Marijuana is the number one illegal drug of abuse in the United States; in second place is the nonmedical use of prescription medications such as pain relievers, tranquilizers, stimulants and sedatives. The National Institute on Drug Abuse is intensifying its research in understanding mechanisms that underlie the reinforcing, addictive and toxic properties of prescription medications, and developing medications with less abuse potential.
Alarmed by escalating abuse of prescription drugs during the past five years, the National Institute on Drug Abuse (NIDA) is intensifying its research in two areas--understanding mechanisms that underlie the reinforcing, addictive and toxic properties of the drugs and developing medications with less abuse potential.
Marijuana is the number one illegal drug of abuse in the United States; in second place is the nonmedical use of prescription medications such as pain relievers, tranquilizers, stimulants and sedatives, said NIDA director Nora D. Volkow, M.D., at a recent National Institutes of Health lecture (Volkow, 2004).
"[We] need to explore why it is that we are observing such a high abuse of these medications, and how can we prevent the abuse," she said.
According to newly released findings from the 2003 National Survey on Drug Use and Health, an estimated 6.3 million people (2.7% of the population aged 12 or older) currently use psychotherapeutic drugs nonmedically. An estimated 4.7 million use pain relievers, 1.8 million use tranquilizers, 1.2 million use stimulants and 0.3 million use sedatives (Substance Abuse and Mental Health Services Administration [SAMHSA], 2004).
Particularly worrisome for NIDA is the dramatic increase in the use of opioid painkillers.
"From 1995 until now, [there has been] almost a threefold increase in the abuse of these substances," Volkow said. The steep increase is especially unsettling, because there has been a decrease in abuse of most illegal drugs during the past few years.
National Survey on Drug Use and Health researchers recently stated that the number of Americans aged 12 or older who reported having ever taken a prescription pain medication for recreational use rose from 29.6 million in 2002 to 31.2 million in 2003. Pain relievers with statistically significant increases in lifetime use included such hydrocodone-combination products as Vicodin, Lortab or Lorcet (from 13.1 million to 15.7 million); such oxycodone-combination products as Percocet, Percodan or Tylox (from 9.7 million to 10.8 million); hydrocodone (from 4.5 million to 5.7 million); the oxycodone product OxyContin (from 1.9 million to 2.8 million); methadone (from 0.9 million to 1.2 million); and tramadol (Ultram) (from 52,000 to 186,000) (SAMHSA, 2004).
The 2003 Monitoring the Future Survey--a survey that assesses the extent and perceptions of drug use among 8th, 10th and 12th grade students nationwide--revealed that 10.5% of high school seniors had used Vicodin for recreational use during the past year and 4.5% had used OxyContin (NIDA, 2004).
"We are dealing with not only a problem of the abuse and diversion of these substances, but we are dealing with toxic compounds," Volkow said. "Opioid analgesics can produce death from overdose."
From 2001 to 2002, drug abuse-related emergency department (ED) visits involving narcotic analgesics increased 20% (from 90,232 to 108,320 visits), with hydrocodone and oxycodone being the narcotic analgesics most frequently mentioned (Drug Abuse Warning Network, 2004). Looking at motives underlying drug abuse-related ED visits involving narcotic analgesics, dependence headed the list (47%; 50,623 visits), followed by suicide (22%; 24,308 visits), psychic effects (15%; 16,153 visits), other motives (2%; 1,790 visits) and unknown motive (14%; 15,446 visits).
The reason that alcohol; cocaine; marijuana; heroin or prescription medications such as opioid analgesics, benzodiazepines or stimulants can produce addiction is that all of them have a common characteristic. They increase the concentration of dopamine, Volkow pointed out in her lecture. Methylphenidate (Ritalin, Concerta, Metadate), for example, increases the synaptic concentration of dopamine by blocking the dopamine transporters.
Volkow was among the first researchers to use positron emission tomography (PET) to investigate the nature of acute brain changes in dopamine activity induced by drugs of abuse as well as long-term brain changes in dopamine activity and the functional consequences of these changes in drug-addicted subjects (Volkow et al., 2004a, 2004b).
Such studies, she explained, have corroborated the role of dopamine in the rewarding effects of drugs of abuse in humans and also its involvement in motivation. Imaging studies have shown that the reinforcing effects of drugs of abuse in humans are contingent upon large and fast increases in dopamine that mimic but exceed in the intensity and duration those induced by dopamine cell firing to environmental events (e.g., food, sex, social interaction). In addition, imaging studies have documented a role of dopamine in motivation, which appears to be encoded by fast as well as smooth dopamine increases. Since dopamine cells fire in response to salient stimuli, the supraphysiological activation by drugs is likely to be experienced as highly salient (driving attention, arousal, conditioned learning and motivation) and may also reset the thresholds required for environmental events to activate dopamine cells (Volkow et al., 2004b).
In a recent article, Volkow et al. (2004b) explained that dopamine function is markedly disrupted in drug-addicted individuals. There are decreases in dopamine release and in dopamine D2 receptors in the striatum. This hypodopaminergic state may lead to deregulation of reward, motivation and inhibitory control circuits.
"So what happens when that individual who is addicted is exposed to a natural reinforcer such as food or sex? Well, the amount of dopamine to start with is significantly reduced, and then the receptors are also lower. Therefore, the probability of an interaction of dopamine with a receptor is significantly decreased, and the likelihood of a person who is addicted to perceive a natural reinforcer as pleasant is going to be dramatically affected ... They won't be motivated for basic, natural reinforcers," she said in the lecture.
On the other hand, an addicted person will be motivated by the drug of abuse. "That is one of the basic changes that trigger the aberrant behavior that you see in a person who is addicted," Volkow said. Such behavior is "the compulsion to take the drug, despite the fact there are severe, adverse consequences," she added.
"If [psychotherapeutic] prescription medications have the potential for producing abuse and addiction, why don't they do it frequently?" Volkow asked. The answer lies in the fact that the drug's effects are not just a function of the drug itself but other factors such as dose, frequency of dosing, route of administration, expectations and context of administration.
Volkow cited the example of a patient being prescribed a stimulant for attention-deficit/hyperactivity disorder and being told to take three tablets a day or 10 mg of the drug every three hours. If the patient is addicted to cocaine or methylphenidate, the patient will likely take it every 30 minutes at 30 mg doses.
"When individuals abuse methylphenidate, they don't take it in a tablet, they inject or snort it. The route of administration determines the speed by which the drug gets into the brain," she said. If individuals inject intravenous methylphenidate, "they will feel a high, which cocaine abusers say is indistinguishable from that they get with intravenous cocaine. However, when you give them oral methylphenidate, they don't feel anything, even though you may be delivering as high a dose as when delivered intravenously."
The effects of expectation on brain responses to drugs of abuse also have been studied. In drug abusers, the subjective responses to a drug are more pleasurable when the person expects to receive the drug than when they do not. Volkow cited an imaging study she and colleagues conducted examining the response of brain glucose utilization to intravenous methylphenidate in cocaine abusers under distinct conditions of expectation and no expectation (Volkow et al., 2003).
Four conditions were tested: 1) individuals expected and received methylphenidate; 2) individuals expected methylphenidate but received placebo; 3) individuals expected placebo but received methylphenidate; and 4) individuals expected and received placebo.
The increases in metabolism were approximately 50% larger when methylphenidate was expected than when it was not, and these differences were significant in the cerebellum (vermis) and thalamus. Methylphenidate-induced increases in self-reports of "high" were also approximately 50% greater when subjects expected to receive it than when they did not.
Studies have also shown that a drug's effects are influenced by the context in which it was given, for example, school versus party environment. Volkow cited a study where methylphenidate was administered while individuals were in a boring context as compared to when they were in an exciting context (Volkow et al., 2004c). Dopamine increases were larger when methylphenidate was given with a task that required cognitive performance that was remunerated than when it was given with a task that did not require performance and was not remunerated.
In looking at other factors influencing the abuse of prescription medications, Volkow pointed to the tremendous increase in availability, media coverage and the World Wide Web. "Prescriptions for stimulant medications, for example, have doubled every five years over the past 15 years," she said. "Last year, one of the most frequently prescribed drugs in this country was Vicodin. So the increase in prescribing has contributed to the increased availability of these drugs."
Awareness of the drugs has increased through television advertisements and such magazine stories as Newsweek's "Ritalin: Are We Overmedicating Our Kids?" and the New York Times' "The OxyContin Underground: How a Prescription Painkiller is Turning Into a Pernicious Street Drug," she added.
"The Web, of course, is a very valuable tool in terms of disseminating information," Volkow said. "Unfortunately, it [also] is a valuable tool for the diversion of drugs. If you go to Google tonight and enter 'prescription drugs' and then enter 'prescription drugs, no prescription required,' you will get thousands of sites where you can actually get prescription medications without the need for a prescription ... The only thing you need is a credit card number. You could be 10 or 12 years of age, nobody will check that ... Now we have access to these pharmacies, many of them illegal and many of them in other countries where the quality control of the medications cannot be assured, increasing the likelihood of toxicity."
What is the role of NIDA in fighting prescription drug abuse? Volkow said, "We have a multi-target approach that involves multiple projects."
These projects include developing medications to treat the problem of addiction to opioid analgesics; developing medications that can treat pain but do not have the abuse potential; and educating the public and health care professionals about prescription drug abuse.
Volkow noted that NIDA has launched a very large educational campaign to alert the public and health care professionals on the most frequently prescribed drugs that have the potential for abuse and to provide them resources for more information such as NIDA's Web site .
According to Volkow, one of the initiatives they are pushing to do with their sister agencies, SAMHSA and the Office of National Drug Control Policy, is the education of physician specialists about the dangers of narcotic analgesics and proper management of pain. Many specialists believe that if an opioid analgesic is given for pain, the patient is not going to become addicted.
"That is what they teach you in medical school," Volkow said. "That's true if they give you the opioid analgesic for a very short period of time, such as one week. The problem starts when an opioid analgesic is given for a chronic condition such as back pain. Anywhere from 5% to 7% of people prescribed opioid analgesics for chronic pain are going to become addicted. So there is this false belief that you are not going to become addicted if you have pain, and that has led some physicians to prescribe opiates much more than they should."
On the other hand, Volkow said, we have also been hearing for many years about patients with severe pain who never get the proper medications and as a result suffer a lot of handicaps. To help, NIDA is promoting the development of compounds that have analgesic properties yet are not addictive.
Non-Addictive Pain Treatments
Frank Vocci, Ph.D., NIDA's director of the Division of Pharmacotherapies and Medical Consequences of Drug Abuse, told Psychiatric Times that NIDA is looking at drugs that are cannabinoid agonists. Cannabinoids diminish responses to painful stimuli. There are two types of cannabinoid receptors, according to Vocci: CB1 receptors are found in the brain, while CB2 receptors are found primarily in peripheral tissues with immune functions. Through the research of medicinal chemist Alexandros Makriyannis, Ph.D., of Northeastern University, NIDA is exploring whether CB2 receptor agonists may hold the promise for medical treatment of pain without central nervous system effects. The research is still in the preclinical stage.
There is another project with a drug called resiniferatoxin (RTX) that has been shown to be effective for treatment of severe pain in several animal models, Vocci said. "Hopefully, we will have clinical studies in 2005. We are in the final stages of discussing this with the [U.S. Food and Drug Administration]. A package has been sent to them, and we are going to have a conference with them about this," he added. The medications will be tested in terminal cancer patients for whom opiate analgesics no longer provide pain relief.
The lead researcher on that study is expected to be Andrew Mannes, M.D., anesthesiologist at NIH's Warren Grant Magnuson Clinical Center.
For individuals suffering from chronic pain, who have become addicted to opioid analgesics, NIDA is evaluating alternative medications.
"NIDA has developed buprenorphine [Subutex or Suboxone when combined with naloxone] that has much less potent effects than heroin, morphine or Demerol [meperidine]," said Volkow. "It is an opiate that has analgesic properties. We are going to be launching a large clinical trial to evaluate the benefit of this medication in the treatment of individuals who have pain but are also addicted to opiate analgesics."
According to Vocci, the protocol for the clinical trial is being developed. The trial is expected to be underway in the summer of 2005.
Vocci was asked what other medications besides buprenorphine are being developed to treat problems of addiction to opioid analgesics. One approach is a "depot" formulation of naltrexone (ReVia), an opiate receptor antagonist. The oral form of naltrexone is indicated for use in the treatment of alcohol dependence and for the blockade of exogenously administered opioids.
The depot formulation, currently being studied for treatment of alcoholism, was studied by NIDA for opiate addiction. "We actually funded three separate companies to do research on it," Vocci said, and at least one of the companies is clearly working toward a drug application with the FDA.
Another drug being developed with NIDA's help is called lofexidine. Lofexidine is an -2 adrenergic agonist that is increasingly used in the management of opiate withdrawal--notably in the United Kingdom.
"We have done one major clinical trial with it, and we are going to help a company develop a second major clinical trial," Vocci said. "We will start between April and June of 2005. The sites are still being picked, and we are determining who the lead researcher will be."
Vocci was asked what psychiatrists could be doing to help reduce prescription drug abuse. He said they need to "be aware of the addiction potential of certain drugs," and they could become more educated about dealing with individuals who have histories of drug abuse, adding that he would like to see more psychiatrists move into treatment of addictions as a subspecialty.
For physicians, generally, Vocci said they need to identify patients with prior histories of any kind of substance abuse. If years ago a patient drank too much or abused amphetamines or other drugs then that patient may have problems with prescription opiates.
Urine monitoring is also an aid. "Oftentimes, people who abuse prescription drugs take them by mouth, so they don't have track marks or other stigmata of using drugs. They may appear healthier looking that those who inject drugs, yet they may be taking large amount of prescription opiates," Vocci said. "Use of urine drug monitoring might keep them more honest."
Physicians also need to assess what is actually going on with patients and whether patients actually need narcotics for a certain duration. Look for patterns that do not match the clinical situation, Vocci advised. For example, patients who postoperatively should be gradually feeling better yet they ask their physicians to increase their dose of painkillers.
If a physician feels a patient is developing chronic pain problem or addiction to medication, Vocci suggested the physician consider referring the patient to a chronic pain specialist.
Volkow was asked during her lecture about the role of 12-step groups, given the biochemical underpinnings of addiction. She explained that when individuals become addicted to illicit or prescription drugs, they often lose their jobs and their families and start to isolate themselves. The biochemical changes in their brains make them much less sensitive to natural reinforcers, and they become socially isolated.
"Basically, the addicted individuals are cornered into the utilization of drugs as the only mechanism by which they can escape the state of discomfort," she said. "But bringing them to [Alcoholics Anonymous], you are doing a therapeutic intervention. Why? One of the most powerful social drives we have as humans is that of belonging to a group," she said. "You are giving the individual an alternative behavior other than the drug. Also, you are decreasing the stresses associated with the loss of control that they feel vis-à-vis their intake of the drug. So those two components are likely to play an extremely important role in helping the person who is addicted to overcome the compulsion to take drugs."
Drug Abuse Warning Network (2004), The DAWN Report: Narcotic Analgesics, 2002 Update. Available at: http://dawninfo.samhsa.gov/old_dawn/pubs_94_02/shortreports/
files/DAWN_tdr_na2002.pdf. Accessed Dec. 16.
NIDA (2004), NIDA InfoFacts: Prescription Pain and Other Medications. Available at: www.nida.nih.gov/infofax/painmed.html. Accessed Nov. 22.
SAMHSA (2004), Overview of Findings from the 2003 National Survey on Drug Use and Health (NSDUH Series H-24, DHHS Publication No. SMA 04-3963). Rockville, Md.: Office of Applied Studies.
Volkow ND (2004), Addiction to medications: what are the risks and who is vulnerable? NIH Clinical Center, Medicine for the Public: 2004 Lecture Series. Available at: http://videocast.nih.gov/PastEvents.asp?c=55. Accessed Nov. 16.
Volkow ND, Fowler JS, Wang GJ (2004a), The addicted human brain viewed in the light of imaging studies: brain circuits and treatment strategies. Neuropharmacology 47(suppl 1):3-13.
Volkow ND, Fowler JS, Wang GJ, Swanson JM (2004b), Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry 9(6):557-569.
Volkow ND, Wang GJ, Fowler JS et al. (2004c), Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain. Am J Psychiatry 161(7):1173-1180.
Volkow ND, Wang GJ, Ma Y et al. (2003), Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers. J Neurosci 23(36):11461-11468.