Aug
05
2017

Death From Heartburn Drugs

A study was recently published showing that death from heartburn drugs can come early, when compared to controls. The study was published in June 2017 in the online British Medical Journal Open. The researchers were located at the Washington University School of Medicine, Saint Louis, Missouri, USA.

They compared 349, 312 US veterans on proton pump inhibitors (PPI) to an equal amount of veterans on conventional H2 blockers. Over a follow-up period of 5.71 years there was an increased risk of death of 25% when patients took PPI drugs. No matter to what the researchers compared the PPI group to, there were always more deaths in the PPI group versus other control groups.

Causes of death

According to the senior author, Dr. Ziyad Al-Aly many deaths were due to kidney disease, dementia, fractures, pneumonia, Clostridium difficile infections and cardiovascular disease. Out of 500 patients who took the PPI drug there was one death within one year. But over the years the deaths increased. Dr. Al-Aly thinks that the PPI drug is interfering in some way with the genetic expression of some genes and suppressing others. These genetic differences may explain the early deaths.

As this was a retrospective study, it can only show an association of PPI drugs with earlier deaths, but this does not prove causation. It would require a prospective random study to prove causation.

Other studies regarding the risk of PPI drugs

An Icelandic study from May 2017 showed that there was a 30% increased risk of fractures in males and females following PPI drugs when observed over 10 years. Opiates had a risk of almost 50%, sedatives a 40% risk of increased fractures. Control groups of NSAIDs, statins and beta-blockers showed no increased fracture risk, nor did histamine H2-antagonists.

Side effects of PPI’s

An article from March 2017 is a critical review of the safety of PPI drugs. It notices that with long-term use there are adverse effects like fractures of the long bones, enteric infections and hypomagnesemia. PPI’s can increase the risk for heart attacks and can cause kidney disease and dementia. One of the problems is that gastroesophageal reflux usually dictates the long term use of anti acid drugs like PPI’s, but the longer patients are taking these drugs, the higher the death rate and side-effect rate. The physician should only use PPI drugs initially and after a few weeks switch to the less potent histamine H2-antagonists (like ranitidine).

Listeriosis as side effect of PPI’s

A Danish study from April 2017 noted an increased risk for listeriosis in patients who were on PPI drugs. Over 5 years there was a 2.81-fold higher risk of developing listeriosis in patients on PPI’s compared to a control group. If patients were on corticosteroids and a PPI the risk was even higher, namely 4.61-fold increase to develop listeriosis. In contrast, using histamine H2-antagonists had a risk of only 1.82-fold of developing listeriosis.

Poor prescribing habits for PPI’s

Dec. 2016 study from Dublin, Ireland with patients older than 65 examined their PPI drug use. The comparison of data occurred between 1997 and for 2012. The researchers noted that the maximal PPI dose for long-term use was 0.8% of individuals in 1997 and 23.6% in 2012. The risk of prescribing high dose PPI drugs in 2012 was 6.3-fold in comparison to the risk in 1997. Examination of the health records showed that the indication for prescribing PPI drugs had no correlation with significant gastrointestinal bleeding risk factors. The study concluded that there was definitely room for improving prescribing habits.

Triple therapy

This January 2016 paper describes the standard treatment of H. pylori and gastric and duodenal ulcer treatment, which involves the triple therapy consisting of a PPI and two antibiotics. It pointed out that this treatment protocol “improves healing and prevents complications and recurrences”.

PPI’s causing risk for fractures

A paper from Leipzig, Germany dated July 2016 reviews the usage of PPIs. It mentions that there has been a significant increase of prescriptions in the past 25 years. Patients on PPI’ are at a greater risk for fractures. There is also a risk of low B12 levels from malabsorption of B12. The physician should check this from time to time, and if necessary give B12 injections.

Clostridium difficile infections

A Canadian study from May 2015 found that Clostridium difficile infections (CDI) were linked to chronic antibiotic use or to prolonged use of high doses of PPI drugs. There was a 1.5-fold risk of recurrent CDI in patients older than 75 years who were taking PPI drugs continuously. There was a 1.3-fold recurrence of CDI after antibiotic re-exposure.

Alternative remedies for heartburn

  • Dr. Weil recommends the use of deglycyrrhizinated licorice (DGL) for heartburn or early ulcers.
  • Here is a clinical study with 56 patients with duodenal and gastric ulcers that was published in 1968. Both radiographic evidence as well as clinical findings showed that the ulcers healed and that stomach spasms subsided with DGL treatment. Nobody knew at that time that DGL had antibacterial effects and that often chronic heartburn, stomach and duodenal ulcers can be due to H. pylori infections that are simultaneously present.
  • A December 2016 study showed that probiotics could be a valuable adjunct in triple therapy for H. pylori infection. The study also points out that H. pylori is present in about 50% of the world’s population.

Antibacterial effects of DGL

  • A paper of December of 2012 shows that an important tooth decay bacterium responds to DGL.
  • In a 1989 study 20 patients with aphthous mouth ulcers were followed. DGL mouthwash led to a 50 to 75% improvement in 15 patients within one day of treatment and by the 3rd day there was complete resolution.
  • Here is a suggestion of a four-step approach against H. pylori.
  • DGL has been shown to be useful in gut regeneration in patients with Clostridium difficile infection.

Discussion

I started with a review of a recent paper that pointed out the side effects of PPI drugs. PPI’s are common medications for acid reflux disease, stomach and duodenal ulcers, either alone or as part of the triple therapy. Chronic infection of H. pylori is often the cause of these problems. I reviewed the literature surrounding deglycyrrhizinated licorice (DGL), a natural antacid remedy. It turns out that DGL can be quite useful either as a parallel treatment or instead of the triple therapy.

The problem over the past 25 years is that physicians have been treating acid problems with higher and higher doses of PPI’s. They are also using ASA prophylaxis against heart attacks and strokes more often. This has caused gastric erosions that are bleeding, which in turn caused physicians to prescribe more PPI’s. The side effects of PPI’s belongs to the iatrogenic (doctor- induced) diseases. This is an artificial disease that occurs from the side effects of overprescribed medicine. PPI’s are a very useful short-term anti-acid medication. However, do not use this medication for more than 4 to 8 weeks. But as patients receive years and years of this medication, serious problems like heart attacks, fractures, kidney disease, dementia, and pneumonia as well as Clostridium difficile infections become the consequence. Overall there was an increase of the death rate of 25%.

It sounds quite reasonable that doctors should return to a more conservative approach as the FDA has suggested. This includes alternative natural methods including DGL and probiotics.

Death From Heartburn Drugs

Death From Heartburn Drugs

Conclusion

A recent study from the online British Medical Journal Open has pointed out a high death rate among long-term proton pump inhibitor (PPI) drug users. The se drugs are used to suppress acid formation in the stomach. They are helpful, if there are significant gastrointestinal bleeding risk factors present. But prolonged use of PPIs causes severe side effects as described, including a chronic persistent Clostridium difficile infection (CDI) of the gut that can become resistant to antibiotic therapy. In cases of recurrent CDI one important step is to discontinue PPIs. The physician should consider switching to one of the conventional histamine H2-antagonist drugs (like ranitidine). Overusing PPIs in an older population is not responsible, as this leads to disease that is caused by a physician! There is no need for this to happen.

Avoiding toxic drug levels of PPI’s

The prescribing physician has to exercise caution and restraint and the patients, and their loved ones need to be aware of multidrug interactions. PPIs belong to the drugs that are eliminated in the liver through the cytochrome P450 enzyme system (CYP2C19). But this enzyme system interfering with the drug elimination process may also eliminate other drugs taken by the patient. The end results can be toxic drug levels of PPIs. It can potentiate the side effects and become responsible for the 25% increased risk of death when the patient takes PPI drugs chronically. Even though PPIs are the newer medication, newer does not always mean better.

Sep
28
2013

Sleepless Nights

Sleeping problems (insomnia) are very common. About 10% of the population suffers from chronic insomnia; 30% of the population suffers from occasional sleep problems. In a large outpatient population of a clinic consisting of 3500 patients who had at least one major clinical condition, 50% complained of insomnia, 16% had severe symptoms, 34% had mild symptoms (Ref.1). Insomnia is more common among women, and older people as well as in people with medical or psychiatric illnesses. Long-term studies have shown that the same insomnia problems persist throughout many years. It is not possible to offer a simple remedy for insomnia, because insomnia is a complex problem. Here I will discuss some of the causes of insomnia and also discuss some of the treatment options.

Symptoms of insomnia

The person who suffers from insomnia will usually state that they have problems falling asleep. Worries of the day suddenly circulate through their thoughts and they toss and turn nervously looking at the clock from time to time and getting more and more anxious that they cannot sleep. Others fall asleep OK, but in the middle of the night they wake up perhaps to visit the restroom, but then they cannot go back to sleep. Others wake up 2 hours before their normal alarm clock time and they feel their stomach rumbling making it impossible to fall back to sleep. Older people with chronic diseases and general poor health suffer more from insomnia. In this setting insomnia may be more related to the underlying disease rather than old age. Psychiatric disorders also are associated with more insomnia. Treat the underlying psychiatric illness, and the insomnia disappears.

Although insomnia is a sleep disturbance during the nighttime, people who are affected with this complain of daytime fatigue, of overstimulation, yet they catch themselves making frequent mistakes, and their inability to pay attention gets them involved in accidents and falls. Longitudinal studies have shown (Ref. 1) that people with chronic insomnia are more likely to develop psychiatric disease, such as major depression,  anxiety disorder and alcohol and substance abuse. Unfortunately these disorders can by themselves again cause insomnia, which reinforces chronic insomnia. Insomnia leads to poorer social and physical functioning, affects emotions, leads to a lack of vitality and physical endurance, contributes to worsening of pain and can affect general and mental health.

Research about insomnia

Much has been learnt from sleep studies using polysomnography monitoring during a full night’s sleep. These studies have been used mainly as a research tool. In such studies eye movements, brain wave activity, muscle activity, chest movements, airflow, heart beats, oxygen saturation and snoring (with a microphone) are all simultaneously recorded. This way restless leg syndrome, sleep apnea, snoring, seizure disorders, deep depression etc. that can all lead to insomnia can be diagnosed and separated from insomnia. The stages of sleep (wakefulness, stage 1 to 3 sleep and the REM sleep stage) can also be readily measured using polysomnography (Ref.2). According to this reference the majority of insomnia cases do not need this complex procedure done.

Sleepless Nights

Sleepless Nights

Causes of insomnia

Traditionally insomnia cases are classified into primary insomnia and secondary insomnia. Secondary insomnia is caused by all of the factors discussed below. When they are dealt with, we are left with cases of primary insomnia.

The following medical conditions can cause insomnia: heart disease, pulmonary diseases like asthma and chronic obstructive pulmonary disease (COPD); gastrointestinal disease like liver cirrhosis, pancreatitis, irritable bowel syndrome, ulcers, colitis, Crohn’s disease; chronic kidney disease; musculoskeletal disease like arthritis, fractures, osteoporosis; neurodegenerative disease like MS, Parkinson’s disease, Alzheimer’s disease; endocrine disease like diabetes, hyper- or hypothyroidism, adrenal gland fatigue and insufficiency; and chronic pain conditions. Also, psychiatric conditions like major depression, schizophrenia and anxiety disorders can cause insomnia.

This list in not complete, but it gives you an idea of how complex the topic of insomnia is.
The physician who is seeing a patient with insomnia needs to rule out any of these other causes of insomnia to be certain that the only condition that is left to treat in the patient is insomnia itself. The other diagnoses have to be dealt with separately or else treatment of insomnia will fail.

Ref. 1 points to a useful model of how to think about causation of insomnia: there are three points to consider, namely predisposing, precipitating, and perpetuating factors. Let’s briefly discuss some of these.

Predisposing factors

We are all different in our personal make-up. If you are well grounded, chances are you are not susceptible to insomnia. Anxious persons or persons who have been through a lot of negative experiences in life will have personality traits that make them more prone to insomnia. Lifestyle choices such as late nights out, drinking with the buddies in a bar (extreme circadian phase tendencies) will have an impact on whether or not you develop insomnia.

Precipitating factors

A situational crisis like a job change or the death of a loved one can initiate insomnia.  However, there could be a medical illness such as a heart attack, a stroke or the new diagnosis of a psychiatric illness that has become a precipitating factor. Sleep apnea and restless leg syndrome belong into this group as well as would the stimulating effect of coffee and caffeine containing drinks. Jet lag and nighttime shift work can also be precipitating factors.

Perpetuating factors

Daytime napping to make up for lost sleep the night before can undermine sleep initiation the following night, which can lead to a vicious cycle. Similarly, the use of bedtime alcoholic drinks leads to sleep disruption later that night and can become a perpetuating factor, if this habit is maintained. Even the psychological conditioning of being anxious about whether or not you will fall asleep easily or not the next night can become a perpetuating factor.

I will return to this classification and the factor model of causation of insomnia when we address treatment options.

Drugs that can cause insomnia

One major possible cause for insomnia  can be side effects from medications that patients are on (would belong to the ‘perpetuating factors’ among causes). Physicians call this “iatrogenic insomnia”. The antidepressants, called selective serotonin reuptake inhibitors (SSRI’s) like Prozac are particularly troublesome with regard to causing insomnia as a side effect. Other antidepressants like trazodone (Desyrel) are used in small doses to help patients with insomnia to fall asleep. Some asthmatics and people with autoimmune diseases may be on prednisone, a corticosteroid drug. This can cause insomnia, particularly in higher doses; so can decongestants you may use for allergies; beta-blockers used for heart disease and hypertension treatment; theophylline, an asthma medication and diuretics. Central nervous stimulants like caffeine or illicit drugs can also cause insomnia. Hormone disbalance in general and hyperthyroidism specifically as well as Cushing’s disease, where cortisol levels are high will cause insomnia.

Treatment of insomnia

So, how should the physician approach a patient with insomnia? First it has to be established whether there is secondary insomnia present due to one of the predisposing, precipitating or perpetuating factors. In other words, is there secondary insomnia due to other underlying illnesses? If so, these are being addressed first. Lifestyle choices (staying up late every night) would have to be changed; alcohol and drug abuse and overindulging in coffee or caffeine containing drinks needs to be dealt with. Cognitive therapy may be beneficial when mild depression or anxiety is a contributing factor to insomnia.

The remaining insomnia (also medically termed “primary insomnia”) is now being treated.

The following general points are useful to get into the sleeping mode (modified from Ref. 3):

  1. Ensure your bedroom is dark, soundproof, and comfortable with the room temperature being not too warm, and you develop a “sleep hygiene”. This means you get to sleep around the same time each night, have some down time 1 hour or so before going to bed and get up after your average fill of sleep (for most people between 7 to 9 hours). Do not sleep in, but use an alarm clock to help you get into your sleep routine.
  2. Avoid caffeine drinks, alcohol, nicotine and recreational drugs. If you must smoke, don’t smoke later than 7PM.
  3. Get into a regular exercise program, either at home or at a gym.
  4. Avoid a heavy meal late at night. A light snack including some warm milk would be OK.
  5. Do not use your bedroom as an office, reading place or media center. This would condition you to be awake.  Reserve your bedroom use only for intimacy and sleeping.
  6. If you wake up at night and you are wide awake, leave the bedroom and sit in the living room doing something until you feel tired and then return to bed.
  7. A self-hypnosis recording is a useful adjunct to a sleep routine. Listen to it when you go to bed to give you something to focus on (low volume) and you will find it easier to stop thinking.

Drugs and supplements for insomnia

1. In the past benzodiazepines, such as diazepam (Valium), lorazepam (Ativan), fluorazepam (Dalmane), temazepam (Restoril), triazolam (Halcion) and others were and still are used as sleeping pills. However, it was noted that there are significant side effects with this group of drugs. Notably, there is amnesia (memory loss), which can be quite distressing to people such as not remembering that someone phoned while under the influence of the drug, you promised certain things, but you cannot remember the following morning what it was. Another problem is the development of addiction to the drugs with worse insomnia when the drugs are discontinued. Many physicians have stopped prescribing benzodiazepines.

2. There are non-benzodiazepines drugs that are used as sleeping pills (hypnotics), such as Zaleplon (Sonata), Zolpidem (Ambien) and Eszopiclone (Lunesta).  They seem to be better tolerated.

3. Ramelteon, a melatonin agonist, is available by prescription in the US. It probably is the best-tolerated mild sleeping pill and works similar to melatonin, but is more expensive. Chances are that your physician likely would prescribe one of the non-benzodiazepines drugs or Ramelteon for you as they do not seem to be addicting.

4. However, there is an alternative: Many patients with insomnia tolerate a low dose of trazodone (Desyrel), which is an antidepressant with sleep restoring properties. A low dose of 25 to 50 mg at bedtime is usually enough for insomnia. This allows the patient to fall asleep within about 30 minutes of taking it, and sleep lasts through most of the night without a hangover in the morning. Many specialists who run sleep laboratories recommend trazodone when primary insomnia is diagnosed. However, this is still a drug with potential side effects as mentioned in the trazodone link, but 50 mg is only ¼ of the full dose, so the side effects will also be less or negligible.

5. I prefer the use of melatonin, which is the natural brain hormone designed to put us to sleep. Between 1 mg and 6 mg are sufficient for most people. We know from other literature that up to 20 mg of melatonin has been used in humans as an immune stimulant in patients with metastatic melanoma with no untoward side effects other than nightmares and some tiredness in the morning. A review from the Vanderbilt University, Holland found melatonin to be very safe as a sleeping aid. There are several melatonin receptors in the body of vertebrates (including humans), which are stimulated by melatonin.

6. Other natural methods are the use of L-Tryptophan at a dose of 500 mg at bedtime, which can be combined with melatonin. It is the amino acid contained in turkey meat, which makes you tired after a Thanksgiving meal. GABA is another supplement, which is the relaxing hormone of your brain, but with this supplement tolerance develops after about 4 to 5 days, so it is only suitable for very short term use. Herbal sleep aids are hops, valerian extract and passionflower extract. They are available in health food stores.

Conclusion

A lack of sleep (insomnia) is almost a given in our fast paced lives.

When it comes to treatment, all of the other causes of secondary insomnia need to be treated or else treatment attempts would fail. What is left is primary insomnia. This is treated as follows:

We need to review our sleeping habits, lifestyles and substance abuse. Remove what is detrimental to your sleep. Start with the least invasive treatment modalities such as self-hypnosis tapes, melatonin, L-Tryptophan or herbal extracts. Should this not quite do the trick, asks your doctor for advice. The non-benzodiazepines drugs or Ramelteon would be the next level up. It may be that an alternative such as low dose trazodone would be of help. Only, if all this fails would I recommend to go to the more potent sleeping pills (keep in mind the potential for addiction to them).

References

1. David N. Neubauer, MD (John Hopkins University, Baltimore, MD): Insomnia. Primary Care: Clinics in Office Practice – Volume 32, Issue 2 (June 2005)  © 2005, W. B. Saunders Company

2: Behrouz Jafari, MD and Vahid Mohsenin, MD (Yale Center for Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA): Polysomnography. Clinics in Chest Medicine – Volume 31, Issue 2 (June 2010), © 2010 W. B. Saunders Company

3. Jean Gray, editor: “Therapeutic choices”, 5th edition, Chapter 8 by Jonathan A.E. Fleming, MB, FRCPC: Insomnia, © 2008, Canadian Pharmacists Association.

Last edited Sept. 28, 2014