Kindling
KINDLING OVERVIEW[3]
Many patients report that they have previously discontinued the use of benzodiazepines without any repercussions (or with only mild, short-lived withdrawal). However, when they subsequently use and then attempt to discontinue the use of benzodiazepines, they experience a distressing withdrawal reaction. Why is the subsequent withdrawal different? One explanation is a phenomenon called kindling. Kindling, as a result of substance withdrawal, refers to the neurological condition that occurs with repeated withdrawals from sedative-hypnotic drugs like alcohol or benzodiazepines (click here for a paper on kindling in alcohol withdrawal). With each withdrawal, individuals are at a higher risk for experiencing more severe withdrawal symptoms – up to and including seizures, psychosis and/or death. While kindling in alcohol withdrawal has been described well, it has received less notice for benzodiazepines. This indicates the need for a greater understanding of this phenomena common to sedative-hypnotics, and a resultant change in prescriptive practice.
It is important to note that kindling is likely to occur if benzodiazepines are used on a prn (“as-needed”) basis while withdrawing or recovering from benzodiazepine physiological dependence.
KINDLING DETAILS AND IMPACTS ON PRESCRIPTIVE PRACTICE
Kindling, as defined by a publication of the National Institute of Alcohol Abuse[4], is “… a phenomenon in which a weak electrical or chemical stimulus, which initially causes no overt behavioral responses, results in the appearance of behavioral effects, such as seizures, when it is administered repeatedly.” Per Wikipedia, “Kindling refers to the phenomenon of increasingly severe withdrawal symptoms, including an increased risk of seizures, that occurs as a result of repeated withdrawal from alcohol or other sedative–hypnotics with related modes of action. Ethanol (alcohol) has a very similar mechanism of tolerance and withdrawal to benzodiazepines, involving the GABAA receptors, NMDA receptors and AMPA receptors, but the majority of research into kindling has primarily focused on alcohol. An intensification of anxiety and other psychological symptoms of alcohol withdrawal also occurs.”
Here is another way to think of it. It is as if the nervous system has a “memory” of the withdrawal(s) and/or damage from a substance like benzodiazepines. This “memory” of prior withdrawal(s) and/or damage somehow remains “imprinted” within the nervous system. Subsequent withdrawals and/or damage are worse because the nervous system “recalls” that it has been sensitized or damaged in prior withdrawal(s).
Alcohol, which is also a sedative-hypnotic, has a very similar mechanism of dependence and tolerance to benzodiazepines, involving some of the same receptors. The majority of research on the kindling phenomenon is focused on alcohol. In alcohol withdrawal, in addition to increased risk of seizures with each subsequent withdrawal, an intensification of anxiety, fear, cognitive impairments, and other psychological symptoms (e.g., alcohol-related psychosis) can also occur.
The mechanisms underlying the kindling effect – or the exacerbation of withdrawal symptoms – following repeated withdrawal episodes from sedative-hypnotics is currently unknown. There are several hypotheses, ranging from a “priming effect” – caused by repeated exposure to the substance itself – to the repeated experience of withdrawal. There are also hypotheses implicating the excitatory glutamate system. The glutamate system is believed to play an important role in this kindling phenomenon with a subtype of glutamate receptors being altered by repeated withdrawals from benzodiazepines. The changes which occur after withdrawal in these subtype glutamate receptors in animals have been found in regions of the brain which govern anxiety and seizure threshold; thus kindling may result in increased severity of anxiety and a lowered seizure threshold during repeated withdrawal. More research is clearly needed into this phenomenon in prescribed benzodiazepine-dependent patients.
Kindling is clearly a clinically significant phenomenon with benzodiazepines, in that past withdrawals may predict the severity of future withdrawals. For this reason, all prescribers should determine a patient’s history of benzodiazepine, z-drug and/or alcohol use and withdrawal before prescribing more benzodiazepines or z-drugs. This is especially important if they are being or have been prescribed long-term, past the recommended 2-4 week guidelines, where tolerance and physiological dependence can develop or has developed in the past. Due to the kindling phenomena, most benzodiazepine experts advise that anyone who has experienced dependence, tolerance and/or withdrawal from benzodiazepines should avoid any future exposure beyond short-term only. Even with short-term re-exposures to benzodiazepines and/or alcohol, there are some anecdotal reports that people became physiologically dependent very quickly, or that the same symptoms they experienced with the previous withdrawal recurred – also referred to as a “setback”.
Prescriber adherence to guidelines for the recommended use of benzodiazepines would negate most of the risk of kindling. Patients would be less likely to become physiologically dependent, except for that minority of patients that have developed physiological dependence to benzodiazepines within a period of time shorter than 4 weeks. It is also important to note that the intermittent long-term use of a short-acting benzodiazepine or z-drug can cause repeated acute dependence followed by acute withdrawal, which may also result in a protracted withdrawal and recovery period.
REFERENCES
[3] This information was from the description provided courtesy of World Benzodiazepine Awareness Day (W-BAD.org).
[4] Becker HC. Kindling in alcohol withdrawal. Alcohol Health Res World. 1998;22(1):25-33. Review. PubMed PMID: 15706729.
