Covert drug dependence should be the null hypothesis for explaining drug-withdrawal-induced clinical deterioration: The necessity for placebo versus drug withdrawal trials on normal control subjects
Bruce G. Charlton
Medical Hypotheses. 2010; 74: 761-763.
Just as a placebo can mimic an immediately effective drug so chronic drug dependence may mimic an effective long-term or preventive treatment. The discovery of the placebo had a profound result upon medical practice, since it became recognized that it was much harder to determine the therapeutic value of an intervention than was previously assumed. Placebo is now the null hypothesis for therapeutic improvement. As David Healy describes in the accompanying editorial on treatment induced stress syndromes , an analogous recognition of the effect of drug dependence is now overdue. Drug dependence and withdrawal effects should in future become the null hypothesis when there is clinical deterioration following cessation of treatment. The ideal methodology for detecting drug dependence and withdrawal is a double-blind placebo controlled and randomized trial using disease-free normal control subjects. Normal controls are necessary to ensure that the possibility of underlying chronic disease is eliminated: so long as subjects begin the trial as ‘normal controls’ it is reasonable to infer that any clinical or psychological problems (above placebo levels) which they experience following drug withdrawal can reasonably be attributed to the effects of the drug. This is important because the consequences of failing to detect the risk of covert drug dependence may be considerably worse than failing to detect a placebo effect. Drug dependent patients not only fail to receive benefit and suffer continued of inconvenience, expense and side effects; but the drug has actually created and sustained a covert chronic pathology. However, the current situation for drug evaluation is so irrational that it would allow chronic alcohol treatment to be regarded as a cure for alcoholism on the basis that delirium tremens follows alcohol withdrawal and alcohol can be used to treat delirium tremens! Therefore, just as placebo controlled trials of drugs are necessary to detect ineffective drugs, so drug withdrawal trials on normal control subjects should be regarded as necessary to detect dependence-producing drugs.
Just as a placebo can mimic an immediately effective drug, so chronic drug dependence may mimic an effective long-term or preventive treatment
The discovery of the placebo had a profound result upon medical practice. After the placebo effect was discovered it was recognized that it was much harder to determine the therapeutic value of an intervention than previously assumed. As David Healy describes in the accompanying editorial on treatment induced stress syndromes , an analogous recognition of the effect of drug dependence is now overdue, especially in relation to psychoactive drugs.
Therefore, just as placebo controlled trials of drugs are regarded as necessary to detect ineffective drugs, so drug withdrawal trials on normal control subjects should be regarded as necessary to detect dependence-producing drugs.
Determining the specific benefit of a drug
Throughout most of the history of medicine it was naively assumed that when a patient improved following a specific therapy, then this positive change could confidently be attributed to the beneficial effects of that specific therapy. But it is now recognized that clinical improvement may have nothing to do with the specific treatment but may instead have general psychological causes to do with a patient’s expectations. So that when a drug treatment is begun and the patient gets better, the change may not be due to the drug but some or all of the observed benefit could be due to the placebo effect.
Indeed, nowadays the placebo effect is routinely assumed to be the cause of patient improvement unless proven otherwise. Placebo effect is therefore the null hypothesis used to explain therapeutic improvements.
This tendency to regard the placebo effect as the default explanation for clinical improvement has led to major methodological changes in the evaluation of putative drug therapies; because the first aim of drug evaluation is now to show that measured benefits cannot wholly be explained by placebo. This has led to widespread adoption of placebo controlled trials which compare the effect of the putative drug with a placebo. Only when the drug produces a greater effect than placebo alone, is it recognized as a potentially effective therapy.
The effect of withdrawing a drug upon which a subject has become dependent can be regarded as analogous to the placebo effect, in the sense that drug dependence resembles the placebo effect in being able to mislead concerning clinical effectiveness.
It may routinely be assumed that if a patient gets worse when drug treatment is stopped, then this change is due to the patient losing the beneficial effects of the drug, so that the underlying disease (for which the drug was being prescribed) has re-emerged. That is, when a patient does better when taking a drug than after cessation, it seems apparent that the patient benefits from this drug. So the naïve assumption would be that worsening of a patient’s condition on withdrawal implies that the patient had a long-term illness which was being treated by the drug, and the chronic illness was revealed when drug treatment was withdrawn.
However, this naïve assumption is certainly unjustified as a general rule because drug dependence produces exactly the same effect. When a patient has become dependent on a drug, then adverse consequences following withdrawal may have nothing to do with revealing an underlying, long-term illness. Instead, chronic drug use has actually made the patient ill, the drug has created a new but covert pathology; the body has adapted to the presence of the drug and now needs the drug in order to function normally such that the covert pathology only emerges when the drug is removed and body systems are disrupted by its absence.
In other words, the drug dependent patient may have had independent pathology which has disappeared, or else drug treatment may have been the sole cause of pathology. But either way, clinical deterioration following withdrawal is mainly or wholly a consequence of drug dependence and not a consequence of underlying independent chronic pathology.
So, before assuming that the patient benefits from a drug the possibility of covert drug dependence must first be eliminated as an explanation. Healy’s argument is that drug dependence and withdrawal effects should in future become the null hypothesis in evaluating the chronic need for therapy in the same way as placebo is now a null hypothesis for clinical improvement following drug therapy. Worsening of the patient’s condition following cessation or dose reduction of a drug should therefore be assumed to be caused by withdrawal unless otherwise proven.
However, current methods of therapeutic evaluation cannot reliably detect stress induced drug dependence. This implies that a new kind of clinical trial is required explicitly to test for covert drug dependence and withdrawal effects in a manner analogous to the placebo controlled therapeutic trial.
Assumptions about the cause of post-withdrawal clinical deterioration
It has not yet been generally recognized that eliminating drug dependence as an explanation for withdrawal effects cannot be achieved in the context of normal clinical practice, nor by the standard formal methodologies of controlled clinical trials.
Just as eliminating the possibility of placebo effects requires specially designed placebo controlled therapeutic trails, so eliminating the occurrence of covert drug dependence requires also specially designed withdrawal trials on normal control subjects.
At present, it is usual to assume a drug does not cause dependence, except when it is proved that a specific drug does cause dependence. This means that when no information on dependence is available, or when the information about dependence on a particular drug is either incomplete or inconclusive, then the standard accepted inference is that the drug does not cause dependence. In effect, the onus of proof is currently upon those who are trying to argue that a drug causes dependence.
The situation for withdrawal trials testing for dependence is therefore exactly the opposite of that applying to therapeutic trials and the placebo effect. Consequently, as Healy describes, prevailing clinical evaluation procedures may systematically be incapable of detecting withdrawal effects. Even worse, current procedures systematically tend to misattribute the creation of dependence and harm following withdrawal, as instead being evidence of drug benefit with implication of the necessity for continued treatment of a supposed chronic illness.
The currently prevailing presumption therefore favours new drugs about which little is known; and it favours a perpetuation of the state of ignorance, since no evidence of dependence is almost invariably being interpreted as evidence of no dependence. In other words, as things stand; a drug that actually creates chronic dependence is instead credited with curing a chronic disease; despite that the chronic disease is actually a stress syndrome disease state which that same drug has actually caused.
The current situation is equivalent to chronic alcohol treatment being regarded as a cure for alcoholism on the (warped) basis that delirium tremens follows alcohol withdrawal and alcohol can be used to treat delirium tremens!
When to suspect covert dependence
The almost-total lack of awareness of covert drug dependence and withdrawal problems need not be accidental, but could be a consequence of the fact that unrecognized drug dependence is financially advantageous for the pharmaceutical companies who fund and conduct most clinical trials.
Although there are signs which may warn of dependence on a drug, and the possibility of withdrawal effects (e.g. dwindling effects of a drug, or the need for escalating doses in order to maintain its effect) – none of these are easy to discriminate from therapeutic effects.
But dependence may be suspected when what was perceived as an acute and self-limiting illness requiring a time-limited course of treatment, gradually becomes perceived as a chronic disorder requiring long-term drug treatment. This has been a pattern observed for several psychiatric conditions including depression and acute psychosis. Naturally, there can be rationalizations for this – for example, that the disease was previously unrecognized or under-treated.
Nonetheless, the difficulty of resolving such disputes serves to make clear the need for establishing a presumption of drugs being dependence-producing, and the necessity that this possibility be eliminated by withdrawal trials at an early stage in the evaluation of the drug.
Covert dependence generates a long-term demand for drugs by converting acute into chronic disease among the legitimate therapeutic target community. For example, acute and self-limiting depressive illness can be made into an apparent chronic disease if antidepressants create dependence such that drug withdrawal provokes depressed mood – such that a lifetime of antidepressant treatment can then be justified as ‘preventing’ a supposed chronic recurrent depressive disorder which is actually itself a product of drug administration.
Another way in which covert dependence is advantageous for pharmaceutical companies happens when the inclusiveness of diagnostic criteria are expanded. Because the more patients that are treated (on whatever excuse), the more dependence is produced and the more people who then require chronic drug administration.
Possible examples are when the threshold sensitivity for prescribing is reduced for a dependence-producing drug, such as the suggestion that early or preventive treatment of psychosis is beneficial, using an ‘atypical’ or traditional antipsychotic/neuroleptic. And because withdrawal of antipsychotics causes an increased likelihood of psychotic breakdown, preventive drug treatment is an apparently self-fulfilling prophesy. Or when a new and allegedly high prevalence disease category such as ‘bipolar disorder’ is created along with indications for treatment by dependence-producing drugs; this will tend to generate a new cohort of drug dependent patients whose long-term dependence on drugs can be disguised as a newly-discovered and previously-unsuspected type of severe and chronic psychiatric pathology.
In other words, under currently prevailing research standards, mass creation and exploitation of drug dependence may actually be spun as evidence of medical progress!
The necessity for drug-withdrawal trials on normal control subjects
Drug dependence needs a level of recognition comparable to the placebo effect because it is more damaging than the placebo effect. The main problem of failing to detect a placebo effect is that patients may be unnecessarily exposed to the expense and side effects of a drug. So the placebo effect may be clinically desirable, so long as the placebo is inexpensive and harmless.
But the consequences of failing to detect covert drug dependence may be considerably worse than this. When dependence is a problem, patients who receive chronic drug treatment may not only fail to receive any benefit (and thereby suffer unnecessary risk of side effects and expense) but the drug may actually create increasingly severe covert pathology. If a patient is prescribed a drug inappropriately, then they may become drug dependent even when ineffectiveness, inconvenience, expense or treatment side effects mean that they wish (or need) to stop.
In a nutshell, the problem with placebos is merely that a drug fails to treat pathology, but the problem with dependence is that a drug has created pathology.
Clearly, the ideal – and perhaps indispensable – methodology for detecting covert drug dependence is a double-blind placebo controlled and randomized trial using disease-free normal control subjects. Normal controls are necessary to ensure that the possibility of chronic disease is eliminated: since controls begin the trial as ‘normal’ it is reasonable to infer that any clinical or psychological problems (above placebo levels) which they experience following drug withdrawal can reasonably be attributed to the effects of the drug.
A withdrawal trial needs to be prolonged to include not just sufficient chronicity of treatment by the active drug or placebo; but also a sufficient follow-up period after stopping the drug or placebo, during which it can be discovered whether there is any worsening of conditions following withdrawal and an increase in new pathologies. Specifically, what needs to be measured is a comparison of the frequency of post-withdrawal problems in the two randomly-assigned placebo and active drug groups.
Since the nature of withdrawal effects will not be known in advance, such a trial cannot rely upon highly focused and pre-specified questionnaires but would need to include very general questioning about more general feelings of well-being and quality of life; and any signs of problems as perceived by observers. Follow-up could include measures such as all-cause mortality, all source morbidity; and measures of the frequency of adverse events such as suicide, accidents, medical contacts and hospital admissions.
In conclusion, covert drug dependence should be the null hypothesis explanation for post-withdrawal clinical deterioration, especially for new drugs and even more so for drugs acting on the brain. A default assumption is required that lack of evidence concerning drug dependence implies that a drug is dependence-producing.
Because unless covert drug dependence becomes a default assumption, then it remains advantageous for pharmaceutical companies self-servingly to maintain the current state of ignorance in which recommendations for chronic drug treatment are enforced by drug dependence that is systematically misinterpreted as therapeutic effectiveness.
 Healy D. Treatment induced stress syndromes. Med Hypotheses, in press. doi:10.1016/j.mehy.2010.01.038.