Investigating Addiction Responses and Relapses

Researchers are finding that treatment of addictive behavior as a chronic illness rather than an acute illness, as is generally the case, results in lasting benefits. Charles P. O'Brien, M.D., Ph.D., and colleagues conducted a study examining evidence that drug and alcohol dependence is a chronic medical illness (McLellan et al., 2000). Genetic and environmental factors and adherence and relapse rates of drug dependence treatment were compared to that of type 2 diabetes mellitus, hypertension and asthma, and they were found to be similar. These results suggested that long-term care strategies of medication management and ongoing monitoring produce lasting benefits.

"We used to think that addiction was tolerance, withdrawal and physical dependence. This led a generation of physicians to withhold [medications] from people with pain," O'Brien said, adding that surveys of patients treated by oncologists show that 60% of them are not well treated for pain.

"The DSM-IVcalls it dependence, but I call it addiction," he added. "There are three definitions of dependence: personality, physical (which is the normal biological response and not addiction) and loss of control (which is addiction)."

O'Brien defined loss of control as greater intake than intended, encroachment on normal activities, unsuccessful efforts to control use and continued use despite problems.

Data from a study (Anthony et al., 1994) demonstrated that the nicotine in cigarettes has the highest rate of addiction of all drugs. This national survey found that 75.6% of the population sample had a history of tobacco use, with a 32% dependence rate.

O'Brien said that cigarette smoking causes 450,000 unnecessary deaths every year, dwarfing the number of deaths from illegal drugs and alcohol.

"It's the most addicting drug there is," O'Brien said. "And there's a lot more to this than just the biology. People see movie stars using it, so even if they get sick the first time, they keep on [smoking]. So there may be different exposure factors between legal and illegal drugs. It's really a set of multiple simultaneous variables, but in our society, nicotine is the most addicting."

O'Brien stressed that the major treatment difficulty lies not in getting people to stop smoking or using other harmful drugs, but in preventing their restarting.

"Our treatment programs focus on the first part. That's a waste of money-to just detox and not give long-term treatment," he said. "It's like diabetes: You wouldn't just treat it and send the patient home without continued treatment. [Addiction is] chronic. People go from acute abstinence syndrome to protracted abstinence, to being stable and drug-free-meaning they express no desire for the drug, but few people ever reach this [last] stage."

O'Brien and colleagues have concentrated on conditioned responses. The University of Pennsylvania Center for Studies of Addiction, of which O'Brien is the director, was the first to show that addiction produces conditioned responses that continue months or years after the last dose of a drug, thereby increasing likelihood of relapse.

The concept came from a study completed after the lead author observed that a heroin addict showed withdrawal symptoms that were probably conditioned after returning home from inpatient treatment (Wikler and Pescor, 1967). This phenomenon was investigated in rats by conditioning them to experience withdrawal after they had ceased taking drugs.

O'Brien said that the drugs people become addicted to are drugs that change affect and mental state and that the time frame for these changes depends on the drug and how rapidly that drug is mobilized.

"If you're dealing with a short-acting drug like nicotine, this [time frame] can all be collapsed," he explained. "Taking drugs by the lung is the most efficient. There is a perceptible effect with each puff, and there are many, many thousands of these before someone comes in for treatment. This is probably why our success rates for smoking addiction are the worst."

After quitting, environmental cues alone-such as smells or seeing drug paraphernalia-can produce the same biological ups and downs that addicts experience when they are using the substance.

One study showed that withdrawal can be induced just by pairing it in the laboratory with the odor of peppermint oil and later giving the odor alone (O'Brien et al., 1977). A number of physiological changes occur during this conditioned withdrawal, including drop in skin temperature and skin resistance, increased heart rate and blood pressure, tearing of the eyes, runny nose, nausea, and drug cravings.

In addition to cravings and autonomic responses, O'Brien explained that conditioned drug effects include changes in regional cerebral blood flow, regional brain metabolism and neurotransmitter release.

"Once memories like these are set up, they are there for a long time," he said. "Even when you fully extinguish it, you can easily reinstate it, so it never goes away. Therefore, addiction is a conditioned response."

O'Brien said that behavior therapy is effective but limited in treating addiction.

"We produced cravings in drug-free cocaine addicts [O'Brien et al., 1988], taught them behavioral tools and were able to cause the cravings to go down, but it's not really anything to write home about," he said. "Just behavioral therapy is not enough. We need [medications] to combine with it."

Animal studies have demonstrated that the reward system, especially the nucleus accumbens and the amygdala, is very important in addiction. To examine humans, his group has conducted brain imaging studies, wherein former addicts and controls view stimuli on a video screen while in a scanner.

In one such study of cocaine addicts (Childress et al., 1999), subjects were shown two videos: one of nature scenes and the other of people getting and using cocaine. The researchers measured and compared regional cerebral blood flow during both videos and during a resting state.

"Former addicts got cocaine cravings when we showed them the cocaine videos," reported O'Brien. "There was high blood flow in the amygdala, the temporal poles and the cingulate gyrus. The craving was so powerful that we had to have a talk-down procedure to prevent them from getting re-addicted when they left the laboratory."

Simultaneously, O'Brien's group did similar studies with former opiate addicts; the same brain structures seemed to be activated.

"What we're proposing here is that there's an association with reward and pleasure with use of these drugs, even with just thinking about them. People get conditioned to producing these responses with drugs...It's a primary response...They always want more and they're out of control."

This knowledge encouraged researchers to test medications that may help reduce the association between cues and these limbic brain structures. O'Brien noted progress made in medications that influence craving for nicotine, alcohol, opiates and cocaine.

O'Brien said alcohol, once thought to be very nonspecific, is a very complex drug that affects many systems.

A study by Altshuler et al. (1980) was done on a particular subset of monkeys who, unlike most monkeys, liked alcohol and would drink it avidly. When the monkeys were given naltrexone (ReVia), alcohol use dropped 70% to 80%.

In yet another series of studies in rats bred to like alcohol, drinking was blocked again when given this opiate antagonist (Volpicelli et al., 1986). Thus, the researchers proposed the hypothesis that alcohol releases endogenous opioids and that naltrexone blocks the opioid receptor.

Once resistance among clinicians to refer patients was overcome and the study was fully launched at the Philadelphia Veterans Affairs Medical Center, 70 male veterans with alcoholism were studied (Volpicelli et al., 1992). These day-hospital patient-subjects were randomly assigned to placebo or 50 mg/day naltrexone hydrochloride in adjunct to treatment following alcoholism detoxification. After one baseline week, subjects remained on the program for 12 weeks.

"If you take any alcohol drinking [as the measure], you'd say [the treatment] was a failure," said O'Brien, noting that approximately 60% of subjects on placebo drank some alcohol, as did 45% of subjects on naltrexone.

"I stress this because even today, that's the endpoint used in many studies-that one drink equals relapse-and as a clinician, I think that's irrelevant."

Using other criteria, however, revealed quite different results.

"We decoded craving and found most of the patients whose craving decreased had been randomized to naltrexone," explained O'Brien. "In terms of days drinking, patients on naltrexone reported leaving some [alcohol] on the bar-the first time they had ever done that-so naltrexone significantly reduced the amount they drank. And naltrexone patients reported a loss of subjective high, with placebo patients noting no change in the effects of alcohol."

The study defined relapse as having occurred when patients came to the treatment appointment with a blood alcohol concentration greater than 100 mg/dl; reported drinking five or more days within one week; and provided self-reports of drinking more than five drinks on one occasion.

In terms of the survival rate in the study, there was significantly less relapse with naltrexone; 90% on placebo relapsed compared to 40% of the naltrexone group. According to O'Brien, other supportive evidence shows that when people are not drinking as much, the liver tends to be healthier.

O'Brien's group conducted a study of naltrexone in 180 heavy drinkers, defined as having five or more drinks a day. Outcome measures, including clinical deterioration, were examined at three months, six months, nine months, 12 months and 18 months.

All subjects received psychotherapy; a third of the group received placebo throughout the study, a third received naltrexone for three months then placebo, and a third received naltrexone for nine months.

Results indicated that, after three months, there was far less heavy drinking in naltrexone subjects. Very few of these subjects showed any clinical deterioration. In the group for whom naltrexone was stopped, drinking and clinical deterioration soon caught up to the placebo group. The group who received the longer-term treatment with naltrexone, however, showed success that continued for months after the last dose of the medication.

Patient compliance was shown to be an additional factor in the effectiveness of naltrexone in an evaluation of 196 alcohol dependent outpatients treated with 50mg/day naltrexone or placebo for 12 weeks. Compliant patients showed relapse rates of 10% with naltrexone versus 38.6% with placebo, while rates for noncompliant patients were 42.9% with naltrexone and 40% with placebo (Pettinati et al., 2000).

Again, O'Brien stressed that abstinence, while an important eventual goal, should not be considered as the sole endpoint in measuring the success of addiction treatment.

"This is a chronic disorder, and our treatment program has to be long-term and be willing to deal with the slips and small relapses that occur among most patients," he said.

Visit the Charles O'Brien Center for Addiction Treatment website.

References:

References

1.

Altshuler HL, Phillips PE, Feinhandler DA (1980), Alteration of ethanol self-administration by naltrexone. Life Sci 26(9):679-688.

2.

Anthony JC, Warner LA, Kessler RC (1994), Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Experimental and Clinical Psychopharmacology 2(3):244-268.

3.

Childress AR, Mozley PD, McElgin W et al. (1999), Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156(1):11-18.

4.

McLellan AT, Lewis DC, O'Brien CP, Kleber HD (2000), Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 284(13):1689-1695.

5.

O'Brien CP, Childress AR, Arndt IO et al. (1988), Pharmacological and behavioral treatments of cocaine dependence: controlled studies. J Clin Psychiatry 49(suppl):17-22.

6.

O'Brien CP, Testa T, O'Brien TJ et al. (1977), Conditioned narcotic withdrawal in humans. Science 195(4282):1000-1002.

7.

Pettinati HM, Volpicelli JR, Pierce JD Jr, O'Brien CP (2000), Improving naltrexone response: an intervention for medical practitioners to enhance medication compliance in alcohol dependent patients. J Addict Dis 19(1):71-83.

8.

Volpicelli JR, Alterman AI, Hayashida M, O'Brien CP (1992), Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 49(11):876-880 [see comments].

9.

Volpicelli JR, Davis MA, Olgin JE (1986), Naltrexone blocks the post-shock increase of ethanol consumption. Life Sci 38(9):841-847.

10.

Wikler A, Pescor FT (1967), Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid-drinking behavior and "relapse" in morphine-addicted rats. Psychopharmacologia 10(3):255-284.