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11 Prescription Drug abuse

NN0084 Introduction

The National Institute on Drug Abuse (NIDA) supports most of the world’s research on drug abuse and addiction. NIDA-funded research enables scientists to apply the most advanced techniques available to the study of every aspect of drug abuse, including:

• genetic and social determinants of vulnerability and response to drugs; • short- and long-term effects of drugs on the brain, including addiction; • other health and social impacts of drug abuse, including infectious diseases and economic costs; • development and testing of medications and behavioral treatments for abuse and addiction; and • development and evaluation of effective messages to deter young people, in particular, from abusing drugs.

Included in this document are selections of topic-specific articles reprinted from NIDA’s research newsletter, NIDA NOTES. Six times per year, NIDA NOTES reports on important highlights from NIDA-sponsored research, in a format that specialists and lay readers alike can read and put to use. Selections like the current one are intended to remind regular NIDA NOTES readers and inform other readers of important research discoveries during the periods they cover.

We hope the information contained here answers your needs and interests. To subscribe to NIDA NOTES and for further information on NIDA’s drug abuse and addiction research, please visit our Web site at www.drugabuse.gov.

ii Table of Contents

Basic Science Discoveries Yield Novel Approaches to Understanding the Risks of Prescription Drug Abuse Analgesia (V22-1; September 2008)...... 1 (V16-3; August 2001)...... 33 -Induced Immunosuppression, From Brain to Research Eases Concerns About Use of To Spleen (V21-6; June 2008)...... 6 Relieve Pain (V15-1; March 2000)...... 35 Alcohol Abuse Makes Prescription Drug Abuse More NIDA Researchers Developing Problem-Free Pain Likely (V21-5; March 2008)...... 9 Relievers (V12-6; November/December 1997)...... 37 Chromosome 17 Harbors Dependence Genes UNC Scientist Searches for Effective with (V21-5; March 2008)...... 11 Low Abuse Potential (V11-3; May/June 1996)...... 40 Teen Substance Abuse Continues to Decline NIDA Research Expands Horizon for Analgesia (V21-5; March 2008)...... 13 Alternatives (V11-2; March/April 1996)...... 41 Controlling College Students’ ADHD Symptoms Scientists Explore Novel Approaches to Pain Control May Protect Them Against Substance Abuse (V11-2; March/April 1996)...... 43 (V21-4; October 2007)...... 15 Meeting Reviews Progress On Prescription Opioid Misuse (V21-3; April 2007)...... 16 Plus Behavioral Therapy Is Effective For Adolescents With Opioid Addiction (V21-1; October 2006)...... 17 First-time Patients Opt for Office-Based Buprenorphine (V21-1; October 2006)...... 19 High School Seniors Steadily Increase Nonmedical Use of Sedatives Over 15 Years (V21-1; October 2006)...... 20 NIDA and Scholastic Offer Teens and Teachers New Heads Up (V20-4; March 2006)...... 21 Studies Identify Factors Surrounding Rise in Abuse of Prescription Drugs by College Students (V20-4; March 2006)...... 23 NIDA Responds to Changing Drug Abuse Patterns (V20-2; August 2005)...... 25 Confronting the Rise in Abuse of Prescription Drugs (V19-5; January 2005)...... 27 2003 Survey Reveals Increase in Prescription Drug Abuse, Sharp Drop in Abuse of Hallucinogens (V19-4; December 2004)...... 29 Facts About Prescription Drug Abuse and Addiction (V16-3; August 2001)...... 30 NIDA Scientific Panel Reports on Prescription Drug Misuse and Abuse (V16-3; August 2001)...... 31

iii iv Research Findings Volume 22, Number 1 (September 2008)

Basic Science Discoveries Yield Novel Approaches to Analgesia Innovations Research on glial cells and receptors leads to compounds that outperform morphine in preclinical trials.

By Lori Whitten, NIDA NOTES Staff Writer

For millennia, opioid medications have provided the most The Glial Strategy potent tools for pain relief. Yet, although they are the best Dr. Watkins’ research team, in collaboration with we have, opioids fall short of being ideal analgesics: They Dr. Kirk W. Johnson and colleagues at Avigen Inc. of have unpleasant side effects, their efficacy diminishes with Alameda, California, recently relieved neuropathic pain ongoing use, they cause physical dependence, and they in rats by giving them AV411 (also called ibudilast; see pose significant risks for abuse and addiction. Moreover, “AV411 for Pain Relief Without Opioid Side Effects” opioids do not quell all types of pain. For example, they on next page), a compound that inhibits glial cell activ- provide only partial, often temporary relief to people with ity. In other animal studies by Dr. Watkins and other neuropathic pain, which commonly develops when disease researchers, various compounds that inhibit glial cells have or trauma injures nerves and typically produces burning, reduced or abolished pain that simulated many types of stinging, or tingling that doesn’t cease. human chronic neuropathic pain. They also have boosted NIDA-supported research teams are advancing along eight-fold the acute pain relief afforded by morphine. separate paths to develop new compounds that match or Dr. Watkins and colleagues discovered the exceed the pain relief provided by opioids while avoiding potential of glial cell inhibition through pioneering their shortcomings. Dr. Linda R. Watkins and colleagues research that implicates glial cells in the amplification at the University of Colorado at Boulder are pursuing the and long-term maintenance of pain. Their investigations implications of their discovery that glia—nonneuronal showed that tissue or nerve inflammation or damage that nervous system cells—play a previously unrecognized is associated with neuropathic pain heightens activity of key role in the generation of neuropathic pain and in two types of glial cells—microglia and astrocytes—in the spinal cord. The activated glia release biochemicals—including proinflamma- tory cytokines and chemokines, nitrous oxide, and prostaglandins—that excite spinal cord neurons to transmit strong and persistent pain signals to the brain. The finding that glial cells modulate pain in the spinal cord prompted the researchers to explore glial cell inhibi- tion as a broad strategy for controlling many types of pain. Adapted from: Experimental Neurology 80(1):1-13, 2003. Dr. Watkins’ findings extend the roster After spinal cord damage, glial cells called astrocytes proliferate and expand. of important functions attributed to glial cells. It was previously known, for example, that glia maintain hospitable opioid tolerance and withdrawal. Dr. Philip S. Portoghese microenvironments for neurons and provide them with and collaborators at the University of Minnesota and molecular support for carrying out their cellular functions. Louisiana State University are tinkering with opioid mole- Another glial cell activity, clearing cellular debris away cules to capitalize on recent findings showing that opioids from neurons, can last for years—a fact, the researchers produce pain relief by mechanisms separate from those suggest, that may have important implications for the long that produce their less desirable effects. During the past duration of chronic pain. year, both groups have reported highly promising results.

1 Enhancing Opioids And Making Them Safer AV411’s ability to enhance opioid efficacy could be espe- Working with researchers at the University of Adelaide cially valuable for chronic pain patients with histories of in Australia, Avigen has completed an exploratory clini- drug abuse. At a NIDA-sponsored panel at the annual cal trial to test AV411 in patients with neuropathic pain. Society for Neuroscience meeting on November 2, 2007, Patients in the study, who were predominantly diagnosed Dr. Watkins reported preliminary results suggesting that with painful diabetic neuropathy, received fixed regimens the medication counters the opioid-induced reward sensa- of AV411 as well as concomitant analgesics, including tions that can raise such patients’ risk for relapse. Using opioids. Preliminary results indicated that patients receiv- an established experimental model to assess reward, the ing AV411 reduced their opioid use, suggesting that researchers repeatedly infused rats with morphine in a test AV411 relieved pain or reduced opioid tolerance. chamber, then let the animals decide whether to spend time in that chamber or another. The idea that glial modulatory compounds might counter- act opioid tolerance emerged from studies to understand Rats that had been pretreated with AV411 spent roughly the biochemical basis for that phenomenon. In experi- equal amounts of time in both chambers; their lack of ments with animals, Dr. Watkins’ team demonstrated preference for the test chamber suggests that the mor- that opioids, like neuropathy, stimulate glial cells to phine experience was not rewarding for them. In a related release substances that in turn incite spinal cord neurons study at the University of Colorado-Boulder, spearheaded to amplify pain signaling. This response combines with by Dr. Sondra T. Bland, AV411 suppressed—by about the neuroexcitatory glial response triggered by neuropathy half—a biochemical signature of drug reward, the itself to offset the opioid’s analgesic efficacy. morphine-induced dopamine surge in rats’ nucleus

2 accumbens. This research is the first to demonstrate a rela- Dr. Watkins. In addition to working with AV411, Dr. tionship between glial cell activity and opioid reward. Watkins and colleagues are collaborating with Dr. Kenner The pharmacological action that underlies AV411’s Rice of NIDA to create and test highly specific TLR4 beneficial effects against pain, as well as its influence on antagonists that may maximize the potential of this opioid reward and tolerance, appears to be partial inhibi- pharmacological action. tion of a particular receptor on glial cells. This receptor, “Our findings suggest that suppressing glial activation called TLR4, is a member of a family of receptors called with AV411 will help relieve neuropathic pain, as well as toll-like receptors (TLRs). TLR4s sit on the surface of the other types of pain, and also reduce feelings of pleasure glial cells and detect external dangers, such as bacteria; from opioids that drive craving and drug-seeking among some also respond to indicators of tissue damage, such abusers,” says Dr. Watkins. “Our results, when taken as bits of dead cells. Once activated, TLR4s trigger an together with the findings of other researchers, suggest immune response to combat the invader that caused the that AV411 inhibits the cascade of molecular events sur- tissue damage. Dr. Mark R. Hutchinson’s research in Dr. rounding nerve damage in the body as well as the inflam- Watkins’ laboratory suggests that TLRs are also the sites matory response in the brain. AV411 successfully reaches where opioids and nerve damage converge to trigger glial the brain, whereas other inflammation inhibitors do cell responses that amplify and maintain long-lasting pain, not, which likely contributes to its beneficial effects in as well as a likely site where opioids prompt the responses animals.” by glia that enhance opioid reward and tolerance. Dr. David Thomas of NIDA’s Division of Basic “Blocking TLR4 separates morphine’s good and bad Neuroscience and Behavioral Research notes that the effects, and my colleagues and I believe that drugs that results of this animal research look promising. “But clini- block TLR4 will prove to have great clinical utility cal studies are needed to determine whether AV411 will both for making morphine better for pain control and provide relief for people with neuropathy,” he adds. as standalone drugs for treating neuropathic pain,” says

3 Building Better Opioids To create improved opioids, Dr. Portoghese and collabo- rators at the University of Minnesota and Louisiana State University are using newly discovered details about the receptors through which opioids exert their effects on neu- rons. The team’s recently designed compounds provided more pain relief than morphine, and their analgesic effect did not diminish after repeated administration in labora- tory tests. Mice given the compounds also showed no behavioral signs of physical dependence. The researchers’ design strategy is to construct single com- pounds that target both components of a particular dual- . Specifically, the compounds stimulate the mu component and inhibit the delta component of the mu-delta dimer, or linked-pair, receptor. and colleagues recognized that targeting dimers, rather Dual—or dimeric—receptors are a recent discovery. than two independent receptors, could capitalize on the Neuroscientists long supposed that all receptors were sin- special response characteristics of a dimer and balance mu gular entities. The finding that some receptors form pairs activation and delta inhibition. opened up new possibilities for medication development. Each molecule in the team’s new class of opioids compris- Scientists observed that when a specially designed two- es a mu agonist molecule and a delta antagonist molecule part compound simultaneously engages both receptors in linked by a chain of atoms called a spacer (see diagram, a linked pair, the cell reacts differently than when either above). The compounds are called mu-delta agonist-antag- receptor unit is triggered singly. onists, or MDANs. To maximize efficacy, the team sought In fundamental research conducted in the 1990s, Dr. spacer lengths such that once the first molecule settles Portoghese and colleagues set the stage for the develop- into its docking area on the dual receptor, the second has ment of a new class of opioids. The results of an animal just enough chain to reach its docking area. In the experi- study showed that simultaneous stimulation of the mu ments, this criterion was met by a spacer length of 16 to receptor by one compound and inhibition of the delta 21 atoms, and the researchers designated the compounds, receptor by another produced less tolerance and depen- accordingly, MDAN-16 through MDAN-21. Taking dence than mu receptor stimulation alone. With the sub- these compounds into the laboratory, they observed that: sequent discovery of linked-pair receptors, Dr. Portoghese • Several MDANs blunted pain. Infusions of MDAN-16 through -21 directly into the brain increased the time that mice could withstand heat from a strong light beam on their tails. MDAN-21’s analgesic potency was 50-fold that of morphine. • After chronic exposure to MDAN-19, -20, or -21, the mice developed only minimal signs of physical depen- dence. The researchers delivered infusions of either saline, morphine, or an MDAN into the brains of mice for 3 days and the next day pharmacologically precipitated withdrawal. The mice on MDANs exhib- ited fewer withdrawal symptoms ( jumps) than those on morphine. Generally, mice given MDAN-19, -20, or -21 made the fewest jumps. • Chronic administration of MDAN-19, -20, or -21 did not induce tolerance to the compound’s pain-killing effects. Animals maintained on these MDANs via infusions for 3 days demonstrated pain relief from a new dose delivered 4 hours after the final infusion. In contrast, morphine’s pain-killing effects dropped six- fold in the same experimental protocol.

4 • MDAN-19 and MDAN-21 show minimal potential Sources for abuse and have little potential to induce a return to • Hutchinson, M.R., et al. Opioid-induced glial acti- drug-seeking. In a standard behavior test, mice increased vation: Mechanisms of activation and implications their drug-seeking after receiving morphine but not for opioid analgesia, dependence, and reward. The after receiving MDAN-19 or MDAN-21. Other Scientific World Journal 7:98-111, 2007. experiments (see graph, opposite page) suggest that the new compounds are unlikely to induce relapse among • Ledeboer, A., et al. The glial modulatory drug AV411 people recovering from opioid addiction. attenuates mechanical allodynia in rat models of neu- ropathic pain. Neuron Glia Biology 2:279-291, 2007. “Dual-component compounds and dimers open up a new and exciting universe in medication development,” says • Ledeboer, A., et al. Ibudilast (AV-411): A new class Dr. Portoghese. “My colleagues and I believe that there therapeutic candidate for neuropathic pain and opioid may be other combinations of opioid receptors that when withdrawal symptoms. Expert Opinion on Investigative stimulated with such compounds might alleviate pain Drugs 16(7):1-16, 2007. without tolerance and dependence.” • Lenard, N.R., et al. Absence of conditioned place “Dr. Portoghese’s results suggest that MDAN compounds preference or reinstatement with bivalent ligands could form a single drug with two functions—alleviation containing mu-opioid receptor agonist and delta- of pain and reduction of withdrawal, tolerance, and opioid receptor antagonist pharmacophores. European side effects,” says Dr. Paul Hillery of NIDA’s Division Journal of Pharmacology 566(1-3):75-82, 2007. of Basic Neuroscience and Behavioral Research. “The • Daniels, D.J., et al. Opioid-induced tolerance and MDAN compounds are also useful tools for investigators dependence in mice is modulated by the distance who study how stimulating the receptor complexes acti- between pharmacophores in a bivalent ligand series. vates or inhibits neurons.” Proceedings of the National Academy of Sciences 102(52):19208-19213, 2005.

5 Research Findings Volume 21, Number 6 (June 2008)

Morphine-Induced Immunosuppression, From Brain to Spleen Morphine sets off a chain of biological events that stifles the immune response.

By Lori Whitten, NIDA NOTES Staff Writer

Morphine and other opioids suppress the immune system, in the brain—a surge of dopamine into the NAc—averts the body’s innate defense against infections. Because of suppression of NK cells in the spleen. This being the case, this effect, doctors weigh the pain-relief benefits of opioids the researchers reasoned that morphine-induced NK sup- against the added risk of infection they pose to patients, pression must start with something that dopamine does in particularly those being treated for severe burns or certain the NAc. cancers. Opioid abusers, many of whom are already infec- Dopamine’s main action in the NAc is to interact with tion-prone due to unclean needles, repeated injections, proteins called dopamine receptors, which come in several and poor nutrition and living conditions, are rendered subsets—D1, D2, for example. Accordingly, Dr. Lysle and even more vulnerable by these drugs. colleagues conducted experiments to determine whether Morphine affects the body’s immune cells in many ways, any of these receptors were involved in morphine inhibi- both direct and indirect. Recently, NIDA-funded sci- tion of NK cells. They began by giving rats morphine (15 entists pinpointed the biochemical trigger that sets off a mg/kg) or saline. One hour later, they measured NK cell chain reaction that ultimately inhibits an immune cell that activity in the animals’ spleens and found it to be lower by is key in fighting viruses and cancer. If validated in future studies, the work could lead to interventions to bolster the immunity of those who regularly take opioids.

Morphine, Dopamine, And Natural Killers Morphine suppresses the activity of three different types of white blood cells: T lymphocytes, B lymphocytes, and natural killer (NK) cells (see box). NIDA-funded investigators Dr. Donald Lysle, Dr. Timothy Saurer, and their colleagues at the University of North Carolina (UNC), Chapel Hill, concentrated on NK cells, and found that: • morphine-induced immunosup- pression follows activation of dopamine-1 (D1) receptors in the shell of the nucleus accumbens (NAc); and • a train of biochemical events links stimulation of these D1 receptors with reduced NK cell activity in the spleen. In previous studies, the UNC team had established that blocking one of morphine’s pharmacological effects

6 about 40 to 50 percent, on average, among the morphine- might modulate natural killer activity and perhaps the exposed animals, compared with those given saline. They suppressive effects of morphine in rats.” then conducted a series of trials that showed: The investigators confirmed their hypothesis with an • Morphine-induced NK cell suppression depends on experimental strategy parallel to the one they had used to the activation of D1 receptors. Rats injected with a link the brain’s D1 receptors to morphine-induced NK compound (SCH-23390) that prevents dopamine cell immunosuppression: They showed that neither NK from accessing D1 receptors did not develop immu- cell inhibition induced by morphine nor D1-related NK nosuppression when subsequently injected with mor- inhibition occurs when NPY is prevented from interact- phine. In contrast, rats pretreated with a compound ing with its main receptor (Y1) (see graph, first page of (raclopride) that blocks D2 receptors did lose NK article). cell activity. The researchers next wondered whether Y1 receptor acti- • Specifically, D1 receptors that reside in the part of the vation might underlie suppression of other white blood NAc called its shell must be activated for morphine NK cells as well as suppression of NK cells. To find out, they cell suppression to occur. Morphine inhibition of NK stimulated rats’ Y1 receptors with injections of NPY (20 or cell activity was abolished when researchers infused 200 mg). SCH-23390 into rats’ NAc shell (see graph, left The infusion inhibited NK cell activity by 55 percent, on panel), but not the NAc core. average, but had no effect on T and B white blood cells • D1 receptor activation in the shell of the NAc lowers NK in the spleen. Similarly, rats infused with morphine while cell activity even in the absence of morphine. Rats given their Y1 receptors were blocked did not develop NK cell no morphine but a test compound (SKF 38393) that inhibition, but their T and B white blood cells became activates D1 receptors demonstrated 35 to 39 percent inhibited. less NK cell activity than a comparison group of rats The specificity of NPY’s actions—affecting NK cells but injected with saline. not other white blood cells—is not surprising, says Dr. Lysle, because the brain generally seems to communicate Pathway Through The Body with different immune system components in the body in Dr. Lysle and colleagues next turned their attention to the signaling chain that links D1 activity in the NAc to NK cell inhibition in other organs. Prior studies had indicated that mor- phine activates the sympathetic ner- vous system, and sympathetic nerves communicate signals from the brain to NK and other white blood cells in the spleen. The specific chemical involved in conveying the message of NK inhi- bition from brain along the sympa- thetic system to the spleen, however, was unknown. Dr. Lysle and colleagues focused on Y (NPY) as a likely candidate because it is released in the brain when sympathetic nerves are activated, is found at the nerves of the spleen, and interacts with receptors (Y1) in the membranes of white blood cells. “Most important in elevating NPY as a candidate, however, was other researchers’ finding that it sup- pressed the ability of natural killer cells to attack cultured tumor cells,” says Dr. Saurer. “This suggested that it

7 very selective ways. “Our team has identified the language Sources for the suppression of natural killer cells, but other drugs • Saurer, T.B., et al. Suppression of natural killer cell of abuse and different immune system responses may activity by morphine is mediated by the nucleus speak distinct languages—ones that may be discovered in accumbens shell. Journal of Neuroimmunology 173 future research,” he says. (1-2):3-11, 2006. “The team’s findings suggest a brain-to-body pathway • Saurer, T.B.; Ijames, S.G.; and Lysle, D.T. whereby morphine weakens the body’s defenses,” says Dr. Y(1) receptors mediate morphine- Paul Schnur of NIDA’s Division of Basic Neuroscience induced reductions of natural killer cell activity. Journal and Behavioral Research. “In future studies, research- of Neuroimmunology 177(1-2):18-26, 2006. ers might examine immune responses after chronic self- administration of morphine to model more closely the possible immunosuppressant effects of drug abuse.”

8 Research Findings Volume 21, Number 5 (March 2008)

Alcohol Abuse Makes Prescription Drug Abuse More Likely Those under age 25 are particularly vulnerable to dual abuse.

By Elizabeth Ashton, NIDA NOTES Staff Writer

Men and women with alcohol use disorders (AUDs) are Alcohol and Related Conditions (NESARC) between 18 times more likely to report nonmedical use of prescrip- 2001 and 2005. Participants lived across the United States tion drugs than people who don’t drink at all, according in a broad spectrum of household arrangements and to researchers at the University of Michigan. Dr. Sean represented White, African-American, Asian, Hispanic, Esteban McCabe and colleagues documented this link and Native American populations. Although people with in two NIDA-funded studies; they also discovered that AUDs constituted only 9 percent of NESARC’s total sam- young adults were most at risk for concurrent or simulta- ple, they accounted for more than a third of those who neous abuse of both alcohol and prescription drugs. reported NMUPD. “The message of these studies is that clinicians should Since the largest group of alcohol/prescription drug abus- conduct thorough drug use histories, particularly ers were between the ages of 18 and 24, the team’s second when working with young adults,” says Dr. McCabe. study focused entirely on this population and involved “Clinicians should ask patients with alcohol use disorders 4,580 young adults at a large, public, Midwestern universi- about nonmedical use of prescription drugs [NMUPD] ty. The participants completed a self-administered Web sur- and in turn ask nonmedical users of prescription medica- vey, which revealed that 12 percent of them had used both tions about their drinking behaviors.” The authors also alcohol and prescription drugs nonmedically within the last recommend that college staff educate students about the year but at different times (concurrent use), and 7 percent adverse health outcomes associated with using alcohol and had taken them at the same time (simultaneous use). prescription medications at the same time. When alcohol and prescription drugs are used simultane- ously, severe medical problems can result, including alco- Two Studies hol poisoning, unconsciousness, respiratory depression, The authors’ first study looked at the prevalence of AUDs and sometimes death. In addition, college students who and NMUPD in 43,093 individuals 18 and older who drank and took prescription drugs simultaneously were participated in the National Epidemiologic Survey on more likely than those who did not to blackout, vomit, and engage in other risky behaviors such as drunk driving and unplanned sex.

Who, What, And When The prescription drugs that were combined with alcohol in order of prevalence included prescription (e.g., Vicodin, OxyContin, Tylenol 3 with , Percocet), stimulant medication (e.g., Ritalin, Adderall, Concerta), sedative/anxi- ety medication (e.g., Ativan, Xanax, Valium), and sleeping medication (e.g., Ambien, Halcion, Restoril). The college study asked about the respon- dent’s use of medications prescribed for other people while the NESARC explored both use of someone else’s prescription medications as well as the use of one’s own prescription medica-

9 tions in a manner not intended by the prescribing clinician (e.g., to get high). The researchers found that the more alcohol a person drank and the younger he or she started drinking, the more likely he or she was to report NMUPD. Compared with people who did not drink at all, drinkers who did not binge were almost twice as likely to engage in NMUPD; binge drink- ers with no AUDs were three times as likely; people who abused alcohol but were not dependent on alcohol were nearly seven times as likely; and people who were dependent on alcohol were perspective on these studies. “Prescription sedatives, tran- 18 times as likely to report NMUPD (see figure, quilizers, painkillers, and stimulants are generally safe and opposite page). effective medications for patients who take them as pre- While the majority of the respondents in both studies scribed by a clinician,” Dr. Colliver states. “They are used were White (71 percent in NESARC and 65 percent in to treat acute and chronic pain, attention deficit hyperac- the college group), an even higher percentage of the simul- tivity disorder, anxiety disorders, and sleep disorders. taneous polydrug users in the college study were White “The problem is that many people think that, because males who had started drinking in their early teens. The prescription drugs have been tested and approved by the NESARC study also found that Whites in general were Food and Drug Administration, they are always safe to two to five times more likely than African-Americans to use; but they are safe only when used under the direction report NMUPD during the past year. Native Americans of a physician for the purpose for which they are pre- were at increased risk for NMUPD, and the authors scribed.” indicated that this subpopulation should receive greater research attention in the future. Sources Dr. McCabe emphasizes that many people who simultane- • McCabe, S.E., et al. The relationship between ously drink alcohol and use prescription medications have past-year drinking behaviors and nonmedical use no idea how dangerous the interactions between these of prescription drugs: Prevalence of co-occurrence substances can be. “Passing out is a protective mechanism in a national sample. Drug and Alcohol Dependence that stops people from drinking when they are approach- 84(3):281-288, 2006. ing potentially dangerous blood alcohol concentrations,” • McCabe, S.E., et al. Simultaneous and concurrent he explains. “But if you take stimulants when you drink, polydrug use of alcohol and prescription drugs: you can potentially override this mechanism and this Prevalence, correlates, and consequences. Journal of could lead to life-threatening consequences.” Studies on Alcohol 67(4):529-537, 2006. Dr. James Colliver, formerly of NIDA’s Division of Epidemiology, Services and Prevention Research, offers

10 Research Findings Volume 21, Number 5 (March 2008)

Chromosome 17 Harbors Opioid Dependence Genes A comparison of genetic markers of opioid abusers and their relatives brings scientists closer to identify- ing those that contribute to abuse and dependence.

By Lori Whitten, NIDA NOTES Staff Writer

NIDA-funded investigators are homing in on the location The researchers scanned each participant’s DNA for of genes that may influence the risk of opioid dependence. genetic markers—segments of DNA that occur at known Dr. Joel Gelernter, at Yale University School of Medicine, locations on a particular chromosome. These scans Henry Kranzler, at the University of Connecticut, and revealed that certain markers were shared with increased colleagues led a study that has shown a statistical link frequency among family members with drug abuse diag- between one region on chromosome 17 and an increased noses or phenotypes; the specific genes that influence risk risk of opioid dependence. for opioid dependence are likely to be found near these “Opioid addiction results from the activities of multiple markers. genes, many environmental factors—obviously includ- Among the markers with the strongest statistical links ing drug exposure—and interactions among them. Our Dr. Gelernter’s team identified were two on the long arm findings point to specific chromosomal areas as the sites of chromosome 17 (see chart). One of these was con- of some of the contributing genes,” says Dr. Gelernter. nected with severe symptoms of dependence on opioids, Prior studies that estimated the relative contributions of but not other drugs, among both African-American and genes and environmental factors by comparing rates of addiction in twins indicated that genes alone account for an estimated 45 percent to 50 percent of opioid addiction. Twin studies also suggest that certain genes may increase the risk of opioid addic- tion without affecting the likelihood of addiction to other drugs.

Scanning For Genetic Markers At four sites in the eastern United States, Dr. Gelernter and colleagues recruited 393 families with at least one member who abused opioids; in 235 of the families (60 percent), two or more members abused the drugs. The investigators assessed every study participant and categorized those who reported abusing drugs as exhibiting either “low opioid abuse,” “moder- ate opioid abuse,” “severe opioid abuse,” “abuse of nonopioid drugs,” or “severe opioid abuse mixed with dependence on other substances.” Participants in the “severe opioid abuse” cluster reported the highest rates of long-term heavy abuse, injec- tion of opioids, and attempts to quit.

11 European-American participants. Among European- reside in these areas might explain that increased like- American participants only, a second site was linked with lihood? Prime candidates will be any genes whose activi- dependence on other drugs, including cocaine, nicotine, ties affect physiological responses to drugs or behavioral alcohol, and marijuana. characteristics associated with vulnerability to drug abuse. Although the sites on chromosome 17 were the only ones “Each chromosome site where we observed a link could to show statistically significant linkages, the analyses sug- have perhaps 30 to 100 genes, maybe more, and my team gested that the short arm of chromosome 11 and the long is currently assigning each region a priority for further arm of chromosome 3 may also feature genes that influ- study,” says Dr. Gelernter. Scientists may investigate ence dependence on nonopioid drugs. Among African- candidate genes’ impacts in a variety of ways, including American participants only, analyses suggested a link statistical studies to determine the effects of eliminating, between opioid dependence and a site on chromosome 2. activating, or inactivating the genes on animals’ responses The genetic sites linked with risk of many health problems to drugs. differ between European- and African-Americans. Known “The findings of both genomewide and candidate-gene racial differences in the patterns of drug abuse and risk studies represent a good return on NIDA’s investment in factors for addiction also support somewhat separate eti- genetics research and contribute useful and complementary ologies, although there is likely much overlap. information,” says Dr. Harold Gordon of the Division of The findings generally accord with those of prior studies. Clinical Neuroscience and Behavioral Research. “Besides For example, other researchers have linked sites on chro- identifying genes that put people at risk for the disorder, mosome 17 with the risk of smoking and conduct disor- they help us understand how these genes affect neural der. Further, chromosome 17 has a site, albeit in a differ- function and behavior, and facilitate the development of ent location than the ones found by Dr. Gelernter’s team, medications tailored to the individual.” with a suggestive linkage to abuse among almost By scanning for genetic markers common among a sub- 200 families from Yunnan Province in China, according group of individuals with the most severe opioid abuse to preliminary findings from NIDA-funded investigators symptoms, Dr. Gelernter’s team was able to home in on Drs. Ming T. Tsuang and Stephen J. Glatt and colleagues. sites that may harbor genes linked with the unique risk for Similarly, prior studies have linked sites close to the ones opioid dependence, as well as those linked to substance observed by Dr. Gelernter’s team on chromosome 11 abuse in general, Dr. Gordon notes. In future studies, the with risk of nicotine and alcohol addiction and areas of team hopes to use a newer genomewide scanning tech- chromosome 3 with risk of cocaine abuse and conduct nique that can dramatically speed the identification of disorder. specific genes.

Identifying Specific Genes Source Studies such as Dr. Gelernter’s suggest that certain areas • Gelernter, J., et al. Genomewide linkage scan for of the genome are statistically most likely to harbor genes opioid dependence and related traits. American that play a role in drug abuse. Researchers will next turn Journal of Human Genetics 78(5):759-769, 2006. their attention to the question: Which of the genes that

12 Research Findings Volume 21, Number 5 (March 2008)

Teen Substance Abuse Continues to Decline

Use of illicit drugs by students in the 8th, 10th, and 12th grades declined 24 percent over the past 6 years, accord- ing to the 2007 Monitoring the Future (MTF) survey. The rate of past-month illicit drug use dropped from 19.4 percent in 2001 to 14.8 percent in 2007, which indicates that an estimated 860,000 fewer teenagers are current users. Declines among 8th graders were particularly noteworthy. Illicit drug use and cigarette smoking declined signifi- cantly not only in the past 6 years, but also since 2006. Typically, year-to-year changes are within a margin of error and therefore not large enough to be considered significant. NIDA Director Dr. Nora Volkow said the smoking rate for all three grades combined (13.6 percent) was the low- est in the MTF’s 33-year history. “We are especially heart- ened to see the decrease in smoking among 8th graders and will be watching the next 2 years closely to see if this decline will stick as these kids get older,” Dr. Volkow said. “If this change in attitude is carried with them throughout the rest of their teen years, we could see a dramatic drop in smoking-related deaths in their generation.” Marijuana, methamphetamine, and amphetamines are among the drugs most responsible for the overall decline in abuse of illicit drugs over the past 6 years. Although marijuana continued to be the most widely abused illicit drug, past-month abuse rates fell 25 percent, from 16.6 percent to 14.8 percent, since 2001. Past-month meth abuse dropped 64 percent (from 1.4 percent to 0.5 per- cent) and abuse of amphetamines fell 32 percent (from 4.7 percent to 3.2 percent).

Prescription Meds: An Ongoing Concern Another concern is an apparent softening of attitudes Contrary to the general trend, nonmedical use of prescrip- toward MDMA (Ecstasy) and LSD among 8th and 10th tion medications “is holding at near record levels,” said graders, fewer of whom said they perceived these drugs as Dr. Lloyd Johnston of the University of Michigan, the harmful. Ecstasy abuse by teenagers in all three grades has study’s principal investigator. Abuse of prescription pain- decreased over the past 6 years, but 10th and 12th grad- killers such as OxyContin and Vicodin by teenagers is a ers reported an increase in past-year abuse in 2007. Dr. new phenomenon that has emerged in the past 5 years; Johnston noted that these results are worrisome because these medications are being prescribed in record numbers perceived risk is an important predictor of abuse. and kept in households where kids have access to them, For the second year, the survey included questions about observed Dr. Volkow. In 2007, 15.4 percent of 12th grad- the abuse of over-the-counter cough medicines. In both ers reported abuse of prescription drugs in the past year; 2006 and 2007, rates of abuse were 4 percent for 8th Vicodin had the highest rate of abuse—9.6 percent. graders and 5 percent for 10th graders; for 12th graders,

13 the rate dropped from 7 percent to 6 percent, a change The 2007 survey covered 48,025 students in 403 public that was not statistically significant. Taking large quanti- and private schools across the United States. Participants ties of cough medicines with the active ingredient dextro- reported on their use of an extensive list of illicit drugs in order to get high, a practice referred to as and other substances in the past month, past year, and in “robotripping,” can cause brain damage and even death. their lifetime. Further information and the full text of the Robitussin®, Coricidin® HBP, Vicks NyQuil®, and Vicks survey are available at www.drugabuse.gov/drugpages/MTF. Formula 44® are among the most commonly abused html and at www.monitoringthefuture.org. brands.

14 Research Findings Volume 21, Number 4 (October 2004)

Controlling College Students’ ADHD Symptoms May Protect Them Against Substance Abuse

In a survey of 334 students at a college in the Southeast, those who reported having experienced symptoms of attention-deficit hyperactivity disorder (ADHD) during the past 6 months were three times as likely as those whose symptoms were controlled to say they had intensified their smoking, and six times as likely to report increased frequency of abuse of other drugs (besides alcohol and marijuana) during the past year. Of the 76 respondents who said they had been prescribed ADHD medications at some point during their lives, one-quarter said they had abused their medication to get high, and 29 percent said they had given or sold it to someone else. Dr. Himanshu Upadhyaya and colleagues at the Medical University of South Carolina conducted the study. Appropriate treatment of ADHD may reduce college students’ risk of drug abuse.

Source • Journal of Child and Adolescent Psychopharmacology 15(5):799-809, 2005.

15 Research Findings Volume 21, Number 3 (April 2007)

Meeting Reviews Progress On Prescription Opioid Misuse

More than 400 researchers and A new class of opioids—designed and synthesized by clinicians gathered in Bethesda, NIDA-funded researchers—that targets functionally Maryland March 5-6 to discuss a paired receptors in the brain may provide pain treatment growing public health challenge: with fewer side effects to patients and less potential for balancing appropriate pain treat- abuse. The team is testing the compounds in animals, says ment with efforts to minimize Dr. David J. Daniels of the University of Minnesota, with prescription opioid misuse. NIDA promising results: with chronic administration, the pain co-sponsored the conference, “Pain, relieving effects of the compounds do not diminish nor Dr. Pamela Palmer Opioids, and Addiction: An Urgent does physical dependence develop. Behavioral assays in presents “New Opioid Formulations: Hope Problem for Doctors and Patients,” animals also suggest that the compounds would have low on the Horizon” at the with the American Medical potential for abuse. March Conference. Association and in conjunction with With training, people may be able to harness the power the National Institutes of Health of the brain to fight pain. Dr. R. Christopher deCharms Pain Consortium. of Omneuron, Inc. in Menlo Park, California, leads About 50 million people suffer from chronic pain in the research in this new approach to pain management. The United States, and opioids are the most powerful medica- strategy involves training participants to control the activ- tions available for most types of pain. However, opioids ity of neural regions linked with pain by viewing real-time can lead to negative health consequences, including functional magnetic resonance imaging (rtfMRI) scans of abuse and addiction. The number of prescriptions writ- their brains. Volunteers and people with chronic pain who ten for opioid pain relievers has increased dramatically in receive such training can alter the activity of a key brain recent years, thereby increasing opportunities for abuse. region with concomitant pain modification—a result Treatment advances may improve pain relief for patients not seen among participants who trained without the while reducing the risk of abuse. Dr. Pamela P. Palmer rtfMRI. Dr. deCharms and colleagues continue to test this of the University of California, San Francisco, an anes- approach to chronic pain management and have expanded thesiologist and pain medicine physician and researcher, studies to substance abuse treatment. discussed ways that opioid medications can be formu- Meeting participants agreed that research is urgently need- lated to minimize the risk of abuse. Extended-release or ed to support the development of pain treatments with lit- crush-resistant formulations tend to offer a better safety tle or no risk of abuse and the identification of patients profile and reduce the potential for abuse. For example, who may be vulnerable to opioid abuse and addiction. putting opiates into a gel matrix from which they cannot Filling such research gaps will ultimately provide evidence- be extracted for the purposes of abuse may prove to be a based guidance on pain management that minimizes the successful strategy. Similarly, new devices that dispense risks of opioid abuse and addiction. opioids more safely also may improve pain relief for out- patients and inpatients.

16 Research Findings Volume 21, Number 1 (October 2006)

Buprenorphine Plus Behavioral Therapy Is Effective For Adolescents With Opioid Addiction A new study looks at extending the role of buprenorphine for treatment of adolescents.

By Patrick Zickler, NIDA NOTES Contributing Writer

Adolescents addicted to opioids responded better to Continuous abstinence could earn participants $152.50 in buprenorphine than clonidine in a clinical trial in which vouchers redeemable for rewards such as ski passes, CDs, all patients also received behavioral therapy. In the NIDA- gym passes, and clothing. supported comparison trial at the University of Vermont, Buprenorphine and clonidine both supported high rates adolescents who received buprenorphine attended more of abstinence. Among participants who completed treat- scheduled counseling sessions than peers who received ment, rates were 78 percent and 81 percent, respectively, clonidine and had higher rates of successful induction to confirmed by urine samples provided at the thrice-weekly a relapse prevention regimen of . The study, sessions. However, nearly twice as many buprenorphine led by Dr. Lisa Marsch, is the first published randomized as clonidine recipients completed the 4-week treatment controlled study of treatments for adolescents addicted to (72 percent compared with 39 percent). “The high rate opioids. of retention in the buprenorphine group is particularly “Heroin abuse among American teens has doubled over noteworthy,” Dr. Marsch says, “because long-term suc- the past decade, and abuse of prescription opioids such as cess in recovery is directly related to the amount of time OxyContin and Vicodin has increased even more,” says patients spend in treatment.” And, she adds, the willing- Dr. Marsch. “In light of those figures, it’s important to ness of most patients who received buprenorphine to have a scientific basis for selecting treatments for opioid- continue treatment with naltrexone following completion dependent teens. We know from previous research and of the 28-day program is similarly encouraging. Sixty-one clinical experience that buprenorphine and, to a lesser percent of the buprenorphine group, but only 5 percent of extent, clonidine are among the medications that have those who received clonidine accepted naltrexone. been shown to be effective for treating opioid-addicted “Dr. Marsch’s research is an important first step in sys- adults, but we haven’t known how helpful they can be for tematically studying adolescents who are addicted to adolescents.” Dr. Marsch and colleagues enrolled 36 opioid-addicted adolescents, aged 13 to 18, in a 28-day outpatient treat- ment program. Half the participants (9 male, 9 female) received buprenorphine in tablet form, the rest (5 male, 13 female) clonidine via transdermal patch; each patient also was given a placebo resembling the other treatment. Medication dosages varied depending on each partici- pant’s weight and the amount of drug he or she reported abusing before beginning treatment; dosages of buprenor- phine were in the low to moderate range of those typically given to opioid-addicted adults. All participants also received behavioral therapy based on the Community Reinforcement Approach: three 1-hour sessions each week of counseling on methods to minimize involvement in situations that might lead to drug-taking, training to help recognize and control urges to abuse opi- oids, and encouragement to recruit family members as allies for abstinence. Participants earned vouchers worth $2.50 for the first opioid-negative urine sample, plus an additional $1.25 for each subsequent one, and a $10 bonus for each set of three consecutive negative samples.

17 opioids,” says Dr. Ivan Montoya of NIDA’s Division of to 2 months rather than 28 days,” she says. “We will also Pharmacotherapies and Medical Consequences of Drug examine the most effective doses and dosing regimens for Abuse. “We know that there are differences in the patterns various subgroups of young patients.” of opiate abuse and addiction in young people compared with adults. We need dedicated studies like this one to Source understand how teens are affected by opiate drugs and • Marsch, L.A., et al. Comparison of pharmacological how best to treat them.” treatments for opioid-dependent adolescents: A ran- The next step in Dr. Marsch’s research will involve a domized controlled trial. Archives of General Psychiatry larger sample of young opioid abusers. “We want to evalu- 62(10):1157-1164, 2005. ate buprenorphine’s effectiveness if treatment is extended

18 Research Findings Volume 21, Number 1 (October 2006)

First-time Patients Opt for Office-Based Buprenorphine

Patients starting buprenorphine treatment in a New Haven, Connecticut primary care clinic (PCC) are more likely to be new to treatment than those beginning at an opioid treatment program (OTP), report Dr. Lynn Sullivan and colleagues at Yale University School of Medicine. The findings suggest that compared with methadone, office-based buprenorphine treatment attracts individuals who have less extensive addiction histories, are relatively healthier, and have more socioeconomic resources. The investigators compared 96 patients entering a clinical trial of buprenorphine/ nal- oxone in a PCC with 94 participants entering a local OTP. Fifty-four percent of PCC patients were new to treatment, compared with 39 percent of those in the OTP. Among PCC patients, treatment novices were younger and more likely to be White than peers with prior methadone treatment. PCC patients reported fewer years of opioid addiction (10 versus 15, on average), lower rates of injection drug use (44 versus 60 percent), and less hepatitis C (25 versus 61 percent). Three-fourths of PCC patients versus half of OTP participants were male, and more PCC patients were employed full-time (46 versus 15 percent). Consistent with prior research, methadone history did not affect treatment retention or abstinence rates attained with buprenorphine.

Source • Drug and Alcohol Dependence 79(1):113-116, 2005.

19 Research Findings Volume 21, Number 1 (October 2006)

High School Seniors Steadily Increase Nonmedical Use of Sedatives Over 15 Years

20 Research Findings VolumeVolume 20, #, Number Number 4 (March(Month 2006)Year)

NIDA and Scholastic Offer Teens and Teachers New Heads Up

NIDA and Scholastic, Inc., have joined forces to pro- for food and cravings for drugs have a common biologi- duce a third installment of the series Heads Up: Real cal basis in the brain. Both drug abusers and obese people News About Drugs and Your Body. The new science-based tend to have lower than average numbers of the brain pro- articles and vivid, informative graphics will be distributed teins called dopamine receptors, a deficit that could limit to nearly 2 million middle and high school students via the amount of pleasure they gain from ordinary activities the pages of Scholastic’s publications Junior Scholastic, and achievements. Overeating and drug abuse may be Science World, and Up Front. attempts to compensate; both stimu- This year’s materials, which late the dopamine system to higher include a teacher’s guide, once activity levels. again strike the theme of the The article leads readers through unique dangers drugs pose the specific experiments researchers to teens. conducted to find these connections “Research indicates that adoles- and teaches how to design a scientific cence, a time when many changes experiment and calculate their own are occurring in the brain, may be body mass index. It points out that a period of significantly increased people can enhance the brain’s dopa- vulnerability to drugs’ effects,” mine activity without overeating or says NIDA Director Dr. Nora D. taking drugs by exercising and spend- Volkow. By presenting NIDA’s ing time with friends and family. research in an accessible format, Heads Up speaks directly to its Bucking the Trend: Increase in youthful audience about issues Inhalant and Prescription Drug including HIV and drug abuse, Abuse the link between food cravings and The 2005 University of Michigan drug cravings, the health dangers Monitoring the Future (MTF) Survey of inhalants, and the misuse of found that the number of U.S. 8th-, prescription drugs. 10th-, and 12th-grade students who reported abusing drugs in the past Adolescents, AIDS, and Abuse: month dropped 19 percent from 2001 A Deadly Connection to 2005. However, past-year inhalant Between 1998 and 2000, one of every six persons with abuse among eighth-graders increased, and abuse of the a newly diagnosed HIV infection was between the ages prescription drugs (OxyContin) and hydro- of 13 and 25. Along with injecting drugs, which 1 in codone (Vicodin) remained high. “Abuse of Inhalants 50 U.S. high school students report having done at least and Prescription Drugs: Real Dangers for Teens” paints a once, drug-influenced bad judgments can lead to infec- vivid, realistic picture of these substances’ ill effects. Even tion, and drugs can reduce the body’s ability to fight off in an otherwise healthy person, a single session of abus- infection. “Teens, Drug Abuse, and AIDS: The Deadly ing highly concentrated amounts of certain inhalants can Connection” provides young people with the statistics and lower oxygen levels enough to cause asphyxiation or dis- scientific information they need to understand the poten- rupt heart rhythms and cause death from cardiac arrest. tial health consequences of their decisions concerning Prescription medication abuse can cause both short-term drugs and sexual relationships. and long-term health problems, from potentially fatal overdose to addiction and long-term brain changes. In Linking Addictions to Food and Drugs addition to exposing the dangers of these substances, the “Two Teen Health Dangers: Obesity & Drug Addiction” Heads Up article explains how the MTF Survey data were tells readers how NIDA scientists discovered that cravings

21 collected and why these data are important in understand- All Heads Up materials can be found at either www.druga- ing and fighting drug abuse. buse.gov/scholastic.html, or at Scholastic’s Web site, www. scholastic.com/headsup.

22 Research Findings Volume 20, Number 4 (March 2006)

Studies Identify Factors Surrounding Rise in Abuse of Prescription Drugs by College Students By Lori Whitten, NIDA NOTES Staff Writer

Prescription drug abuse among stu- dents in U.S. colleges and universi- ties has been rising for several years. The 2004 Monitoring the Future (MTF) Survey of College Students and Adults—the most recent data available—estimated that 7.4 percent of college students used the painkiller (Vicodin) without a prescription in that year, up from 6.9 percent in 2002, with similar increases for other opioid medications, stimu- lants, and sedatives. Three new NIDA- funded studies reveal which students and campuses have the highest rates of abuse and connect such abuse to other unhealthy behaviors. According to the research, rates of collegiate prescription stimulant abuse are highest among men, Whites, fraternity/sorority mem- bers, and at schools in the Northeast. Students who abused prescription stimulants reported high- er levels of cigarette smoking; heavy drinking; risky driving; Stimulant Abuse Nationwide and abuse of marijuana, MDMA (Ecstasy), and cocaine. Dr. Sean Esteban McCabe and colleagues at the University Compared with other survey respondents, for example, they of Michigan and Harvard University analyzed the answers were 20 times as likely to report past-year cocaine abuse and from the Harvard School of Public Health College Alcohol 5 times as likely to report driving after heavy drinking. Study, which in 2001 surveyed 10,904 randomly selected The campus prevalence of past-year stimulant abuse ranged students enrolled at 119 colleges across the United States. from 0 percent at 20 colleges—including the three histori- Overall, 4 percent of the respondents reported having cally African-American institutions included in the survey— taken a stimulant medication without a prescription at to 25 percent. The prevalence was 10 percent or higher at least once during the previous year. Men were twice as 12 colleges. Students attending colleges in the Northeast, likely as women (5.8 percent versus 2.9 percent) to have schools with more competitive admission standards, and abused methylphenidate (Ritalin), dextroamphetamine noncommuter schools reported higher rates of abuse. (Dexedrine), and amphetamine/dextroamphetamine (Adderall). Stimulant medication abuse was also more prev- One University’s Painkiller Picture alent among students who were: At a large Midwestern university, about 9 percent of • White (4.9 percent versus 1.6 percent for African- 9,161 undergraduates surveyed had taken a prescription Americans and 1.3 percent for Asians); pain medication without a doctor’s order at least once • Members of fraternities or sororities (8.6 percent during the past year; 16 percent reported such abuse in versus 3.5 percent for nonmembers); and their lifetime. Of the latter, 54 percent said they had obtained the drugs from peers, while 17 percent said their • Earning lower grades (5.2 percent for grade point aver- source was a family member. Dr. McCabe and colleagues age of B or lower versus 3.3 percent for B+ or higher). at the University of Michigan Substance Abuse Research Center found that students who obtained medications

23 from peers were “Educating the public remains a critical challenge,” says more likely Dr. Erinoff. to smoke and drink heav- Membership Matters ily and to have Based on responses from more than 5,000 young people abused other who participated in the MTF when they were high school substances— seniors in 1988 to 1997, and also when they were in col- including mari- lege, Dr. McCabe and his Michigan colleagues found that juana, cocaine, active members of college fraternities or sororities engage and other illegal in more heavy episodic, or “binge,” drinking, cigarette drugs—than smoking, and marijuana abuse than nonmembers. those who obtained them The students who joined fraternities or sororities in col- from family lege were the same ones who reported the highest levels members. of substance abuse in high school. Moreover, cigarette smoking, binge drinking, and drug abuse increased for The research- all survey participants as they progressed through college. ers found that Fraternity and sorority members showed greater eleva- exposure to tions in binge drinking and marijuana abuse over time prescription compared with nonmembers. The picture that emerges pain medica- is of students who are already heavy drinkers when they tion early in life come to college selecting fraternities and sororities with a increased the reputation for “partying” and then, as members, further likelihood of increasing their drinking in an environment that supports abuse in college. the behavior. Women who had received prescriptions for pain relievers in elementary school were more than four times as likely as those with no prescribed use to report abuse in the past year. Men “... people need to know with early prescribed use were twice as likely as those the risks of abuse and the dangers without to report such abuse. In addition: of mixing drugs.” • Women students were more likely to be prescribed pain medication, while men were more likely to be approached to sell or give away prescribed medication. “It’s important for each student to explore, perhaps with • More men obtained the drugs from peers while more counseling, a possible mismatch between his or her college women obtained them from family members. environment and individual needs. Some students benefit from settings that emphasize socialization outside of the • Past-year prescription painkiller abuse was higher party scene; these might include group living arrange- among fraternity members than nonmembers (17 ments based on shared academic or extracurricular inter- percent versus 9 percent) and among sorority mem- ests,” Dr. McCabe says. bers compared with nonmembers (9.6 percent versus 8.6 percent). Sources “Students abuse prescription drugs to get high, to self- • McCabe, S.E., et al. Non-medical use of prescription medicate for pain episodes, to help concentrate during stimulants among US college students: Prevalence exam time, and to try to relieve stress. Regardless of the and correlates from a national survey. Addiction motivation, people need to know the risks of abuse and 100(1):96-106, 2005. the dangers of mixing drugs,” says Dr. Lynda Erinoff, for- merly of NIDA’s Division of Epidemiology, Services and • McCabe, S.E., et al. Selection and socialization effects Prevention Research. Most people assume that if a medi- of fraternities and sororities on U.S. college student cation is available on the market, it must be safe—even if substance use: A multi-cohort national longitudinal it has not been prescribed for them, says Dr. Erinoff, “but study. Addiction 100(4):512-524, 2005. a drug or dose that a doctor orders for one person is not • McCabe, S.E.; Teter, C.J.; and Boyd, C.J. Illicit necessarily appropriate for another, and prescription abus- use of prescription pain medication among college ers are potentially taking a serious risk.” NIDA continues students. Drug and Alcohol Dependence 77(1):37-47, to work with doctors and pharmacists and to link preven- 2005. tion specialists with researchers focusing on the problem.

24 Research Findings Volume 20, Number 2 (August 2005)

NIDA Responds to Changing Drug Abuse Patterns By NIDA Director Nora D. Volkow, M.D.

Two new NIDA initiatives address the other medications. We also need research accelerating increase in abuse of opioid that tells us whether pain patients are pain medications and bring a powerful more vulnerable or less vulnerable to the new transdisciplinary conceptual frame- addictive effects of these drugs, and how work called social neuroscience to bear on best to treat co-occurring pain and addic- the broad questions of abuse and addic- tion. Can we develop medications that act tion. Together, the initiatives exemplify at the site of pain rather than deep within the depth of NIDA-supported research the central nervous system, as opioids do? capabilities and the flexibility that makes it NIDA’s intensified investigation will help possible to respond quickly to new patterns assure that pain patients have the treat- in drug abuse and to incorporate innova- ment they need, with medications carrying tive research approaches. the smallest possible risks for abuse and addiction. Abuse of Opioid Pain Medications Opioid analgesics, medicine’s most effec- Social Neuroscience tive tools for relieving severe and chronic Researchers have described in detail many pain, are being diverted and abused on an alarming scale. of the biological variables in drug abuse and addiction, In 2003, an estimated 31.2 million Americans aged 12 and they have identified a wide array of social circum- or older abused a prescription pain medication (took the stances that foster or protect against the problems that drug for the feeling it produced, not the condition for NIDA is dedicated to reducing and eventually eliminat- which it was prescribed) at least once, an increase of more ing. Our newest initiative will merge these historically than 1.5 million over the year before. The prevalence of separate investigatory realms to examine how neurobiol- opioid analgesic abuse is alarming among adolescents; in ogy and the social environment interact in the processes of 2003, high school seniors abused opioids more than any initiation, maintenance, relapse to, and treatment of abuse other illicit drug except marijuana. and addiction. The abuse of opioids by adolescents is a major focus of Our social neuroscience initiative will help us better NIDA’s research. Most of our understanding of opioid understand how neurobiological mechanisms and respons- abuse and addiction is derived from research in 20- to es—genetic, hormonal, and physiological—underlie, 40-year-olds; however, exposure to opioids during adoles- motivate, and guide social behaviors related to abuse and cence—a critical time for brain development—may result addiction. In one example of such a relationship, NIDA- in neurobiological changes and behavioral consequences funded scientists recently found that when they trans- that differ from those in adulthood. NIDA’s initiative ferred monkeys from isolation to group living, the animals will help determine how short-term and chronic opioid that became dominant in the new social structure under- administration affect the developing brain. Among the went biological changes that resulted in stronger limbic important questions are: Does exposure to these medica- dopamine signaling and less interest in cocaine compared tions in one’s teens and early 20s increase the likelihood of with the animals that became submissive (see “Social abuse later in life? Will adolescents who have been treated Environment Appears Linked to Biological Changes in with opioids or abused them require higher therapeutic Dopamine System, May Influence Vulnerability to doses as adults to achieve adequate pain management? Cocaine Addiction,” NIDA NOTES, Vol. 17, No. 5). A In addition to intensifying our investigations of opioids’ social neuroscience perspective might also investigate the effects in adolescents, the initiative will stimulate research neurobiological mechanisms underlying the heightened into questions that apply to the elderly, who might be at sensitivity to social influences and decreased sensitivity to increased risk for developing addiction because of age- negative consequences that—together with other special related changes in metabolism or because they are taking characteristics of their age—make adolescents particularly vulnerable to drug abuse. In adults, too, the confluence of

25 the brain’s neurobiological response to drugs and influences and consequences of drug abuse, social neuroscience might from the social environment can have a profound impact help explain how group, 12-step, or faith-based interven- on whether an individual begins, continues, or quits abus- tions might bring about positive change. ing drugs. In addition to new insights into the initiation

26 Research Findings Volume 19, Number 5 (January 2005)

Confronting the Rise in Abuse of Prescription Drugs By NIDA Director Nora D. Volkow, M.D.

The misuse and abuse of prescription be designed and conducted by NIDA’s medications is a growing public health Clinical Trials Network. NIDA research concern. The National Survey on Drug also is expanding our understanding of the Use and Health (NSDUH), conducted by risks posed by prescription medications the Substance Abuse and Mental Health in different populations—women, adoles- Services Administration (SAMHSA), esti- cents, racial and ethnic groups, health pro- mates that in 2003, 6.3 million Americans fessionals, those with comorbid substance aged 12 and older abused prescription abuse and mental health disorders, and drugs (that is, took medications not pre- those with HIV/AIDS and other infectious scribed for them or took medications diseases. One group that may be especially solely for pleasure or entertainment) in the at risk is the elderly. Age-related changes month preceding the survey. Most abused may influence the way in which their bod- pain relievers (4.7 million); others abused ies metabolize and respond to prescription tranquilizers (1.8 million), stimulants (1.2 drugs. Older adults are more likely to have million), and sedatives (0.3 million). undiagnosed psychiatric and medical ill- The abuse of prescription medications has ness. They also are more likely to be taking increased in all segments of the population, and in several medications in complex drug regimens, increasing recent years the increase in abuse of prescription painkill- the risk of drug interactions or errors in dosing. Any of ers has been particularly sharp and worrisome. In 2002, these circumstances may contribute to development of the NIDA-supported Monitoring the Future survey unwanted dependence or even addiction to prescribed initiated questions about the prescription pain medi- medications. cations oxycodone (OxyContin) and hydrocodone Patients with chronic pain need medications; the potential (Vicodin). In that year and in 2003, about 4 percent and for abuse should not deter physicians from prescribing 4.5 percent, respectively, of high school seniors reported appropriate medications in adequate dosages. To help nonmedical use of oxycodone in the 12 months preced- primary care providers confidently select the most ing the survey. Roughly 10 percent of seniors reported appropriate medication for the situation, NIDA is nonmedical use of hydrocodone, making it the third working to develop screening and diagnostic tools that most widely abused illicit substance (after marijuana and amphetamine) in this age group. The abuse of prescription pain medications is increasing among adult Americans as well. Among young adults aged 18 to 25, the rate increased from 22.1 percent in 2002 to 23.7 percent in 2003, NSDUH data show. Abuse of oxycodone increased among all age groups from 2002 to 2003: by more than 10 percent among Americans aged 12 to 17, by nearly 40 percent among 18- to 25-year-olds, and by 60 percent for Americans aged 26 or older. NIDA is responding to the increase in prescription drug abuse on several fronts. In September, a Consultant Workgroup meeting brought together researchers and physicians with expertise in pain management and the epidemiology, prevention, and treatment of opiate abuse. primary care physicians can use to assess the potential for This panel developed an outline for a large-scale clinical misuse, abuse, and dependence on prescription drugs in study of treatment for prescription opiate abuse that will their patientsDeveloping new medications free of poten-

27 tial for abuse or diversion to illegal markets is another for sale? Do some health professionals contribute to abuse NIDA priority. We are evaluating potential new medica- of prescription drugs through inappropriate prescribing? tions such as cannabinoids that relieve certain types of Do others provide inadequate treatment because they pain but have reduced risk for addiction and abuse (see fear their patients will become addicted? If these risks are “Novel Cannabinoid Appears Promising for Treatment of significant, what educational efforts will most effectively Chronic Pain,” NIDA NOTES, Vol. 19, No. 2). guide physicians in prescribing appropriate medications We also are working to understand more fully the role for patients who need them? of environmental and social factors in misuse or abuse of NIDA’s expanded commitment will help ensure the avail- prescription medications. For example, how great a threat ability of safe and effective treatment with lessened risk of is posed by Internet sites offering controlled substances dependence or addiction.

28 Research Findings Volume 19, Number 4 (December 2004)

2003 Survey Reveals Increase in Prescription Drug Abuse, Sharp Drop in Abuse of Hallucinogens

The annual National Survey on Drug Use and Health (NSDUH), released in September 2004, indicates that in 2003 more than 19 million Americans—8.2 percent of the popula- tion aged 12 and older—were abusing illegal drugs each month. Overall, this represents no significant change from 2002, but the new data reveal significant changes for some drugs. For example, among youth aged 12 through 17, past-year abuse of MDMA (“Ecstasy”) and LSD fell sharply—by 41 percent for MDMA and 54 percent for LSD. On a less encouraging note, lifetime abuse of prescription pain medications increased in all age groups and for all painkill- ers in the survey. Key findings from the 2003 NSDUH: • Tobacco. An estimated 70.8 million Americans reported current (past-month) use of a tobacco product in 2003. This is 29.8 percent of the population aged 12 or older, similar to the rate in 2002 (30.4 per- cent). The highest rate of past-month ciga- rette smoking was among young adults aged Past-year abuse of Ecstasy declined (from 3.2 million 18 to 25 (40.2 percent). Among all smokers aged 12 to 2.1 million abusers), as did past-year abuse of LSD or older, a higher proportion of males than females (from 1 million to 558,000 abusers) between 2002 smoked cigarettes in 2003 (28.1 v. 23.0 percent), but and 2003. among 12- to 17-year-olds, girls (12.5 percent) were • Prescription Drug Abuse. An estimated 6.3 million as likely as boys (11.9 percent) to smoke. Among girls persons (2.7 percent) aged 12 or over engaged in cur- in this age group, the 2003 figures represent a signifi- rent nonmedical use of psychoactive therapeutic drugs. cant decrease from last year’s rate of 13.6 percent. Of these, 4.7 million abused pain relievers, 1.8 million • Marijuana. Marijuana is the most commonly abused abused tranquilizers, 1.2 million abused stimulants, and illicit drug, with 14.6 million (6.2 percent of the 0.3 million abused sedatives. There was a significant population) persons currently abusing the drug. There increase in lifetime nonmedical use of pain relievers were an estimated 2.6 million new marijuana users between 2002 and 2003 among persons aged 12 or in 2002, roughly two-thirds of whom were younger older, with young adults (18-25) reporting a 15 percent than age 18; half of the new abusers were female. The increase in lifetime and current (past-month) use. 2003 data reveal a drop of 20 percent in the number The 2003 survey report is based on interviews concerning of youth who reported heavy (either daily or 20 or use of alcohol, tobacco, and drugs with 67,784 respon- more days per month) use of marijuana. Significantly dents aged 12 and older. Lifetime use is defined as having higher numbers of youth and young adults said they ever used a substance in one’s lifetime. Past-year use is believe there is a significant health risk associated with having used the substance at least once in the past 12 smoking marijuana. months. Current use is use in the past 30 days. The full • Hallucinogens. The number of current abusers of 2003 NSDUH is available at www.oas.samhsa.gov/nhsda. MDMA decreased between 2002 and 2003, from htm. 676,000 (0.3 percent) to 470,000 (0.2 percent).

29 Research Findings VolumeVolume 16, #,Number Number 3 (August (Month 2001)Year)

Facts About Prescription Drug Abuse and Addiction

Prescription drugs can help patients manage chronic reactions, and panic attacks. Other benzodiazepines, such or severe pain, restore emotional or behavioral balance, as triazolam (Halcion) and estazolam (ProSom), are pre- control sleep disorders, or fight obesity. When prescrip- scribed for short-term treatment of sleep disorders. tion medications are abused, however, the consequences- Although the various classes of CNS depressants work including addiction-can be dangerous, even deadly. differently, they all produce a beneficial drowsy or calm- NIDA’s Research Report series on “Prescription Drug ing effect in individuals suffering from sleep disorders or Abuse and Addiction” focuses on the risks associated with anxiety. If one uses these drugs over a long period of time, abuse of three classes of commonly abused prescription the body will develop tolerance, and larger doses will be drugs: opioids; central nervous system (CNS) depressants, needed to achieve the initial effects. In addition, contin- including sedatives and tranquilizers; and stimulants. ued use can lead to physical dependence and, when use is reduced or stopped, withdrawal. Both barbiturates and What are opioids and what are the potential benzodiazepines have the potential for abuse and should consequences of their use and abuse? be used only as prescribed. As with opioids, overdose of Opioids, include morphine, codeine, and related drugs these drugs can be fatal. such as oxycodone (OxyContin), hydrocodone (Vicodin), and meperidine (Demerol) and are commonly prescribed What are stimulants and what are the potential conse- to relieve pain. Opioids can produce drowsiness and, in quences of their use and abuse? higher doses, depress respiration. Opioid drugs also can Stimulants enhance brain activity, increasing alertness, cause euphoria. attention, and energy, raising blood pressure, and elevat- Taken as prescribed, opioids can be used to manage pain ing heart rate and respiration. Stimulants such as methyl- effectively without untoward side effects. Chronic use of phenidate (Ritalin) and dextroamphetamine (Dexedrine) opioids can result in tolerance, which means that users are prescribed for the treatment of narcolepsy, attention- must take higher doses to achieve the same effects. Long- deficit/hyperactivity disorder, and depression that has not term use also can lead to physical dependence and addic- responded to other treatments. They also may be used for tion; withdrawal can occur when an individual discontin- short-term treatment of obesity. ues use of the drugs. Withdrawal symptoms may include Individuals may become addicted to the sense of well- restlessness, muscle and bone pain, insomnia, diarrhea, being and enhanced energy that stimulants can generate. vomiting, cold flashes with goose bumps, and involuntary Taking high doses of stimulants repeatedly over a short leg movements. Individuals who are addicted to opioids time, however, can lead to feelings of hostility or paranoia. are more likely to overdose on the drugs, which could Additionally, taking high doses of stimulants may result be fatal. in dangerously high body temperatures and an irregular heartbeat. What are CNS depressants and what are the potential consequences of their use and abuse? To Receive This Resource Among the most commonly prescribed CNS depressants Copies of the NIDA Research Report “Prescription Drugs: are barbiturates, such as mephobarbital (Mebaral) and Abuse and Addiction” can be obtained through NIDA’s pentobarbital sodium (Nembutal), which are prescribed to Web site at www.drugabuse.gov or www.drugabuse.gov/ treat anxiety, tension, and sleep disorders; and benzodiaze- ResearchReports/Prescription/Prescription.html. pines, such as diazepam (Valium) and alprazolam (Xanax), which typically are prescribed to treat anxiety, acute stress

30 Research Findings VolumeVolume 16, #,Number Number 3 (August (Month 2001)Year)

NIDA Scientific Panel Reports on Prescription Drug Misuse and Abuse By Patrick Zickler, NIDA NOTES Staff Writer

NIDA launched a new initiative on prescription drug abuse, misuse, and addiction at a press conference in Washington, D.C., in April. NIDA developed the initiative in response to reports of increased abuse of prescrip- tion pain relievers and concern over abuse of other prescription drugs. A scientific program following the press conference provided an overview of current research into issues associated with prescription opioid drugs used in pain relief, central nervous system depressants prescribed for anxiety and sleep disorders, and stimulants used to treat attention-deficit hyperactiv- ity disorder (ADHD) and obesity. Dr. Alice Young, a NIDA-supported researcher at Wayne State University In 1998, roughly 1.6 million people used prescription pain relievers nonmedically for the first in Detroit, presented a discussion time—four times as many as in 1980. of the neurobiology of addiction. In subsequent presentations, researchers take multiple drugs, Dr. Schmader said, and are therefore focused on investigations into specific aspects of prescrip- more vulnerable than are younger patients to unintention- tion drug abuse. ally misusing and becoming habituated to prescription medications. In one study of more than 1,500 elderly Dr. Howard Chilcoat of the Johns Hopkins University patients, 50 patients, roughly 3 percent, were abusing School of Public Health and Hygiene in Baltimore dis- prescription drugs. In a study of consecutive admissions cussed research into the epidemiology of prescription drug to a treatment program, 70 of 100 elderly patients admit- abuse. Overall, he said, the number of people who abuse ted for prescription drug abuse were women. Eighty were prescription drugs each year roughly equals the number dependent (that is, they experienced withdrawl symptoms who abuse cocaine-about 2 to 4 percent of the population. if they tried to stop taking the drugs) on sedatives, 49 on Whites are more likely than other racial or ethnic groups opioids, and 3 on stimulants. Thirty-six were dependent to abuse prescription drugs, and many people who abuse on 2 drugs and 8 were dependent on 3. these drugs also have psychiatric disorders. Persons age 18 to 25 are more likely than persons in other age groups to Dr. Timothy Wilens of Massachusetts General Hospital begin abusing prescription drugs. Between the ages of 12 in Boston discussed prospective studies designed to deter- and 17, girls are more likely than boys to begin prescrip- mine whether children treated for ADHD with the stimu- tion drug abuse and are more likely to abuse stimulants lant methylphenidate (Ritalin) are at risk for abuse of and sedatives than other prescription drugs. other stimulant drugs. The research involved two groups of patients diagnosed with ADHD of similar severity: one Dr. Kenneth Schmader of Duke University in Durham, group was treated with methylphenidate and the other North Carolina, said that the elderly (persons age 65 or received treatment that did not include stimulants. Dr. older) represent about 13 percent of the U.S. population Wilens reported that those who were treated with meth- but consume one-third of all prescription drugs. These ylphenidate were less likely to abuse drugs, including pre- patients are generally less healthy than younger persons scribed or unprescribed stimulants, during treatment and and often suffer from multiple diseases for which they throughout youth and adolescence.

31 Dr. Richard Brown of the University of Wisconsin cant improvement in Medical School in Madison said that physicians’ misun- their quality of life. derstanding of the risks associated with prescription drugs Nearly 80 percent can lead to inadequate treatment of some illnesses. Dr. reported improve- Brown based his statement on research in which he and ment in overall aspects his colleagues asked physicians how they would treat a set of daily life such as of hypothetical patients who suffered anxiety disorders, mood, physical func- pain associated with cancer, or back pain. The research- tioning, relationships, ers gave the clinicians detailed profiles of the hypothetical and sleep patterns. patients that included a treatment history and characteris- More than 60 percent tics, such as use of alcohol and history of substance abuse, of patients reported related to possible misuse of prescription medication. some adverse side The researchers compared the physicians’ treatment plans effects from their with a plan developed by a panel of experts. Compared to medication, but only the experts, the 2,000 physicians who participated in the 1.2 percent described study were more reluctant to provide opioids and less cau- the side effects as tious about prescribing sedatives. For example, 5 percent intolerable. Overall, of the respondents would not prescribe opioids for severe roughly 6 percent of cancer pain and nearly 80 percent would avoid opioids patients (or their phy- for severe, chronic back pain that had not responded to sicians) reported abuse other treatments. About 25 percent of the physicians or misuse of pre- would prescribe benzodiazepines (sedatives such as Valium scribed drugs. Drug or Xanax) for a hypothetical patient with an adjustment abuse issues in pain disorder (anxiety or sadness associated with a particular management are com- situation), even though they showed several signs and plex, Dr. Passik said, symptoms of a current alcohol use disorder. but his study results suggest that the risk of opioid abuse Dr. Steven Passik of Community Cancer Care, Inc., is low compared with the benefits of the drugs in chronic in Indianapolis, Indiana, discussed a study designed to pain management. evaluate the risks of misuse or abuse of drugs prescribed As part of its initiative on prescription drug misuse and for management of chronic pain and to compare the addiction, NIDA is distributing 400,000 postcards with risks with the drugs’ benefits. The research involved 264 messages about the dangers of prescription drugs. The patients being treated with opioids for chronic pain not cards are available in restaurants, book stores, clubs, associated with cancer. On average, patients reported that record stores, coffee shops, gyms, and other locations in the drugs relieved nearly 60 percent of their pain, and several major cities. more than 90 percent said the pain relief made a signifi-

32 Research Findings VolumeVolume 16, #,Number Number 3 (August (Month 2001)Year)

Understanding the Risks of Prescription Drug Abuse By NIDA Director Dr. Alan I. Leshner

Prescription drugs can transform lives. For Data from the National Household Survey the millions of patients who take them, on Drug Abuse show that 12- to 14-year- prescription drugs bring dramatic improve- olds reported prescription medications as ments in health and quality of life. But one of two primary drugs used. when abused or misused, many of these In April, NIDA launched a comprehensive medications can have effects that disrupt public information campaign in response rather than improve lives. Some prescrip- to the increased abuse of pain relievers and tion medications-particularly opioids, a growing concern over abuse of other pre- central nervous system (CNS) depressants, scription medications. Our partners in this and stimulants-alter the brain’s activity, effort are the American Pharmaceutical and misuse or abuse of these drugs can Association, the Pharmaceutical Research lead to compulsive drug seeking and use, and Manufacturers of America, the the hallmark of addiction. American Academy of Family Physicians, Data from the National Household Survey AARP, the National Council on Patient on Drug Abuse reveal that an estimated 9 Information and Education, the National million Americans 12 years or older used prescription pain Community Pharmacists Association, and the National relievers, sedatives, or stimulants for nonmedical reasons Chain Drug Store Association. in 1999; more than one-fourth of them reported that they NIDA has published the Research Report, “Prescription had used prescription drugs nonmedically for the first Drugs: Abuse and Addiction,” to answer questions about time in the previous year. the consequences of abusing commonly prescribed medi- The most dramatic increases in new nonmedical use of cations. In addition to summarizing what research has prescription drugs that act on the brain were among 12- taught us about how certain medications affect the brain to 17- and 18- to 25-year-olds. Elderly Americans-those and body, the report also offers information to help 60 years and older-are three times more likely than the patients, health care providers, and pharmacists prevent rest of the population to use prescription drugs. Research and identify misuse or abuse of prescription drugs. (See suggests that the elderly are less likely than younger “Facts About Prescription Drug Abuse and Addiction,” patients to carefully follow instructions for taking medica- NIDA NOTES, Vol. 16, No. 3). tion, making them more vulnerable to the dangers of mis- use of prescription drugs. To help reverse these trends, NIDA is initiating several The most dramatic increases in new new projects. Some of these efforts are directed toward improving our understanding of the basic mechanisms nonmedical use of prescription drugs involved in the action and effects of prescription drugs, as were among 12- to 17-year-olds and well as interactions that may occur between different med- ications when they are taken together. Other efforts seek 18- to 25-year-olds. to inform the general public and health care profession- als of the risks of misuse of prescription drugs; a recent national survey revealed that 46.6 percent of primary care As part of the public launch of NIDA’s prescription drugs physicians find it difficult to discuss prescription drug initiative, a panel of investigators briefed the press on abuse with patients for whom they prescribe the medica- important aspects of prescription drug misuse and abuse. tions. For some patients, misunderstanding the risks of (See “NIDA Scientific Panel Reports on Prescription prescription drugs or failing to closely follow a medication Drug Misuse and Abuse,” NIDA NOTES, Vol. 16, No. regimen is what leads to misuse and addiction. 3). One theme united all their presentations: We need to learn more.

33 anabolic steroids. The program will allow us to better understand the rela- tionship between prescription medica- tions, the conditions for which the medications are prescribed, and envi- ronmental and individual factors that might contribute to abuse. It will facili- tate research into questions such as: • Whether some prescription medications can trigger relapse in for- mer drug abusers; • Whether some patient populations receive too little medication to meet their needs or so much medication that they are needlessly at risk for adverse effects; • What types of prevention programs can effectively lower risk for prescrip- tion drug misuse and abuse, particularly among patient populations with high vulnerability; • How to improve the recognition and assessment of prescription drug misuse and abuse among patients being treated for disorders such as acute and chronic pain or psychiatric illnesses; In order to broaden and deepen our understanding of the • How to treat pain, anxiety, sleep disorders, and other extent of the problem of prescription drug abuse-to iden- conditions in patients with histories of abusing the tify the drugs and classes of drugs that are being abused; medications that are commonly used to treat those to understand the pathways that lead from use to misuse, conditions; and abuse, and addiction; and to identify populations most • How to help patients maintain abstinence from affected-NIDA has announced an expanded program of prescription drug abuse. research into basic science, epidemiology, prevention, and clinical practices relevant to abuse and misuse of prescrip- Taken together, our initiatives will significantly reduce the tion drugs. (See “Program Announcement PA-01-048” on public health and social consequences associated with pre- NIDA’s Web site www.drugabuse.gov.) scription drug abuse or misuse and help assure that pre- scription medications, which play such a vital role in the This program will support investigations on all classes of lives of millions of patients, continue to heal and help. prescription drugs with abuse liability, including analge- sics, stimulants, sedative/hypnotics/anxiolytics, and muscle-building/performance-enhancing drugs such as

34 Research Findings VolumeVolume 15, #, Number Number 1 (March(Month 2000)Year)

Research Eases Concerns About Use of Opioids To Relieve Pain By Robert Mathias, NIDA NOTES Staff Writer

Many physicians limit their use of powerful opioid pain For the last 7 years, Dr. Zacny has conducted a series medications because they think that patients may become of studies aimed at filling this critical gap in clinical addicted to them. Now, accumulating evidence from a knowledge. His research has examined the subjective and series of NIDA-funded studies indicates that the abuse behavioral effects of powerful opioid medications, such as potential of opioid medications is generally low in healthy, morphine and , in non-drug-abusers. Dr. Zacny’s non-drug-abusing volunteers. The findings from this research was recently recognized with a NIDA MERIT research could help to improve the use of opioid medica- Award that will enable him to continue and expand his tions to treat a variety of pain conditions. work. The term “opioids” describes morphine and other natu- “Most of what is known today about the mood-altering, ral and synthetic chemicals that are structurally similar psychomotor, and reinforcing aspects of opiates among to morphine. Opioids include codeine and meperidine people who don’t abuse opioid drugs has come from and other medications that are used to treat pain, as well Dr. Zacny’s research,” says Dr. Cora Lee Wetherington as heroin, an abused drug. Research has provided much of NIDA’s Division of Neuroscience and Behavioral information about the addictive mechanisms and mood- Research. Generally, he has found that non-drug-abusing altering and behavioral effects of opioids in opioid abus- volunteers who are given these drugs do not report feeling ers. However, little is known about whether non-opioid- the euphoria that opioid abusers do, she says. They also abusers being treated for postoperative pain experience experience more drowsiness and impairment of psycho- similar effects. motor functions such as reaction time and eye-hand coor- “There is a prevailing notion that patients can read- dination from opioids than do opioid abusers, she adds. ily become addicted to opioid medications, but it is not Dr. Zacny’s research also has shown that pain may based on scientific evidence,” says Dr. James Zacny of the modulate some of the subjective and behavioral effects University of Chicago. This belief in a high risk of addic- produced by opioids in non-drug-abusers. In one study, tion often leads to underuse of opioid medications for non-opioid-abusing volunteers immersed their forearms pain relief and causes unnecessary suffering in patients, he either in ice-cold water, inducing constant pain, or luke- says. While research shows that several opioid medications warm water, inducing no pain. When volunteers were commonly used for post-operative pain relief are likely to given intravenous morphine while experiencing pain be abused by opioid abusers, few studies have examined from the ice water, they reported feeling less euphoric, their abuse potential and subjective effects in people who lightheaded, and sleepy than they felt following morphine don’t abuse drugs. administration when their arm was immersed in lukewarm water. However, regardless of whether or not they were experiencing pain, study participants did not feel the same “The majority of healthy non-drug amount of euphoria from morphine that drug abusers report, Dr. Zacny says. abusing volunteers do not report “In our studies, we find the majority of healthy non-drug- euphoria after being administered abusing volunteers do not report euphoria after being opioids in the lab either with administered opioids in the lab either with or without pain,” Dr. Zacny stresses. “Since euphoria appears to be a or without pain” factor in opioid abuse, it seems that the abuse potential of these opioid medications is generally low in such people,” he says. Further clinical studies now are needed to assess “The majority of healthy non-drug-abusing volunteers do the range of effects experienced by patients who receive not report euphoria after being administered opioids in opioid medications in hospitals, as opposed to labora- the lab either with or without pain.” tory settings, Dr. Zacny says. “Such studies could tell us if patients who have been given an opioid following an

35 these medications’ abuse liability in this population and determining if they significantly impair performance, Dr. Zacny says. In the future, Dr. Zacny would like to examine how opi- oid medications affect non-drug-abusing patients who receive them on a long-term basis for chronic pain. This research could have clinical implications for people suffer- ing from such conditions as cancer, osteoarthritis, or even chronic lower back pain, he says. For example, research into long-term use of these medications could help deter- mine if repeated use leads to euphoria in these patients, could provide information about possible cognitive and psychomotor impairments, and could establish whether and how tolerance to their effects develops over time. Studies of the effects of opioids in chronic pain patients will be complex and will have to consider many other Dr. James Zachy records a volunteer’s report of the effects of intra- venous morphine while she is experiencing pain from immersing her factors affecting chronic pain patients’ reactions to these arm in ice water. drugs. These factors include different disease states, coex- isting conditions, such as depression, and other medica- operation experience absolutely no euphoria or if some tions, Dr. Zacny says. “The MERIT Award will enable patients do experience such an effect.” me to enter this realm of research where the potential for gaining important new information is very great,” he says. Dr. James Zacny records a volunteer’s report of the effects of intravenous morphine while she is experiencing pain Source from immersing her arm in ice water. • Conley, K.M.; Toledano, A.Y.; Apfelbaum, J.L.; Currently, Dr. Zacny is studying other opioids with dif- and Zacny, J.P. The modulating effects of a cold ferent mechanisms of action that are commonly given for water stimulus on opioid effects in volunteers. pain relief following operations. This research is examin- Psychopharmacology, 131:313-320, 1997. ing the extent to which different doses of meperidine, , and administered in the presence About the MERIT Award of a painful stimulus produce such subjective effects as NIDA’s MERIT-Method to Extend Research in Time- sedation, he says. “Our findings should give clinicians a Award program gives outstanding NIDA researchers up to better sense of how patients are feeling from these drugs.” 10 years to focus on innovative research without the admin- Dr. Zacny also is studying the behavioral effects of oral istrative burdens of preparing and submitting full grant opioids, such as oxycodone (Percodan) and hydrocodone applications for the MERIT extension. The 4- or 5-year (found in Vicodin), and propoxyphene (Darvon), that extendable awards are granted to researchers who have sometimes are given to people with pain that is expected received approval and outstanding priority scores for regular to last for a few days to a week. None of these medica- NIDA research projects. MERIT awardees are nominated tions, which typically are given following such procedures by NIDA program staff, reviewed by a panel of staff and as outpatient surgery or extraction of wisdom teeth, have outside scientists convened by the NIDA Director, recom- been carefully scrutinized for their behavioral effects, he mended by the National Advisory Council on Drug Abuse, says. Characterizing these effects in people in pain with- and finally, selected by NIDA’s Director. out a history of drug dependence could aid in assessing

36 Research Findings Volume 12, NumberVolume 6 (November/December #, Number (Month 1997)Year)

NIDA Researchers Developing Problem-Free Pain Relievers By Steven Stocker, NIDA NOTES Contibuting Writer

New compounds for treating pain may soon be avail- chemicals that able for use with patients. Some appear to reduce pain reduced pain with only minimal side effects, whereas others might be by stimulat- administered in combination with existing analgesics to ing the opioid enhance their pain-relieving properties or eliminate their receptors just as side effects. morphine and The most effective analgesics currently available are the the other opioid opioids, including morphine and related synthetic com- analgesics did. pounds. Although they are highly potent pain relievers, Subsequently, current opioid analgesics cause side effects, including con- other NIDA- stipation and reduced breathing. funded research- ers discovered Further, if currently available opioids are used regularly these natural, for longer than several weeks, most people develop some or endogenous, tolerance to the medications, meaning that they need to opioid anal- use more to get the same pain relief. Patients may also Dr. Victor Hruby of the University of Arizona synthesized a promising analgesic from one of gesics in the experience some degree of physical dependence, mean- the body’s natural pain-relieving compounds. nervous system. ing that they have mild withdrawal symptoms - such as Scientists specu- insomnia, irritability, and mild anxiety - when they stop lated that if they taking the medications. were to produce derivatives of the endogenous opioids, When patients use these medications over prolonged particularly derivatives that were delta or kappa agonists, periods, a few develop a craving for their euphoric effects. they might be able to create medications that produced Although addiction to analgesics among pain patients is analgesia without causing addiction or other side effects. rare, physicians sometimes underprescribe these analgesics Researchers around the country, including many at because the physicians or their patients are concerned pharmaceutical firms, started producing derivatives of about the possibility of addiction. endogenous opioids, but despite synthesizing several These drawbacks associated with current analgesics have thousand compounds, they failed to produce one that prompted researchers to look for new compounds that was superior to existing medications. Interest in this area are as potent as the current medications but do not cause rapidly declined, and pharmaceutical firms turned to other increased tolerance, addiction, or other side effects. This approaches for developing analgesics. search gathered momentum in the 1970s when NIDA- funded scientists found that opioid analgesics reduced DPDPE: The Parent Compound pain by acting as agonists. Agonists stimulate molecules Research in this field might have died off entirely, except called receptors - in this case, opioid receptors - on the for continued funding from the National Institutes of surface of nerve cells. Three classes of opioid receptors Health. In 1983, this support was rewarded when Dr. were eventually identified - mu, kappa, and delta. The Victor Hruby at the University of Arizona in Tucson and scientists determined that it was the mu receptor that was Dr. Henry Mosberg - then in Dr. Hruby’s lab and now at primarily responsible for the analgesic effects of morphine the University of Michigan at Ann Arbor - and their col- and the other opioid analgesics as well as their addictive leagues produced a promising compound by chemically properties and other side effects. modifying an endogenous opioid. This compound, called The researchers knew that agonists stimulate cell receptors DPDPE, selectively stimulated the delta receptor and by mimicking the effects of naturally occurring chemicals effectively reduced pain in rats and mice. This showed for in the body, but at that point, they did not know which the first time that a compound does not have to be a mu body chemicals the opioid analgesics were mimicking. agonist to produce analgesia but that a delta agonist can They reasoned that perhaps the nervous system contained also be effective. Furthermore, DPDPE produced fewer

37 side effects than morphine colleagues, biphalin has been tested extensively by Dr. and the other mu agonists Porreca, Dr. Hruby, and others at the University of did - it did not produce Arizona. constipation, and it caused Dr. Philip Portoghese of the University of Minnesota less physical dependence. found that some compounds can block the development DPDPE is not without its of morphine dependence without blocking morphine’s drawbacks, however. It is analgesic effect. not as potent as morphine “Biphalin has incredible efficacy,” says Dr. Porreca. “It or as long lasting, but its Dr. Frank Porreca of the University is one of the most potent analgesic compounds we know major problem is that it of.” Studies with animals have shown that, when injected of Arizona discovered that cer- has difficulty getting into tain compounds can enhance directly into the fluid that bathes the brain, biphalin is morphine’s analgesic effect with- the central nervous system, 257 times more potent than morphine for reducing pain. out increasing morphine’s side or brain and spinal cord, When injected into the abdomen of animals, biphalin is as effects. which is where analgesics potent as morphine without causing constipation or sig- exert most of their effects. nificant physical dependence. Like DPDPE, biphalin has When DPDPE is injected into a vein or a muscle, very difficulty crossing the blood-brain barrier when injected little of the compound is able to cross the blood-brain into the abdomen, but the small amount that crosses is barrier that prevents potentially damaging cells and large potent enough to produce considerable analgesia, Dr. molecules from leaving the blood and entering the brain. Porreca says. A NIDA- As a fairly large molecule, DPDPE has difficulty navigat- funded clinical trial with ing this barrier. biphalin is being planned Dr. Frank Porreca of the University of Arizona discovered by the same researchers that certain compounds can enhance morphine’s analgesic who will be conducting effect without increasing morphine’s side effects. the DPDPE clinical trial. To enhance the permeability of DPDPE and other delta Biphalin will be adminis- agonists, Dr. Hruby and his colleagues have been chemi- tered intravenously. cally modifying them. A few of the new compounds cross Studies show that biphalin the blood-brain barrier with greater efficiency than their acts by stimulating both parent compounds, and at least one produces a greater mu and delta receptors in Dr. Philip Portoghese of the analgesic effect than DPDPE does. University of Minnesota found the central nervous sys- NIDA-supported researchers at the University of Arizona, that some compounds can block tem. When delta receptors New England Medical Center in Boston, and University the development of morphine are activated at the same dependence without blocking time as mu receptors, the of California at San Diego are preparing to conduct a morphine’s analgesic effect. clinical trial of DPDPE in patients with cancer pain and analgesia produced by patients who are recovering from prostate surgery. In both the mu receptors is greatly groups, DPDPE will be injected intrathecally, or into the enhanced, but the side effects associated with mu recep- fluid surrounding the spinal cord, which solves the prob- tors, such as constipation and physical dependence, lem of how to get DPDPE past the blood-brain barrier. are not. “We chose DPDPE for a clinical trial because it is the This mu-delta interaction effect may be useful for treat- most studied of our delta agonists,” says Dr. Frank ing painful conditions that do not respond well to mor- Porreca, Dr. Hruby’s colleague at the University of phine and other standard pain treatments, Dr. Porreca Arizona, who tests the potential analgesics in animals. suggests. An example is neuropathic pain, which occurs “DPDPE is important for establishing whether delta ago- when nerves outside the spinal cord are damaged from, for nists can produce analgesia in humans, but it would prob- example, trauma or a tumor. ably not make a lot of money for drug companies because it would have to be given by the intrathecal route. Some SNC 80: The Small Compound patients routinely receive intrathecal administration of Like DPDPE and biphalin, many delta agonists that have analgesics, but not many.” been developed have trouble crossing the blood-brain barrier. One way that scientists are attempting to solve Biphalin: The 2-for-1 Stimulator this problem is by producing smaller delta agonists. A big A compound that may have more potential for widespread step in this direction was the synthesis of a compound use is biphalin. Synthesized by Dr. Andrzej Lipkowski called SNC 80 by investigators at the National Institute of of the Polish Academy of Sciences in Warsaw and his Diabetes and Digestive and Kidney Diseases’ and NIDA’s

38 intramural research pro- The mu agonist component produces analgesia by stimu- grams, the University of lating the mu receptor, just as morphine does, and the Arizona, and Burroughs delta antagonist component prevents the development Wellcome Company. Tests of tolerance and dependence. “Preliminary tests with show that SNC 80 is a rats have shown that this compound is about 50 percent highly selective delta ago- more potent than morphine when administered into the nist that produces analgesia brain,” says Dr. Schiller. “When we gave high doses of it when injected into the to rats for a relatively long period, it did not produce any brain, spinal cord, or abdo- physical dependence, and it produced less tolerance than Dr. Peter Schiller of the Clinical men of laboratory animals. morphine.” Dr. Schiller is continuing to develop other mu Research Institute of Montreal It is even somewhat effec- agonist-delta antagonist compounds, as is Dr. Portoghese. has produced a promising anal- tive when given orally. gesic compound that does not Dr. Rao Rapaka of NIDA’s Division of Basic Research cause dependence. The computer “SNC 80 is the compound thinks that the more analgesics of different types devel- screen shows a model of a type of that has really lit the fire oped, the better. “You want as many compounds as possi- “receptor” molecule found on the again in the delta agonist ble so that you can switch medications if there is a need,” surface of nerve cells. Many of the field,” says Dr. Porreca. says Dr. Rapaka. “If one medication doesn’t work with a potential new analgesics act at these molecules.. “It has been the stimulus particular patient, then you can try another.” to synthesize a variety of compounds that can cross Sources the blood-brain barrier. I don’t think that SNC 80 itself • Bilsky, E.J.; Calderon, S.N.; Wang, T.; Bernstein, is the right compound for testing in humans, but other R.N.; Davis, P.; Hruby, V.J.; McNutt, R.W.; compounds based on SNC 80 may be.” Rothman, R.B.; Rice, K.C.; and Porreca, F. SNC 80, a selective, nonpeptidic, and systemically active DIPP[psi]-amide: The Stimulating Inhibitor opioid delta agonist. The Journal of Pharmacology and In other research, scientists have found that interesting Experimental Therapeutics 273(1):359-366, 1995. effects can also be obtained by blocking the delta recep- • Horan, P.J.; Mattia, A.; Bilsky, E.J.; Weber, S.; Davis, tor rather than stimulating it. Dr. Philip Portoghese, T.P.; Yamamura, H.I.; Malatynska, E.; Appleyard, Dr. Akira Takemori, and others at the University of S.M.; Slaninova, J.; Misicka, A.; Lipkowski, A.W.; Minnesota in Minneapolis have tested the effects of com- Hruby, V.J.; and Porreca, F. Antinociceptive pro- bining morphine with a delta antagonist, a compound file of biphalin, a dimeric analog. The that prevents chemicals from binding to the delta recep- Journal of Pharmacology and Experimental Therapeutics tor, thereby blocking their action. “We knew that if you 265(3):1446-1454, 1993. give a delta agonist, you enhance the analgesic effect of morphine, so we wondered what would happen if you • Miyamoto, Y.; Portoghese, P.S.; and Takemori, give a delta antagonist,” explains Dr. Portoghese. “We A.E. Involvement of delta2 opioid receptors in the were surprised to find that delta antagonists block the development of morphine dependence in mice. The development of both morphine dependence and tolerance Journal of Pharmacology and Experimental Therapeutics without blocking morphine analgesia.” 264(3):1141-1145, 1993. Dr. Peter Schiller of the Clinical Research Institute of • Rapaka, R.S.; and Porreca, F. Development of Montreal has produced a promising analgesic compound delta opioid as nonaddicting analgesics. that does not cause dependence. The computer screen Pharmaceutical Research 8(1):1-8, 1991. shows a model of a type of “receptor” molecule found on • Schiller, P.W.; Weltrowska, G.; Schmidt, R.; Nguyen, the surface of nerve cells. Many of the potential new anal- T.M.-D.; Berezowska, I.; Lemieux, C.; Chung, N.N.; gesics act at these molecules.. Carpenter, K.A.; and Wilkes, B.C. Four different types Dr. Peter Schiller of the Clinical Research Institute of of opioid peptides with mixed mu agonist/delta antago- Montreal has developed a compound called DIPP[psi]- nist properties. Analgesia 1:703-706, 1995. amide that is both a mu agonist and a delta antagonist.

39 Research Findings VolumeVolume 11, Number #, Number 3 (May/June (Month 1996)Year)

UNC Scientist Searches for Effective Analgesics with Low Abuse Potential By Michael Mueller, NIDA NOTES Staff Writer

NIDA MERIT Award winner Moreover, she is turning her attention to opioids that Dr. Linda A. Dykstra inves- interact with both mu and delta receptors. “The added tigates drugs that effectively benefit of these compounds is that they can produce relieve pain but have a low strong analgesia but with less respiratory depression, likelihood of being abused. another of morphine’s unwanted effects,” she says. Her behavioral pharmacol- According to Dr. Dykstra, the MERIT Award has ogy research at the University brought an important element of freedom to her research. of North Carolina (UNC) at “It has meant a long period of secure support during Chapel Hill is directed at how which I have had more freedom to change directions in opioid receptors help bring response to discoveries in our laboratory as well as in the about analgesia. broader scientific community,” says Dr. Dykstra. “It has Dr. Dykstra is studying three allowed me to take more chances and engage in more opioid receptors—delta, kappa, innovative research.” and mu—and the ways that opioid pain relievers interact Many students at the University of North Carolina at with them. Opioid receptors are molecules built into the Chapel Hill have benefited from the research environment walls of nerve cells. There are many kinds, each designed provided by Dr. Dykstra’s MERIT Award. “It has allowed to receive or bind with a specific type of chemical. us to create an environment that is optimal for training Morphine, like other currently licensed opioid analgesics, new students, as the long period of secure funding gives binds to opioid receptors to bring about pain relief, but the students a chance to pursue innovative ideas,” explains leads to tolerance over time. Dr. Dykstra. “At least a dozen graduate and undergraduate During the earlier part of her MERIT Award research, students have been involved in the studies I’ve conducted Dr. Dykstra found that the analgesic effects of morphine since receiving the award.” are determined in part by how the drug interacts with Dr. Dykstra has studied the behavioral pharmacology of the mu receptor. “This kind of knowledge can direct us analgesics for nearly 20 years. In addition to the MERIT in developing new drugs that have morphine’s analgesic Award, she has received a NIDA Research Scientist effects, with less likelihood of possibly leading to physical Award. At present, Dr. Dykstra is director of a NIDA dependence,” says Dr. Dykstra. training grant for predoctoral training in research on drug Currently, Dr. Dykstra is exploring the effects of partial abuse; she holds another research grant for the study of agonists. Partial agonists bind to opioid receptors and opioids’ effects on immune function. reduce pain, but they are not as powerful as morphine. Dr. Dykstra served on NIDA’s National Advisory Council Thus, they do not produce as strong a reinforcing effect, on Drug Abuse from 1991 to 1994. In 1972, after receiv- a key factor in the progression to drug dependency. Other ing her Ph.D. in psychology from the University of opioid analgesics act on different opioid receptors, pro- Chicago, she was awarded a NIDA Postdoctoral Research ducing different effects. Fellowship in pharmacology. Dr. Dykstra is the William Dr. Dykstra also is testing the analgesic effects of new Rand Kenan, Jr., Professor in the Departments of drugs that bind with kappa and delta types of receptors. Psychology and Pharmacology at UNC-Chapel Hill.

40 Research Findings Volume Volume11, Number #, Number 2 (March/April (Month 1996)Year)

NIDA Research Expands Horizon for Analgesia Alternatives By John A. Bowersox, NIDA NOTES Contributing Writer

NIDA’s commitment medications can produce limit their effectiveness and con- to basic neuroscience tribute to the need for alternative analgesics. research continues NIDA-supported researchers are addressing this need to result in impor- through a number of experimental approaches. These tant advances in the include: understanding of pain and how it might • Developing opioid compounds, synthetic derivatives be controlled more of opiates, that promote pain relief without producing effectively. NIDA- the euphoria, or “high,” that can lead to addiction; supported studies of • Developing “promoter compounds” that enhance the the pain-relieving, or pain-relieving effects of opioids so that smaller doses analgesic, properties can be used; and of addictive drugs and how they work have • Developing nonopioid analgesics that function broadened the horizon through a different pain-relief process and presumably will not produce the negative side effects of opioids. Opiate drugs produce their analgesic for analgesia research, effects by preventing pain signals from as scientists discover Research conducted by Dr. Hough and his colleagues being transferred from the spinal cord that pain relief can holds promise for the development of clinically useful to the brain. One group of researchers be effected through a nonopioid analgesics. For years, says Dr. Hough, scientists is exploring ways to improve the spinal variety of processes. have known that the brain activates a number of pain- administration of opiate analgesics that will exploit their pain-relieving proper- “There are multiple relieving systems in response to stress. Several of these ties while bypassing their harmful or pain-relieving mecha- systems appear to require histamine, a natural substance unpleasant side effects. nisms and many pieces released by the body during stress. Histamine produces to the puzzle of how a variety of effects associated with the stress response, they work,” says Dr. including the stimulation of gastric secretion, the constric- Lindsay Hough, a NIDA-funded researcher at the Albany tion of muscles of the respiratory system, and the dilation Medical College in New York. By putting these pieces of blood vessels. together, NIDA-supported researchers hope to develop Dr. Hough added to the number of known effects of his- new pain-relief strategies and improve existing analgesia tamine by showing that, in rats, morphine does not pro- medications. duce optimal analgesia unless histamine is released from A main focus of NIDA-supported analgesia research is to a brainstem structure called the dorsal raphe nucleus or develop medications that relieve pain without producing its surrounding tissue, known as the periaqueductal grey. unwanted side effects. Opiate analgesics such as morphine are among the most effective medications currently avail- able for treating long-term pain. Nonetheless, because Studies have found that the many opiates have addictive side effects, physicians often fear of becoming addicted to under-prescribe them because they or their patients fear that the use of these medications could lead to opiate opiates used clinically to addiction. These perceptions linger even though studies treat pain is unfounded have found that the fear of becoming addicted to opi- ates used clinically to treat pain is unfounded. (See “Pain Relief vs. Physical Dependency and Addiction: A Doctor’s Dilemma,” NIDA NOTES, Vol. 8, No. 3). He also found that histamine itself can produce analgesia when injected into this same part of the brain. Histamine- Still, these fears and debilitating side effects, such as nau- induced analgesia can be inhibited by simultaneously sea, sedation, confusion, and constipation, that opiate

41 injecting morphine antagonists, compounds that interfere fenfluramine, an appetite suppressant that promotes the with the interactions between morphine and brain cells, release of serotonin from neurons, required 25 to 50 per- into the same brain region. These findings, he says, suggest cent less morphine to relieve their pain than did those that histamine works with morphine or other opioid com- who received a placebo. pounds to relieve pain through a shared brain pathway. Dr. Shen is continuing this research to test a class of In recent studies, Dr. Hough and his colleagues showed antidepressant medications known as selective serotonin that certain compounds derived from histamine can re-uptake inhibitors (SSRIs). As their name suggests, induce powerful analgesia in rats. Most importantly, SSRIs inhibit serotonin-releasing neurons from taking the says Dr. Hough, the histamine derivatives, unlike hista- neurotransmitter back up after it has been released. Thus, mine, are not blocked by opiate antagonists. This finding serotonin remains in the spaces between neurons, free to implies the existence of a pain relief pathway in the brain repeatedly activate those that have serotonin receptors. that functions independently of the pathway used by mor- A consortium of NIDA-supported investigators that phine and other opiates. includes Dr. Shen, Dr. Christopher Bernards of the “We think the histaminergic system is central to analge- University of Washington, and Dr. Tony L. Yaksh of the sia,” says Dr. Hough, referring to the nerve cells and brain University of California at San Diego is trying to deter- regions that use histamine as their neurotransmitter, or chemical messenger. Although still at an early stage, Dr. Hough’s research into histamine-derived analgesics could A main focus of NIDA-supported lead to a new class of nonopioid pain relief medications. analgesia research is to develop While NIDA-supported researchers such as Dr. Hough are trying to develop novel pain-relief strategies that are medications that relieve pain not mediated by opioid compounds, others are trying to without producing unwanted improve existing opioid medications by finding ways to enhance their analgesic properties. side effects. Researchers have long known that amphetamines and other central nervous system stimulants increase the anal- mine the best way to deliver opiate analgesics directly to gesia induced by opioid medications. Anecdotal evidence the spinal cord. Dr. Yaksh was the first to demonstrate suggests that medications that activate brain regions that that opiates with an action limited to the spinal cord use the neurotransmitters serotonin and norepinephrine could produce a powerful analgesia. This work has led to can produce similar effects. NIDA-funded researchers the characterization of other spinal receptor systems that hope to exploit these effects through the development of also can produce analgesia. a pain-relief strategy known as enhancement or promoter therapy. Spinal drug delivery reduces the discomfort that morphine can cause. However, some morphine is still able to seep The principal aim of enhancement therapy research is to into the bloodstream and thus be carried into the brain identify nonanalgesic drugs that can selectively enhance and other organs, where opiates’ side effects originate. the pain-relieving effects of morphine and other opiates, Researchers suspect that improving the spinal administra- says NIDA researcher Dr. Danny Shen. This approach tion of opioids could present yet another opportunity to ultimately could allow physicians to prescribe smaller exploit the analgesic properties of opiates while bypassing doses of opioids while achieving the same or greater their harmful or unpleasant side effects. degrees of pain relief. Smaller doses of opioids also could make the detrimental side effects of these medications less Sources of a consideration in treatment decisions. • Coda, B.A.; Hill, H.F.; Schaffer, R.L.; Luger, T.J.; Dr. Shen and Dr. Barbara Coda, his colleague at the Jacobson, R.C.; and Chapman, C.R. Enhancement of Fred Hutchinson Cancer Research Center in Seattle, are morphine analgesia by fenfluramine in subjects receiv- investigating whether compounds that either promote or ing tailored opioid infusions. Pain 52:85-91, 1993. prolong the activity of serotonin, a neurotransmitter that • Thoburn, K.K.; Hough, L.B.; Nalwalk, J.W.; and some neurons use to communicate with each other, can Mischler, S.A. Histamine-induced modulation of enhance analgesia. nociceptive responses. Pain 58:29-37, 1994. In a NIDA-supported study, these investigators confirmed • Yaksh, T.L., and Rudy, T.A. Analgesia mediated by a the long-held belief that activation of the brain’s seroto- direct spinal action of . Science 192:1357- nergic pathways can enhance opiate-induced analgesia 1358, 1976. in people. In this study, subjects who were given

42 Research Findings Volume Volume11, Number #, Number 2 (March/April (Month 1996)Year)

Scientists Explore Novel Approaches to Pain Control By John A. Bowersox, NIDA NOTES Contributing Writer

Two recent studies conducted by scientists in NIDA’s phine combination could be to control pain in patients Division of Intramural Research (DIR) at the Addiction who do not respond to opiates alone, he adds. Such Research Center (ARC) in Baltimore add to the variety of patients might respond to the enhanced analgesia pro- possible alternative methods of pain control. One study moted by verapamil. examined whether a medication used primarily for heart Dr. Vaupel notes that the most novel finding, however, problems might also be useful for treating pain; the other was that the euphoria and other pleasant feelings associ- investigated a pain-relief pathway that is controlled by ated with the morphine high that were reported by the sensory nerves in the body’s periphery and thus does not study subjects declined more rapidly in individuals who involve the central nervous system. received verapamil than in those who received morphine In the first study, Drs. Bruce Vaupel, W. Robert Lange, only. This effect also could help reduce the dependence and Edythe D. London of the DIR demonstrated that the liability of analgesic or pain-relieving doses of morphine. medication verapamil boosted the analgesic effect of mor- This study involved volunteers with histories of heroin phine and moderated the “high” that is a common side abuse who were subsequently offered referrals to drug effect of morphine and other opiates. abuse treatment programs. Verapamil’s effect on mor- A calcium channel blocker, verapamil closes the pas- phine-induced analgesia may be even more pronounced in sageways through which calcium enters and exits cells. nondrug-abusing patients, says Dr. Vaupel. “Because each Manipulating calcium channels with medications can individual in the study had a history of heroin abuse, each serve a variety of therapeutic purposes. Physicians often may have had a tolerance for morphine,” he says. Drug- prescribe verapamil and other calcium channel blockers tolerant individuals require more of a drug to experience to treat high blood pressure, irregular heartbeat, and chest the same effects that lower doses cause in drug-naive pain caused by heart disease. In animal experiments, cal- subjects. cium channel blockers also have been shown to increase “We may be underestimating the effect,” Dr. Vaupel says. the pain-relieving effect of morphine. If so, the verapamil-morphine combination might pro- duce even greater analgesia in nondrug-abusing patients. Further research is necessary to determine verapamil’s Calcium channel blockers, which effects in drug-naive populations, he adds. are used primarily to treat high Animal experiments conducted for the second study at the ARC suggest the possibility of developing a new genera- blood pressure and other heart tion of analgesics that function by stimulating injured problems, have been shown to tissue to release endogenous opioids, naturally occurring painkillers produced by the body. increase the pain-relieving effect of The study, which was conducted by Dr. Christoph Stein morphine in animals. and Dr. Michael Schäfer, found that two immune sys- tem substances, interleukin-1 (IL-1) and corticotropin- releasing factor (CRF), inhibited pain when injected into In their study, which was the first demonstration of this inflamed tissue in rats. IL-1 and CRF did not inhibit pain effect in humans, Dr. Vaupel and his colleagues found in noninflamed tissue. that individuals who received a combination of morphine The researchers suspected that the pain-relieving effects of and verapamil had a higher pain threshold than did indi- IL-1 and CRF were related to the presence of endogenous viduals who received only morphine. “Verapamil could opioids, also known as , in the inflamed tissue. allow greater pain relief with smaller doses of morphine” Three experiments confirmed their predictions. IL-1 and and thus be of clinical benefit, says Dr. Vaupel. Another CRF failed to produce analgesia when antibodies that potential therapeutic application of the verapamil-mor- bind to and inactivate endorphins were injected into the

43 inflamed tissue. Pain relief also was blocked by injecting of endorphins following injury. By binding to opioid opioid receptor antagonists into the tissue. Opioid antago- receptors on sensory nerve cells at the site of injury, locally nists neutralize endorphins by blocking the sensory nerve acting endorphin analgesics would not cause unpleasant side cell receptors to which they bind. Finally, the researchers effects, such as nausea, sedation, confusion, and breathing measured the release of endorphin from immune cells difficulties, which can result from the use of opioids that grown in the laboratory. bind to receptors in the brain. Based on these findings, Dr. Stein, an associate profes- sor of anesthesiology at the Johns Hopkins School of Sources Medicine, hypothesizes that IL-1 and CRF relieve pain by • Schäfer, M.; Carter, L.; and Stein, C. Interleukin-1 releasing endorphins from inflamed tissue. These endog- b and corticotropin-releasing factor inhibit pain by enous opioids then bind chemically to opioid receptors releasing opioids from immune cells in inflamed located on sensory nerve terminals in the inflamed tissue tissue. Proceedings of the National Academy of Sciences to produce potent analgesia. 91:4219-4223, 1994. The findings, say Dr. Stein and Dr. Schäfer, clearly • Vaupel, D.B.; Lange, W.R.; and London, E.D. suggest the existence of a functional link between the Effects of verapamil on morphine-induced euphoria, immune and sensory nervous systems. The study findings analgesia, and respiratory depression in humans. The also suggest that it may be possible to develop a new gen- Journal of Pharmacology and Experimental Therapeutics eration of analgesics that would promote the local release 267:1386-1394, 1993.

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