Benzodiazepines – Adverse Effects

On November 25, Mad in America posted a link to an article in the Journal of Neurological Sciences.  The article is by Harnod et al, and is titled An Association between Benzodiazepine Use and Occurrence of Benign Brain Tumors.  The authors studied the records of  62,186 individuals in Taiwan  who had been prescribed a benzodiazepine for at least 2 months between 2000 and 2009.  They compared the incidence of brain tumors in these patients with the incidence in patients in a matched-pairs control group.  The hazard ratio for benign brain tumors (benzo group vs non-benzo group) was 3.15 (95% confidence interval: 2.37-4.20).  The hazard ratio for malignant brain tumors was 1.21 (95% confidence interval: 0.52-2.81).  What this means essentially is that one can be 95% confident that the benign tumor association is real, but that the malignant tumor result might have arisen by chance.

The authors also discovered that dosage is an important factor.  The hazard ratios for benign brain tumors increased with dose.  At doses between 36 and 150 mg/year the hazard ratio was 2.12 (1.45-3.10); at doses above 150 mg per year, the hazard ratio was 7.03 (5.19-9.51).

The study in question is a matched-pairs cohort study, rather than a randomized controlled trial, so one can’t state with absolute certainty that the drugs caused the tumors, but given the large number of participants, the meticulous control of confounding factors, and the magnitude of the hazard ratio (three-fold), the results need to be taken very seriously.

There might also be a tendency to dismiss these results on the grounds that the tumors are benign.  But benign tumors can have serious implications..  Here’s what the American Brain Tumor Association says:

“…the location of a benign brain tumor can have a significant impact on treatment options and be as serious and life-threatening as a malignant tumor.”

HISTORY

The first benzodiazepine, Librium, was introduced in 1960, followed in 1963 by Valium.  Today there are dozens of benzodiazepine-class drugs in regular use.

The Harnod et al study is by no means the first time that researchers have drawn attention to the dangers of long-term benzodiazepine use.

Here is a short list of studies that found significant adverse effects for benzodiazepines:

Lader MH, Petursson H, 1981: Benzodiazepine derivatives–side effects and dangers.

“A range of paradoxical effects can occur of which release of aggressive and hostile feelings has excited most attention.”

Lader MH, Petursson H, 1984: Computed axial brain tomography in long-term benzodiazepine users. 

“The mean ventricular/brain area measured by planimetry was increased over mean values in an age- and sex-matched group of control subjects but was less than that in a group of alcoholics.” [Benzo users had more brain shrinkage than controls, but less than alcoholics]

Tata PR, et al, 1994: Lack of cognitive recovery following withdrawal from long-term benzodiazepine use.

“Despite practice effects, no evidence of immediate recovery of cognitive function following BZ withdrawal was found. Modest recovery of certain deficits emerged at 6 months follow-up in the BZ group, but this remained significantly below the equivalent control performance.”

Burke, KC et al, 1995: Medical services use by patients before and after detoxification from benzodiazepine dependence.

“Although a retrospective record review suffers from a range of limitations, the findings suggest that detoxification from benzodiazepines may be effective in reducing use of outpatient medical and mental health services and presumably in reducing costs of care.”

Cohen, SI, 1995: Alcohol and benzodiazepines generate anxiety, panic and phobias.

“In almost half the patients seeking advice for anxiety, panic and phobias the cause was alcohol or benzodiazepines.”

Barker MJ et al, 2004: Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis.

“Results of the meta-analyses indicated that long-term benzodiazepine users do show recovery of function in many areas after withdrawal. However, there remains a significant impairment in most areas of cognition in comparison to controls or normative data.”

Stewart SA, 2005: The effects of benzodiazepines on cognition.

“In an attempt to settle this debate, meta-analyses of peer-reviewed studies were conducted and found that cognitive dysfunction did in fact occur in patients treated long term with benzodiazepines, and although cognitive dysfunction improved after benzodiazepines were withdrawn, patients did not return to levels of functioning that matched benzodiazepine-free controls.”

Berger A et al: 2012: Change in healthcare utilization and costs following initiation of benzodiazepine therapy for long-term treatment of generalized anxiety disorder: a retrospective cohort study.

“Healthcare costs increase in patients with GAD beginning long-term (≥90 days) treatment with a benzodiazepine anxiolytic; a substantial proportion of this increase is attributable to care associated with accidents and other known sequelae of long-term benzodiazepine use.”

Kao CH et al, 2012: Benzodiazepine Use Possibly Increases Cancer Risk: A Population-Based Retrospective Cohort Study in Taiwan. 

“In the group with benzodiazepine use, the overall risk of developing cancer was 19% higher than in the group without benzodiazepine exposure…”

Other studies can be found that dispute details of the adverse effects spectrum, but there is general agreement that these effects are wide ranging and, in many cases, serious.

DRUG DEPENDENCE

Benzodiazepines were initially promoted as non-habit-forming, but in fact reports of dependence for each of the various products emerged, usually within a few years of its launch.  Withdrawal reactions from Librium were noted in a 1961 article (Withdrawal reactions from chlordiazepoxide (Librium), in the journal Psychopharmacologia 1961, 2: 63-68).  Reports of addiction to Valium were noted in a letter to the BMJ in 1967 (Addiction to diazepam (Valium), Br Med J 1967;1:112.1).  In 1976, a report of withdrawal symptoms in newborns who were exposed to benzodiazepines in utero appeared in the American Journal of Obstetrics and Gynecology.  In 1977, a similar report appeared in the Journal of Pediatrics.  In 1986, Professor Heather Ashton, DM FRCP, of the University of Newcastle, UK, wrote a comprehensive account of the benzodiazepine withdrawal syndrome in an article titled Adverse Effects of Prolonged Benzodiazepine Use.  Here are some quotes:

“The syndrome can be of considerable severity and has similarities to abstinence syndromes associated with alcohol, opiates, and barbiturates.”

“Agoraphobia, other phobias, and depression are common during withdrawal…”

“Perceptual distortions (sometimes hallucinations) and feelings of depersonalisation and unreality are characteristic. Acute psychotic episodes occur occasionally, but obsessions, intrusive thoughts and memories, and paranoid feelings are not uncommon. Irritability, rage, and aggression are also frequent…”

“Neurological symptoms include episodes of paraesthesiae and numbness, tremor, muscle pains, stiffness, weakness and fasciculation, ataxia, and blurred or double vision…”

“Major convulsions or temporal lobe seizures sometimes occur on abrupt withdrawal.”

“Gastrointestinal symptoms are very common…”

“Cardiovascular symptoms (palpitations, flushing, chest pain), hyperventilation, urinary symptoms (frequency, urgency, incontinence), and loss of libido are similar to those seen in anxiety states. An influenza-like syndrome with prostration and increased upper respiratory tract secretion may occur and resembles that seen after narcotic withdrawal, although it is more protracted.”

In an American Journal of Psychiatry editorial in 1991, Carl Salzman, MD, Chair of the APA Task Force on Benzodiazepine Dependence, Toxicity, and Abuse, acknowledged that:

“True physical dependence can arise from chronic therapeutic use, defined by the appearance of a constellation of discontinuance symptoms following abrupt withdrawal.”

Some individuals withdrawing from benzodiazepines experience protraction of withdrawal symptoms for months, and in some cases more than a year.  Lader M et al (2009), in Withdrawing Benzodiazepines in Primary Care, state:

“No clear evidence suggests the optimum rate of tapering, and schedules vary from 4 weeks to several years.”

Prescriptions for benzodiazepines continue to rise.  Alprazolam (generic Xanax) is the most prescribed psycho-pharmaceutical product in the US today.  The number of prescriptions written for this drug increased 9% from 2009 to 2011 (PsychCentral).

Psychiatrists claim that anxiety is an illness, and that the prescription of benzodiazepines is a legitimate medical intervention.  The reality is that anxiety is the natural consequence of the relentless, stressful, isolative, unfulfilling kind of lifestyle that is becoming increasingly common in the US and other industrialized countries.  Benzodiazepines are a fast-acting, addictive drug that dulls the pain, but often at enormous cost.  Their effects, including long-term adverse reactions, are similar to alcohol, but they can be used discreetly in situations where alcohol use would attract disapproval (workplace) or even legal consequences (public places).

Popping a benzo to cope with life’s difficulties and challenges is essentially on a par with taking a nip from a hip flask filled with whisky.  It might get one through the day, but it’s not an effective or personally fulfilling way to tackle life’s problems, and the adverse consequences can be truly horrendous.

 

  • Francesca Allan

    I haven’t taken Ativan for years but I do remember needing more and more of them to achieve the same effect and I did have considerable trouble giving them up. The last time I had trouble with anxiety, I had the insight to decline my doctor’s very prompt offer of this kind of relief. Couldn’t agree with you more about the real causes of anxiety (and all mental illnesses).

  • Phil_Hickey

    Francesca,

    There’s a article here that I found particularly tragic. It seems to suggest that benzodiazepines are just the thing we need for our fast-paced society!

  • Edward Boss

    I’ve took Benzodizapines for 15 yrs which reduce my anxiety which I believe is good for other health issues. Yes they stop working somewhat after prolonged use and many people only take them to not have the withdrawls. I stopped hydrocodone fairly easy after an illness, but Benzodizapines seem easy to reduce but almost impossible to just stop cold turkey. Other people may have different reactions.

  • Phil_Hickey

    Edward,

    Thanks for your comment. You’re right; people do indeed react differently to different substances. I hope things continue to go well for you.