The issues of dependence and withdrawal have come up repeatedly through these pages. They are a primary concern of any taker of psychoactive medication.
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Physical dependence type 1
It has been traditional to distinguish between physical dependence and psychological dependence. Physical dependence is the state that produces withdrawal syndromes. The classical instances are alcohol-induced delirium tremens (DTs) and opiate-induced ‘cold turkey’. These are intensely physical states with shakes, palpitations, sweating and sometimes even convulsions and death.
Psychological dependence, in contrast, was initially thought to be purely a psychological problem that did not involve anything physical in the brain. It gives rise to symptoms of craving that lead addicted individuals to start taking a substance again, often after they have gone through the horrors of a withdrawal, which one might have imagined would have scared any reasonable person off taking that particular drug again.
These old ideas, however, are giving way. Before considering the implications of recent research, we must exclude a type of physical dependence that occurs with a great number of drugs and that is ordinarily of little consequence.
REBOUND SYMPTOMS AND WITHDRAWAL REACTIONS
Many drugs cause rebound symptoms once they are discontinued. Receptors blocked by drug antagonists become hypersensitive. When the blocking drug is then removed, these receptors are flooded with the normal neurotransmitter and they respond vigorously. It may take 48–72hours for them to settle back to normal.
Examples of this are the rebound phenomena that may occur with beta-blockers such as propranolol. Propranolol rebound may lead to palpitations, sweating and flushing. Cholinergic rebound in response to anticholinergics may produce poor sleep and nausea or vomiting. These syndromes are not serious. They clear up quickly and without consequence.
This has traditionally been thought to be quite different from the physical dependence that produces full-blown withdrawal reactions in response to alcohol, the barbiturates, the benzodiazepines and the opiates. Of these compounds by far the most dangerous withdrawal syndrome is produced by alcohol. In its full-blown form, delirium tremens, this can still be fatal. Very few alcohol-dependent individuals now ever have delirium tremens, although many think that having experienced the ‘shakes’ that go with alcohol withdrawal, or perhaps even having the fits that may occur or having heard voices, they must have had the DTs.
The least serious is probably opiate withdrawal, which has a fearsome reputation but is never fatal – except historically where medical zeal has intervened. 1 In between lie benzodiazepine and barbiturate withdrawal. These may lead to delirium and fits but rarely, if ever, death. The benzodiazepines seem to lead to marked withdrawal only in susceptible individuals when given in high doses for sustained periods.
In Chapter 23, it will become clear that antidepressants and antipsychotics can be linked to serious withdrawal problems. Companies have tried to portray these as simple rebound symptoms, but they are not. Neither, however, are they the kind of withdrawal problem linked to alcohol withdrawal, which typically are problematic for 2–3 weeks. Antidepressant and antipsychotic withdrawal can last for much longer. Companies have tried to introduce new terms to differentiate these from withdrawal, such as discontinuation syndromes and symptoms on stopping – for more details see Chapter 23.
BRAIN PHYSIOLOGY
Understanding withdrawal syndromes needs some appreciation of the physiology of the brain. In 1954 Marthe Vogt discovered noradrenaline (norepinephrine) in brain cells. This was the first demonstration that neurotransmitters existed in the brain, which had until then been thought to operate electrically rather than chemically. In 1964, it was shown that neurones containing noradrenaline formed a system within the brain that has its roots in the most primitive parts of the brain, the pons and the medulla oblongata, which are responsible for vital functions such as breathing, cardiac activity and arousal. As cell bodies that contain noradrenaline stain blue, the ‘nucleus’ of noradrenaline-containing cells came to be known as the locus coeruleus (the blue spot).
This system extends up through other areas of the old brain into the cortex of the brain. It is paralleled as it goes by another system, termed the raphe system, which uses serotonin (5-HT) as its neurotransmitter. In general, these two systems act in a complementary fashion. Where the noradrenergic system arouses, the serotonin system sedates. In addition to its role in sleep, breathing and cardiac functioning, the locus coeruleus has a role in vigilance, alerting us to things going on around us (or within us, such as a full bladder) that may be of interest or a potential threat. It is in this role that it plays a part in anxiety, which is a state of hypervigilance in which we get ready to fight or flee.
