly aspirin, can cause gastrointestinal bleeding and ulcers.

In my experience, Cannabis sativa exhibits all the beneficial effects of the NSAIDs and inhibits COX-1 and COX-2 pathways specifically, but without any of the toxicities documented here.

The Fine Print: Side Effects of Prescription Pain Medications

According to the US Institute of Medicine, "All of the currently available analgesic (pain-relieving) drugs have limited efficacy for some types of pain. Some are limited by dose-related side effects and some by the development of tolerance or dependence." (5)

Opioid analgesics commonly used to combat pain include codeine (Dolacet[R], Hydrocet[R], Lorcet[R], Lortab[R]); morphine (Avinza[R], Oramorph[R]); oxycodone (Vicodin[R], Oxycontin[R], Roxicodone[R], Percocet[R], Roxicet[R]); propoxyphene (Darvon[R], Darvocet[R]) and tramadol (Ultram[R], Ultracet[R]). These medicines can cause psychological and physical dependence, as well as constipation, dizziness, lightheadedness, mood changes, nausea, sedation, shortness of breath, or vomiting. Taken in high doses or mixed with alcohol, analgesics can slow breathing, a potentially fatal condition.

Patients in pain are frequently also prescribed muscle relaxants such as Robaxin[R] and Flexeril[R]; anti-anxiety agents such as Valium[R], Sinequan[R], Vistaril[R], Ativan[R], and Xanax[R]; hypnotics such as Halcion[R], Restoril[R], Chloralhydrate[R], Dalmane[R], and Doral[R]; and anti-emetics such as Zofran[R], Compazine[R], Phenergan[R], Tigan[R], and Marinol[R].

Anzemet[R], Kytril, and Zofran[R], newer anti-emetics, are serotonin antagonists, blocking the neurotransmitter that sends a vomiting signal to the brain. Rare side effects of these drugs include fever, fatigue, bone pain, muscle aches, constipation, loss of appetite, inflammation of the pancreas, changes in electrical activity of heart, vivid dreams, sleep problems, confusion, anxiety, and facial swelling.

Ativan[R] and Xanax[R], benzodiazepine drugs, are prescribed to combat the anxiety associated with chronic pain. Ativan can cause amnesia. Abruptly stopping the drug can cause anxiety, dizziness, nausea and vomiting, and fatigue. It can cause drowsiness, confusion, weakness, and headache when initially starting the drug. Nausea, vomiting, dry mouth, changes in heart rate and blood pressure and palpitations are possible side effects.

Benadryl[R], an antihistamine, is given along with Reglan[R], Haldol[R], Inapsine[R], Compazine[R], and Torecan[R] to counter side effects of restlessness, tongue protrusion, and involuntary movements. Its side effects include sedation, drowsiness, dry mouth, dizziness, confusion, excitability, paranoia, and decreased blood pressure.

Compazine[R] and Torecan[R] are phenothiazines, the first major antinausea drugs. Both have tranquilizing effects. Common side effects include dry mouth and constipation. Less common effects are blurred vision, restlessness, involuntary muscle movements, tremors, increased appetite, weight gain, increased heart rate, and changes in electrical activity of heart. Rare side effects include jaundice, rash, hives, and increased sensitivity to sunlight.

Flexeril[R] is a frequently prescribed muscle relaxant that can cause abnormal heartbeat (arrhythmia), aggressive behavior, agitation, anxiety, bloated feeling, blurred vision, confusion, constipation, convulsions, decreased appetite, depressed mood, diarrhea, difficulty falling asleep or staying asleep, difficulty speaking, disorientation, double vision, excitement, fainting, fatigue, fluid retention, gas, hallucinations, headache, heartburn, hepatitis, hives, increased heart rate, indigestion, inflammation of the stomach, itching, lack of coordination, liver diseases, loss of sense of taste, low blood pressure, muscle twitching, nausea, nervousness, palpitations, paranoia, rash, ringing in the ears, severe allergic reaction, stomach and intestinal pain, sweating, swelling of the tongue or face, thirst, tingling in hands or feet, tremors, unpleasant taste in the mouth, urinating more or less than usual, vague feeling of bodily discomfort, vertigo, vomiting, weakness, or yellow eyes and skin.

Haldol[R] and Inapsine[R] are tranquilizers that block messages to the part of the brain responsible for nausea and vomiting. Possible side effects include decreased breathing rate, increased heart rate, decrease in blood pressure when changing position and, rarely, change in electrical activity of the heart.

Reglan[R], a substituted benzamide, increases emptying of the stomach, thus decreasing the chance of developing nausea and vomiting due to food remaining in the stomach. When given at high doses, it blocks the messages to the part of the brain responsible for nausea and vomiting. Side effects include sleepiness, restlessness, diarrhea, and dry mouth. Rarer side effects are rash, hives, and decreased blood pressure.

Robaxin[R] is reported to have side effects that include abnormal taste, amnesia, blurred vision, confusion, dizziness, drop in blood pressure and fainting, drowsiness, fever, flushing, headache, hives, indigestion, insomnia, itching, light-headedness, nasal congestion, nausea, pinkeye, poor coordination, rash, seizures, slowed heartbeat, uncontrolled eye movement, vertigo, vomiting and yellow eyes and skin.

Cannabis Efficacy

Cannabis sativa (THC and CBD) exhibits significant pain release by blocking the nerve pathways (COX-1 and COX-2) which form the basis of common pain reactions. (6) Chronic inflammation in particular usually dissipates rapidly, and pain is reduced or resolved. Cannabis sativa has no known toxicities other than possible sleepiness when one first initiates therapy or when consuming too much. Opioids and NSAIDs have significant side effects, including increasing risk of heart attack if a high dosage is taken daily.

Cannabis has been used for millennia and has been shown to be an effective medication for almost any form of pain or insomnia. An important property of Cannabis sativa is that it does not alter the cycles of REM sleep which add to overall relaxation during sleep, improve anabolic processes (tissue repair), and restore or maintain circadian rhythm. In cases of pain, when standard pain medications are not sufficient, cannabis can be an effective alternative or complement to pain management. Small amounts of Cannabis sativa (THC and CBD) added to opioids may diminish the need for opioids by 50% to 70%, which is especially crucial in palliative care.

My clinical experience over the last 45 years treating AIDS and cancer patients has confirmed the synergistic effects between cannabis and opioids. In combination, low doses of Cannabis sativa (or dronabinol) paired with low doses of opioids are effective for longer periods of time with fewer side effects, clearly benefitting many patients in pain.


(1.) Bally M, et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ 2017;357:j1909.

(2.) da Costa B, et al. Effectiveness of non-steroidal antiinflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet. 2016;17:03.

(3.) Sondergaard KB, Gislason G. NSAIDS and cardiac arrest: Non-steroidal anti-inflammatory drug use is associated with increased risk of out-of-hospital Cardiac Arrest: A nationwide Case-Time-Control study. European Heart Study. June 2017; 38(23): 1788-89.

(4.) Claridge LC Acute liver failure after administration of paracetamol at the maximum recommended daily dose in adults. BMJ 2010;341:c6764.

(5.) Institute of Medicine. Marijuana and Medicine: Assessing the Science Base. Washington, DC: The National Academies Press. 1999.

(6.) Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008 Feb;4(1):245-259.

by Robert Gorter, MD, PhD

Robert Gorter, MD, PhD, holds degrees from the University of Amsterdam Medical School in the Netherlands, UCSF Medical School, and a PhD from the University of Witten/Herdecke in Germany. For approximately 10 years, he worked as a physician and researcher in the treatment of AIDS patients at UCSF. Those efforts provided the foundation for research and clinical practice in immunotherapy and the development of effective nontoxic cancer treatment, today known as the Gorter Model. This approach was applied at his treatment center, the Cologne Medical Center, in a teaching hospital in Germany, and at treatment centers he developed in Cairo, Egypt, and Istanbul, Turkey. He is coauthor of Fighting Cancer: A Nontoxic Approach from North Atlantic Press and a forthcoming book, Cannabis as Medicine.

Consulting Services. Dr. Gorter is available to physicians and patients to discuss the suitability and applications of cannabis medicine for a range of medical issues, based on his clinical experience working with thousands of patients with AIDS, cancer, and other serious health conditions. While he cannot give specific medical advice to individuals who are not his patient, he can speak to his experience with others who have dealt with similar conditions. Consultations with Dr. Gorter and colleagues can be schedule through his website:

Medications and Dosages Associated with Increased Risk for a Cardiovascular Event

Celecoxib (Celebrex[R]) > 200 mg Diclofenac (Voltaren[R], Cambia[R], Solaraze[R])

* 100 mg

Ibuprofen (Advil[R]) > 1200 mg

Naproxen (Midol[R], Aleve[R], Naprelan[R])

* 750 mg

Paracetamol (Tylenol[R]) > 3 gram
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Author:Gorter, Robert
Publication:Townsend Letter
Article Type:Report
Date:Nov 1, 2018
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