Addiction Treatment Blog

Dependence

Before considering this in detail, we must exclude a type of physical dependence that occurs with a great number of drugs and ordinarily is of little consequence. Many drugs will cause rebound symptoms once they are discontinued. This happens particularly if they block receptors. This blockade leads to the blocked receptors becoming hypersensitive. When the blocking drug is then removed, these receptors are flooded with the normal neurotransmitter and they respond vigorously. It may take 48-72 hours for them to settle back down to normal.

Examples of this are the rebound phenomena that may occur with beta-blockers, such as propranolol, and the cholinergic rebound that may happen after stopping antidepressants with marked anticholinergic effects. Propranolol rebound may lead to palpitations, sweating and flushing. Cholinergic rebound may produce poor sleep and nausea or vomiting. These syndromes are not serious, and high doses of the relevant compounds are stopped abruptly.

This is quite different to the physical dependence that produces full-blown withdrawal reactions. There are only four groups of drugs known to produce this form of physical dependence.

• Alcohol.
• Barbiturates.
• Benzodiazepines.
• Opiates.

Of these compounds, by far the most dangerous withdrawal syndrome is produced by alcohol. In its full-blown form, delirium tremens, this can be fatal. Very few alcohol dependent individuals 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, that they must have had the DTs.

The least serious is probably opiate withdrawal, which has a fearsome reputation but which is never fatal – except historically where medical zeal has intervened (1). Between lie benzodiazepine and barbiturate withdrawal. These may lead to delirium and fits but rarely, if ever, death. The benzodiazepines only seem to lead marked withdrawal in susceptible individuals when given in high doses for sustained periods.

What causes withdrawal syndromes? To understand this needs some appreciation of the physiology of the brain.

In 1954 Marthe Vogt discovered noradrenaline in brain cells and suggested that it functioned as a neurotransmitter. This was the first demonstration that neurotransmitters existed in the brain, which had up till then been thought to operate electrically only. In 1964, it was shown that neurones containing noradrenaline formed a system, within the brain. This system had its roots – where the cell bodies lay – 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/alertness. As the cell bodies which contain noradrenaline stain blue the ‘nucleus’ of noradrenaline containing cells came to be known as the locus ceruleus (the blue spot).

This system extends through other areas of the old brain and into cortical areas. It is paralleled as it goes by another system, termed the raphe system, which uses 5-HT as its neurotransmitter. In general, these two systems act in a complementary fashion. Where the noradrenergic system arouses, the 5-HT system sedates.

In addition to its role in sleep, breathing and cardiac functioning, the locus ceruleus has a role in vigilance, alerting us to things going on around us (or within us) 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. It is interference with these systems and only interference with these systems that produce the withdrawal reactions noted for opiates and to some extent the other physical dependence producing agents. Before finding out exactly how, another phenomenon of drug use needs to be considered, which is tolerance.

For a number of psychoactive drugs, there is the observation that it may overtime take more and more of the substance to induce the same effects after repeated dosing. For example, 100 mg of morphine given to someone unaccustomed to taking it, would be a large amount – large enough to cause significant respiratory depression, which is what kills in opiate overdoses. Yet for a chronic opiate abuser, doses of 4 g can be tolerated without undue suppression of breathing.

Early attempts to explain tolerance focused on an aspect of the metabolism of taken in ever increasing doses, with the subject becoming progressively more tolerant as the dose rises. It was discovered that an enzyme in the liver, which is sure to these drugs. Hence, it was argued, one has to take more and more of the drug simply to get the amount one had in the first place. The development of tolerance of this type, it has been argued is what leads to withdrawal.

Comparable factors, it was thought, must be involved in opiate, alcohol and benzodiazepine tolerance and withdrawal. However, it is now accepted that this is not what causes tolerance, which also has no clear relation to withdrawal. For example, a number of drugs, such as cocaine, caffeine and LSD, cause tolerance but do not lead to withdrawal. It is also clear that far from being a purely physical matter, tolerance appears to involve a considerable amount of learning.

One does not have to take alcohol or barbiturates to become aware of the effects of tolerance. Living on a busy street or beside a train line produces a comparable phenomenon. When first exposed to the noise it may be deafening, but after a few days one hardly hears it any more – only if a particularly large truck roars past the front window or the train driver sounds his horn is the passing traffic likely to intrude into awareness once again. No changes in enzyme levels or brain receptors need be postulated to explain what is going on, rather the brain has simply learned not to pay any heed.

What seems to be involved here relates to survival. Organisms pay heed to novel events, until they have assessed the threat that such events pose. When they are judged to be harmless, less heed is paid to them. If it remains uncertain what is going on, attention is maintained. This means that the event remains in awareness and is subjected to all the processing capacities that the animal can bring to bear on hat is happening. Drugs are one such event. Like loud noise or unusual visual events, they bring about change in the internal milieu. While the change is novel and its significance uncertain, experimental animals and human beings will react sensitively to it. If repeated administration proves harmless enough, reactions will be increasingly blunted.

The event being reacted to is rarely something simple like a noise but is rather the situation in which the noise occurs. Similarly in the wild, animals faced with novel sounds, sights or smells react not just to those stimuli but to an entire environment. The issue is not simply one of deciding whether the beast that makes that strange noise is dangerous or not, but rather whether the environment in which such beasts occur is a safe one.

This is particularly the case with drugs. While there is no salient environmental danger, the environment in which drugs are being taken needs assessing. Work in animals clearly reveals this. For example morphine makes animals analgesic, but there are striking interactions between the environment, in which analgesia is tested for, and the amount of analgesia produced. To test for analgesia day after day in the same experimental situation, more and more morphine is required daily to bring about a constant level of analgesia (2,3).

However, if one changes the room or the apparatus used for testing for analgesia, much less morphine may be needed even for an animal that has previously become tolerant to much higher doses of morphine. Indeed their tolerance to these higher doses can be rolled back by a change of environment – at least the drug induced changes are something that can be safely ignored. This would seem inconsistent with purely biological explanations – such as altered receptor number or enzyme level.

Drinkers or drug takers are all aware of similar phenomena associated with the usage of alcohol and other drugs. Typically, drinking in one single environment at one point of the day can lead to the development of an ability to handle quite large amounts of alcohol without becoming inordinately discoordinated or slurred of speech. However, having a drink over a business lunch or in the morning may go one’s head much quicker.

Withdrawal

This account of the development of tolerance does not explain why some drugs should lead to withdrawal. Not hearing a train go past my window is not something that is likely to plunge me into a delirious state. But it does play a part, in that the drugs that cause physical withdrawal all produce tolerance also. This leads to subjects taking them chronically, often ending up on very large amounts.

In each case, also, the drugs in question compromise locus ceruleus/raphe function. This, however, cannot be substantially compromised without death ensuing. These systems, as outlined above, are crucially concerned with the regulation of vital functions such as breathing, temperature and blood pressure, functions which cannot be turned off. Accordingly, effects of drugs that would tend to turn such functions off must by counteracted. This is achieved by the locus ceruleus adapting to the threat by increasing its activity.

If the depressing stimulus of morphine or alcohol is then removed, the locus ceruleus is left more active than it need be for the purposes of vital functions. It is this overactivity that constitutes the core of the withdrawal syndrome, with the subject overbreathing, becoming hyperthermic and having rising blood pressure. In the face of all these internal events, happenings in the external environment are not as likely to be processed accurately if at all – this is what constitutes delirium.

Whether a drug interferes with locus ceruleus, activity or not is however a matter of accident rather than a question of the perversity of personal dispositions or any intrinsic evil in the compound. For example the hallucinogens, cocaine and the amphetamines do not cause withdrawal syndromes of this type.

Detoxification from Alcohol

The current management of alcohol withdrawal involves the use of diazepam, chlordiazepoxide (see Occasions of Anxiety) or chlormethiazole to suppress the manifestations of withdrawal. Locus ceruleus function will usually return to normal somewhere between 7-14 days after withdrawal from alcohol. There have been reports indicating a use for clonidine and calcium channel blockers but, as management with minor tranquillisers is safe and established, it seems unlikely that these will find much place.

There have now been two large studies in which alcohol dependent subjects were detoxified and put on a regime of either naltrexone or a placebo, and both have indicated that those on naltrexone are less likely to relapse. The reason for this is at present uncertain, and it is not clear whether this effect holds for all types of alcohol dependencies or for a subset in particular. A number of other agents are also being studied for their potential effects on post-withdrawal craving.

Detoxification from Opiates

On theoretical grounds, the opiates interact more cleanly to suppress locus ceruleus function than does alcohol or benzodiazepines, which do a range of other things as well. Based on their effects on locus, it was predicted that clonidine, which reduces locus ceruleus activity, would suppress opiate withdrawal. This has proved to be the case, although clonidine has been replaced in recent years by lofexidin, a related agent. These drugs offer significant benefit but do not completely abolish withdrawal from opiates.

Treatment with either lofexidine or clonidine starts at 200 µg twice a day increasung up to 1.2 mg/day for clonidine in divided doses and 2.4 mg for lofexidine. It is maintained for 7-10 days and then reduced over 2-4 days.

More recently, there has been a trend to combine clonidine with the opiate antagonists, naloxone or naltrexone (4). These push opiate users into withdrawal more rapidly than would otherwise be the case. Using them, it is possible to shorten the length of time that detoxification takes, although the process becomes somewhat more severe than it would otherwise be.

Naltrexone is then sometimes given, in much the same way that disulfiram (Antabuse) is given to an alcoholic, in order to block the pleasurable effects of subsequent opiate intake. A more recent fashion has been to give naloxone under general anaesthesia to produce rapid withdrawal with minimal distress. The whole procedure only takes a matter of hours (5), although residual symptoms may persist for some days.

Barbiturate and Benzodiazepine Detoxification

In the case of barbiturate withdrawal, individuals are switched to benzodiazepines and withdrawn according to the schedule in occasions of anxiety article. Where the benzodiazepines concerned the schedule in that article is standard practice at the moment, despite the development of the benzodiazepine antagonist, flumazenil.

References

1. Bakalar JB, Grinspoon L: Drug control in a free society. Cambridge: Cambridge University Press; 1985.
2. Baker TB, Tiffany ST: Morphine tolerance as habituation. Psychol Rev 1985, 92:78-108.
3. Jaffe JJ: Addictions: what does biology have to tell? Int Rev Psychiatry 1989, 1:51-62.
4. Preston KL, Bigelow GE: Pharmacological advances in addiction treatment. Int J Addict 1985, 20:845-867.
5. Loimer N, Schmid RW, Presslich D, Lenz K: Continuous naloxone administration suppresses opiate withdrawal symptoms in human opiate addicts during detoxification treatment. J Psychiatr Rs 1989, 23:81-86.

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