Effect of experience
There is no doubt that experience with the medication increases the amount of decrease in craving and drinking (see Figures 1, 2, 3, 4, 8). Thus the prediction of the extinction hypotheses is supported. One might argue however, that some medicines (eg. Prozac) show benefits only after several days of administration, so the increase in the effect of naltrexone could still be caused by direct actions of the medicine. None of the clinical trials starting with abstinence, however, has reported the ability of naltrexone to block craving and drinking increases as a function of the number of days on the medication whilst abstinent. Instead, patients generally have more ability to remain abstinent early in the trial than after several weeks on naltrexone. It is far more likely that naltrexone, nalmefene and naloxone produce tolerance rather than sensitization. Blocking receptors causes a homeostatic increase in the number of receptors – an up regulation, resulting in temporary supersensitivity once the antagonist is gone from the body. Figure 6 shows the up regulation in the number of opioid receptors in AA rats produced specifically when naltrexone was being used to reduce alcohol drinking.
Figure 6: Recovery from up regulation in AA rats caused by prior administration of naltrexone (1 mg/kg orally twice daily for 8 days). (38)
Preclinical studies have shown clearly that the antagonists given during abstinence do not develop the ability to decrease subsequent alcohol drinking. Instead, the treatment tends to increase alcohol drinking relative to that shown by controls, both in the case of nalmefene (39) and naltrexone (40).
Extinction curves: Rescorla-Wagner
The previous sections have been tests primarily of whether the antagonists directly suppress craving (left column), with extinction (right column) only providing an alternative explanation. This section, however, deals with a new test for whether the antagonists function through the mechanism of extinction. The direct action hypothesis does not predict any form for the decrease in craving with experience drinking on the medication because it does not predict there should be any such decrease (as covered in the previous section). The decrease in response strength produced by extinction follows a specific curve, called an extinction curve. The Rescorla-Wagner (41) equation for the extinction curve states that the change in response strength on each extinction session is: ΔV=S[Vmax-(V-Vsum)] where V is the strength of the response prior to the session; ΔV is the change in strength produced by the extinction session; S is a constant related to the salience of the situation; Vmax is zero for extinction; Vsum is the strength of the response produced in other ways. Mathematically, it is simply an exponential curve, similar to that for radioactive decay and many other processes (including patients dropping out of a trial), with the additional terms Vmax and Vsum added. When Vmax is not zero, the formula accounts for learning data. Vsum is not zero when there are other stimuli heling to elicit the response, which is usually the case outside of the laboratory. It has the form Vτ=Voe-yt. For the data in Figure 8, this becomes: Vt=05e -0.91629t.
Extinction curves: computer simulation of extinction
The Rescorla-Wagner formula is not based on any specific neurological mechanism for how extinction is caused. Figure 7 shows the results from a computer simulation of extinction (42). An exponential curve with the addition of a Vsum term ie. a Rescorla-Wagner extinction curve, accounts for 99.7% of the variability in the computer simulation results. Therefore, the two are essentially the same, except the computer simulation also accounted for the spontaneous recovery seen in empirical data (eg. in Figure 2 here).
Figure 7: Upper: Theoretical extinction curve produced by a computer simulation of extinction in neural networks with the strength of synapses obeying the ‘rest principle’ rule. ×ιιι
Lower: The best fitting exponential curve for all but the last data point accounts for 99.7% of the variability:
V=12.336e -0.525t – 12.212
The 12.212 is the sam as the Vsum constant in the Rescorla-Wagner formula.
Curve fitting to preclinical data
Curve fitting begins by supplying values for the constants in the formula, on the bases of theoretical considerations if possible, or on the basis of what produces the curve that best fits the observed empirical data ie. what curve explains the highest percentage of the variability in the data. Compare the Rescorla-Wagner extinction curve in Figure 8 here with the actual results in Figure 2. It is almost a perfect fit. The formula accounts for 99.3% of the variability in the actual data (R²=0.996). Notice that the Rescorla-Wagner formula does not account for the extinction burst ie. the slightly higher responding sometimes seen on the first extinction session, or for spontaneous recovery usually seen on the first post-extinction session after a delay.
Figure 8: The Extinction Curve according to the Rescorla-Wagner formula, where V was initially set at the pre-treatment level of drinking, 0.478: ΔV is the change in strength produced by the extinction session; S was set at 0.6; Vmax is zero for extinction; Vsum was set at 0. So the formula shown here is ΔV=0.6*[0-(0.5-0)] = 0.6* (-0.5) for the first effect of the first nalmefene session. Compare the theoretical results here with the observed results in Figure 2. The Rescorla-Wagner formula accounts for 99.3% of the variability in these six data points.
Curve fitting to clinical data
The extinction curves for the clinical data were already shown on the figures. The mean craving data from all patients on naltrexone, shown in Figure 1, is very closely matched by the Rescorla-Wagner formula with Vsum set at 2.10. In exponential form it is Vt=2.431e-0.03t + 2.10. It accounted for 98.9% of the variability in the empirical data. In Figure 4, which showed the daily drinking records of the alcoholics on naltrexone, the theoretical extinction curve from the Rescorla-Wagner equation with V set at the pre-treatment mean, 6.1 drinks per day, Vsum set at 1.6 drinks per day and S set at 0.018, accounted for 66.4% of the variability. This is far lower than the preclinical data, probably because of the extraneous factors that affect the day-to-day drinking of humans more than the intake by laboratory rats. It also is lower than the clinical data, probably due to factors in addition to craving that influence human drinking. The results support the conclusion that extinction is responsible for the decrease in craving produced by naltrexone, and plays a major role in the reduction in drinking.
Direct measure of cue-induced craving
There have been several studies examining the effect of naltrexone on how much craving people report when seeing stimuli related to alcohol. (43, 44, 45). Each of these experiments, however, used patients who were being treated with naltrexone. Thus, they cannot separate the effect of naltrexone itself from the effects of extinction caused by previously having consumed alcohol while on naltrexone, and the data already reviewed indicate that extinction has a powerful effect on craving for alcohol in general. Therefore, we cannot conclude from these studies that naltrexone directly was reducing the elicited craving.
An additional test can be obtained from an experiment we did at ContrAl Clinics (46). When it first was proposed that alcoholism could be treated with naltrexone, several people stated that they thought it would only help with one type of alcoholic. It was assumed that some people drank because they were stressed, had a hangover, or were otherwise unhappy, and they expected alcohol would reduce their pain. Other alcoholics drank because they were in a party mood and expected alcohol to provide euphoria. The pleasure was assumed to be caused by the release of endorphins but the effects against stress, anxiety, hangover etc, came from other neural systems. Therefore, they predicted that naltrexone would only be effective in the alcoholics who drank to get euphoria. These would also be the people who had stimuli related to the pleasant effects become conditioned to release endorphins that then could produce craving and drinking. In contrast, the hypothesis that naltrexone worked by extinction predicted that all sorts of stimuli, not just pleasant ones, would have their ability to trigger craving and drinking weakened. It assumes that any stimulus that is frequently present when alcohol is consumed and endorphins released will have its connections to craving and drinking reinforced by the neuronal actions of the endorphins. Reinforcement is independent of pleasure; it is simply the strengthening of synapses and can even occur unconsciously. Extinction is also independent of pleasure. Any stimulus – pleasant, unpleasant or neutral – which previously had had its’ connections weakened by the mechanism of extinction when the receptors for the endorphins are blocked when alcohol is consumed in response to the stimulus. In order to test the differing predictions of the two theories for the actions of naltrexone, alcoholics coming for treatment at the first Finnish clinic were twice presented with 101 stimuli that might trigger alcohol drinking. Some of the stimuli were external, others were feelings or thoughts. The patients rated each stimulus on a scale of 1 through 5 for how strongly the stimulus was connected to their own drinking. Complete data were obtained from 24 patients. The test was given at Visit 1 (V1), after about 10 days on naltrexone, and again at Visit 6 (V6), after about 100 days. The differences between V6 and V1 ratings of a specific stimulus item were calculated for each subject. As shown in Figure 9, nearly all stimuli showed less reported ability to trigger drinking at the later visit, with the mean reduction for all stimuli combined being highly significant: p=0.0006. Both tests were conducted with patients taking naltrexone. The difference between the two tests was the intervening 90 days of drinking while on naltrexone. The hypothesis that naltrexone has a direct effect on the ability of stimuli to trigger drinking cannot explain why there was a difference between the two tests. The amount of naltrexone in the body would have been at least as high, if not higher, during V1 – when most patients were using naltrexone daily – than at V6 when most of the subjects were using naltrexone only infrequently. Instead it appears that extinction had produced a powerful and consistent reduction in the reported ability of the stimuli to trigger drinking. The results also supported the prediction from the extinction hypothesis that the weakening in the ability of stimuli to trigger drinking should occur for all sorts of stimuli (see Figure 9). The 6 stimuli with the most significant reductions (p<0.001) included two pleasant ones, two unpleasant ones, and two neutral ones.
Figure 9: The reduction in the strength of the connection between 101 different stimuli and drinking from the first visit, about 10 days after starting naltrexone, to the sixth visit, after about 100 days on naltrexone. Nearly every stimulus had a weaker connection to drinking after the additional 90 days of treatment: 36 showed significant (p<0.05) weakening. Of particular theoretical interest, naltrexone worked now only when alcohol might be causing pleasant effects (eg ‘I deserve this’) but also with unpleasant stimuli and neutral stimuli. This is contrary to the common belief that the naltrexone works by blocking the pleasure from alcohol, but it is consistent with the view that extinction weakens the connections from all sorts of stimuli to craving and drinking.
Continued benefits without the medication
The evidence from both preclinical and clinical studies shows that the suppression of alcohol drinking continues long after the last administration of the antagonist. This finding was reported in our first preclinical experiments (47). The rats did eventually return to their previous level of alcohol drinking, apparently because of relearning the behaviour since reinforcement was again obtained, but it took them from 4 days to 2 weeks. In the meantime, drinking was significantly suppressed even though no naloxone remained in the body. The continued efficacy is shown also in Figure 2 here. Alcohol was still significantly suppressed on both the first and second days after the last nalmefene administration (‘Post1’ and ‘Post2’). In an unpublished study (‘Continued Efficacy After Nalmefene Treatment’, used when applying for FDA approval of nalmefene), the first post-treatment access again to alcohol was a week after the last of 4 daily nalmefene injections (0.18 mg/kg subcutaneously); alcohol drinking was still significantly lower than in the saline-injected control animals. The report concluded, ‘The results indicate that treatment with nalmefene, as well as with naloxone, can have a continued efficacy for suppressing alcohol drinking, persisting after all of the antagonist has been eliminated’. The strong reduction in craving shown in Figure 1 is, after the first month or two of treatment, coming primarily from patients who did not have naltrexone in their systems at the time of being tested. At V6, about a quarter of the patients had stopped drinking completely and this, according to the instructions, they were not taking any naltrexone. The others were only taking naltrexone on days when they expected to drink, and in most cases, they had not been drinking or taking naltrexone on the weekdays when they visited the clinic. The result was still clearer in the 3-year follow up with the first naltrexone patients (48). The craving reported at this time was down to 1.4 cm on the VAS scale, which is significantly lower that the mean result of 2.2 cm reported back at V6 after about 100 days of treatment (see Figure 1). The patients in the follow up reported drinking (and taking naltrexone) at most only 1.4 times per week on average. So nearly all of the craving reports made in the follow up study were made by patients without any naltrexone in their systems. These results are important for clinical practice. If craving were only reduced when naltrexone was blocking opioid receptors, doctors should try to make sure that their alcoholic patients continue taking naltrexone every day for the rest of their lives. Fortunately this is not true. The craving remains suppressed, once it has been extinguished, so long as the patient does not drink without first taking naltrexone – and thus relearning the addiction. Consequently, doctors can advise patients that they only need to take naltrexone on the days when they are drinking. Since the patients are seldom drinking, they seldom take naltrexone; most of the time they merely have to carry it with them on the off chance that they might change their minds and decide to drink. This is, of course, both safer and less expensive than taking naltrexone every day.
There is no evidence indication that opioid antagonists have any effect on craving for alcohol in rats or alcoholics prior to the resumption of drinking. Although we cannot claim we know that opioid antagonists have no direct effect (prior to extinction) on the carving for alcohol, since that would be proving the null hypothesis, we can conclude that the data show if there is any such effect, it is too small to have a significant clinical influence on alcohol drinking.
Implications for treatment
The false belief that naltrexone directly blocks craving for alcohol has, we believe, been detrimental for the efficacious use of the medication. Most clinicians have a strong aversion to allowing their patients to drink while on naltrexone. They have throughout their career been telling alcoholics to abstain, and they want to continue telling alcoholics to abstain. Consequently, there is great resistance to the scientific evidence that naltrexone works through extinction because extinction requires the alcoholic to drink alcohol while naltrexone blocks the reinforcement. Clinicians would like naltrexone to block craving directly. If it did, then they could detoxify alcoholics, then instruct them to abstain, and still give them naltrexone at the same time to block the craving and help them remain abstinent. Maintaining the false belief that this is how naltrexone works has allowed clinicians to prescribe the medication in this manner that is of no benefit – and probably even of some detriment – to their patients. As a result of its being prescribed incorrectly ie. along with abstinence, the medication has often not been effective and has gained a poor reputation. This has contributed to very few alcoholics being prescribed naltrexone. An additional problem is poor compliance. Patients who are told that naltrexone will block their craving while they remain abstinent soon discover that they are still craving alcohol. They conclude that naltrexone does not work, since it did not produce the effect they were told to expect. Consequently, they are likely to stop using it without ever having paired it with drinking and benefitting from extinction. It is difficult to persuade clinicians to adopt a protocol that allows extinction. The belief that naltrexone blocks craving, without ever having to taste alcohol while on the medication, has provided clinicians with justification for prescribing naltrexone the way they want to: with abstinence. Opioid antagonists are unlikely to be used effectively for so long as clinicians believe that the presence of the medicine in the body is an effective tool for blocking the craving for alcohol – or for opiates.
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