Category: Opium

— Opiate abuse is a chronic disorder and maintaining abstinence represents a major challenge for addicts.

Individuals recovering from opiate dependence have long reported that while the acute withdrawal symptoms from opiates may pass relatively quickly, they do not feel quite right for several weeks or even months thereafter. Called the "protracted abstinence syndrome," this cluster of vague depressive-like symptoms can include reduced concentration, low energy level, poor sleep quality, and anhedonia.

New data in animals, reported in Biological Psychiatry, now implicates the serotonin system in this phenomenon.

French researchers found that mice with chronic morphine exposure showed decreasing physical dependence during a period of abstinence, with no physical withdrawal symptoms after 4 weeks. In contrast, low sociability and despair behavior clearly developed after 4 weeks of abstinence.

Remarkably, treatment during the abstinence period with the antidepressant fluoxetine prevented the development of both social aversion and despair behavior.

This is important because fluoxetine targets the serotonin system, which is known to influence mood.

Senior author Dr. Brigitte Kieffer explained that this study "establishes a direct link between morphine abstinence and depressive-like symptoms, and strongly suggests a causal effect of serotonin dysfunction in depressive features associated with abstinence."

"The greatest risk associated with protracted abstinence is relapse to drug use," comments Dr. John Krystal, Editor of Biological Psychiatry. "This study provides new insights into a process that may contribute to relapse."

These findings should foster novel research along serotonergic pathways in drug abuse. It is hoped that these findings can lead to real-world clinic use, since serotonergic medication is already broadly available.

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Journal Reference:

1. Celia Goeldner et al. Impaired Emotional-Like Behavior and Serotonergic Function During Protracted Abstinence from Chronic Morphine. Biological Psychiatry, Volume 69, Number 3 (February 1, 2011)

— Retired NFL players use painkillers at a much higher rate than the rest of us, according to new research conducted by investigators at Washington University School of Medicine in St. Louis.

The researchers say the brutal collisions and bone-jarring injuries associated with football often cause long-term pain, which contributes to continued use and abuse of painkilling medications.

The study is published online in the journal Drug and Alcohol Dependence. It involved 644 former NFL players who retired from football between 1979 and 2006. Researchers asked them about their overall health, level of pain, history of injuries, concussions and use of prescription pain pills.

The study found that 7 percent of the former players were currently using painkilling opioid drugs. That's more than four times the rate of opioid use in the general population. Opioids are commonly prescribed for their analgesic, or pain-relieving, properties. Medications that fall within this class of drugs include morphine, Vicodin, codeine and oxycodone.

"We asked about medications they used during their playing careers and whether they used the drugs as prescribed or whether they had ever taken them in a different way or for different reasons," says principal investigator Linda B. Cottler, PhD, professor of epidemiology in psychiatry at Washington University. "More than half used opioids during their NFL careers, and 71 percent had misused the drugs. That is, they had used the medication for a different reason or in a different way than it was prescribed, or taken painkillers that were prescribed for someone else."

Those who misused the drugs during their playing days were more likely to continue misusing them after retiring from football. Some 15 percent of those who misused the drugs as active players still were misusing them in retirement. Only 5 percent of former players who took the drugs as prescribed misused them after they retired from the NFL.

Cottler, director of the Epidemiology and Prevention Research Group in the Department of Psychiatry, says it's not clear from the study whether retired players became dependent on the drugs. What is clear from the survey, she says, is that retired NFL players continue to live with a lot of pain.

"The rate of current, severe pain is staggering," she says. "Among the men who currently use prescription opioids — whether misused or not — 75 percent said they had severe pain, and about 70 percent reported moderate-to-severe physical impairment."

Pain was one of the main predictors of current misuse. Another was undiagnosed concussion. Retired NFL players in the study experienced an average of nine concussions each. Some 49 percent had been diagnosed with a concussion at some point during their playing careers, but 81 percent suspected they had concussions that were not diagnosed. Some players believed they may have had up to 200 concussions during their playing days.

"Many of these players explained that they didn't want to see a physician about their concussions at the time," says Simone M. Cummings, PhD, a senior scientist in psychiatry who conducted phone interviews with the former players. "These men said they knew if they reported a concussion, they might not be allowed to play. And if you get taken out of a game too many times, you can lose your spot and get cut from the team."

She says players with suspected-but-undiagnosed concussions reported they borrowed pills from teammates, friends or relatives to treat the pain themselves, thus misusing opioids in an attempt to remain in the NFL. Although 37 percent of the retired players reported that they had received opioids only from a doctor, the other 63 percent who took the drugs during their NFL careers admitted that on occasion they got the medication from someone other than a physician.

Retired players currently misusing opioid drugs also are more likely to be heavy drinkers, according to Cottler.

"So these men are at elevated risk for potential overdose," she says. "They reported more than 14 drinks a week, and many were consuming at least 20 drinks per week, or the equivalent of about a fifth of liquor."

The ESPN sports television network commissioned the study, which also was funded by the National Institute on Drug Abuse. The ESPN program "Outside the Lines" spoke informally to many retired players about their use of painkillers. One reported taking up to 1,000 Vicodin tablets per month. Another reported ingesting 100 pills per day and spending more than $1,000 per week on painkillers.

Former St. Louis Rams offensive lineman Kyle Turley said in a statement to ESPN that he knew of many players who took drugs to help them deal with the pain inflicted by the injuries they sustained in the NFL.

"I know guys that have bought thousands of pills," Turley said. "Tons of guys would take Vicodin before a game."

The researchers say offensive linemen had particularly high rates of use and misuse of opioids.

"The offensive linemen were twice as likely as other players to use or misuse prescription pain medicines during their NFL careers," Cottler says. "In addition, this group tends to be overweight and have cardiovascular problems, so they represent a group of former players whose health probably should be monitored closely."

In fact, Cottler says it would be a good idea to continue monitoring everyone who has played in the NFL. She says this study revealed that some 47 percent of retired players reported having three or more serious injuries during their NFL careers, and 61 percent said they had knee injuries. Over half, 55 percent, reported that an injury ended their careers.

"These are elite athletes who were in great physical condition when their playing careers began," she says. "At the start of their careers, 88 percent of these men said they were in excellent health. By the time they retired, that number had fallen to 18 percent, primarily due to injuries. And after retirement, their health continued to decline. Only 13 percent reported that they currently are in excellent health. They are dealing with a lot of injuries and subsequent pain from their playing days. That's why they continue to use and misuse pain medicines."

Cottler LB (WU), Abdallah AB (WU), Cummings SM (WU), Barr J (ESPN), Banks R (ESPN), Forchheimer R (ESPN). Injury, pain and prescription opioid use among former NFL football players, Drug and Alcohol Dependence, vol. 113(3), Jan. 28, 2011.

This work was commissioned and supported by a grant from ESPN, with additional funding from the National Institute on Drug Abuse of the National Institutes of Health.

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Journal Reference:

1. Linda B. Cottler, Arbi Ben Abdallah, Simone M. Cummings, John Barr, Rayna Banks, Ronnie Forchheimer. Injury, pain and prescription opioid use among former NFL football players. Drug and Alcohol Dependence, 2011; DOI: 10.1016/j.drugalcdep.2010.12.003

— A little-known morphine-like drug is potentially more potent, longer lasting and less likely to cause constipation than standard morphine, a study led by a Loyola University Health System anesthesiologist has found.

The drug, morphine-6-0-sulfate, has a similar chemical structure to standard morphine. Dr. Joseph Holtman Jr. and colleagues reported that a study they performed in rats "demonstrated potential clinical advantages of morphine-6-0-sulfate compared to morphine."

Holtman is first author of the study, published in the December 2010 issue of the European Journal of Pharmacology.

Holtman is medical director of Loyola's Pain Specialty Service and a professor in the departments of Anesthesiology and Molecular Pharmacology and Therapeutics of Loyola University Chicago Stritch School of Medicine. He directed the study while he was at the University of Kentucky's College of Medicine. He joined Loyola on March 1, 2010.

Opioids, such as morphine, oxycodone and hydrocodone, are standard drugs for treating moderate to severe pain, including cancer pain. But these drugs can have significant side effects, including constipation, nausea, vomiting, drowsiness, cognitive dysfunction and slowed breathing and heart rates. And while opioids work well for conditions such as back pain and post-operative pain, the drugs are less effective against neuropathic pain, such as tingling, burning or shooting pain.

Constipation is a common side effect of morphine and can be so uncomfortable that some patients limit their use of the drug. Doctors typically do not discharge surgery patients until they have had a bowel movement and this can extend hospital stays.

Holtman and colleagues tested standard morphine and morphine-6-0-sulfate on rats. The animals received the drugs three ways — by mouth, by IV and by injection into the space surrounding the spinal cord.

The rats underwent several well-established tests to determine their sensitivity to pain. In one such test, researchers focused a very warm light beam on the tail and measured how long it took for the rat to flick the tail.

In this tail-flick test, morphine-6-0-sulfate was 10 times more potent than standard morphine when administered in the space surrounding the spinal cord, five times more potent when administered by IV and two times more potent when given by mouth. Morphine-6-0-sulfate maintained its maximum effect for three hours, compared with 1½ hours for standard morphine. And it took rats 25 days to build tolerance to morphine-6-0-sulfate, compared with 10 days with standard morphine.

Morphine-6-0-sulfate also was more potent than standard morphine for neuropathic and inflammatory pain.

Researchers found that morphine-6-0-sulfate could cause constipation, but only at doses 10 to 20 times higher than the effective doses.

The findings suggest that morphine-6-0-sulfate "may be an interesting potential drug for further study," Holtman and colleagues wrote.

Co-authors of the study, all at the University of Kentucky, are Peter Crooks, Jaime Johnson-Hardy and Elzbieta Wala.

The study was funded by Insys Therapeutic, Inc., which is has a license to develop the drug for possible use in humans.

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Journal Reference:

1. Joseph R. Holtman Jr., Peter A. Crooks, Jaime Johnson-Hardy, Elzbieta P. Wala. Antinociceptive effects and toxicity of morphine-6-O-sulfate sodium salt in rat models of pain. European Journal of Pharmacology, 2010; 648 (1-3): 87 DOI: 10.1016/j.ejphar.2010.08.034

 Opioids appear to be associated with more adverse events among older adults with arthritis than other commonly used analgesics, including coxibs and non-steroidal anti-inflammatories, according to a report in the December 13/27 issue of Archives of Internal Medicine, one of the JAMA/Archives journals. In a second report assessing only opioid use, different types of drugs within the class were associated with different safety events among older patients with non-malignant pain.

"In the United States, one in five adults received a prescription for an analgesic in 2006, accounting for 230 million prescription purchases; however, the comparative safety of these drugs is unclear," the authors write as background information in one of the articles. "Although the cardiovascular safety of nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs) and selective cyclooxygenase-2 inhibitors (coxibs) has been called into question, there is little comparable information about the third major analgesic group, opioids."

In the first report, Daniel H. Solomon, M.D., M.P.H., and colleagues at Brigham and Women's Hospital, Boston, examined the comparative safety of nsNSAIDs, coxibs and opioids among 12,840 Medicare beneficiaries who received at least one of these analgesics between 1999 and 2005. Using data from a large health care utilization (claims) database, the authors evaluated the occurrence of cardiovascular events (heart attacks, stroke and heart failure, among others), gastrointestinal events (GI tract bleeding and bowel obstruction), acute kidney injuries, toxic effects on the liver, as well as falls and fractures.

Opioid users experienced higher rates for most types of serious adverse events than patients taking coxibs or nsNSAIDs, and nsNSAID users experienced the lowest risks. For example, fractures occurred among 101 per 1,000 opioid users per year, compared with 19 per 1,000 per year among coxib users.

Coxibs and opioids appear to be associated with greater cardiac risks than nsNSAIDs, but use of opioids and not coxibs was associated with a greater risk of hospitalization or death than use of nsNSAIDs. Conversely, the risk of gastrointestinal tract bleeding was reduced among those taking coxibs (12 per 1,000 per year, compared with 21 per 1,000 per year among those taking nsNSAIDs).

"Analgesics are used daily by millions of people; however, current data do not allow patients or physicians to determine which type of agent is safest. We compared nsNSAIDs, coxibs and opioids across a wide range of specific safety events and several composite safety events," the authors write. "Although nsNSAIDs pose certain risks, these analyses support the safety of these agents compared with other analgesics. The recent concerns raised about opioid use in non-malignant pain syndromes appear warranted on the basis of these data."

In a second article, Dr. Solomon and colleagues at Brigham and Women's Hospital studied only those Medicare beneficiaries who received opioids for non-malignant pain between 1996 and 2005. They compared the rates of adverse events after 30 and 180 days among 6,275 patients each taking one of five types of opioids: codeine, hydrocodone, oxycodone, propoxyphene and tramadol.

The risk of gastrointestinal adverse events remained similar for all the medications studied, and thirty days after beginning opioid therapy, the risk of cardiovascular events was also similar across all types. However, after 180 days, the risk of cardiovascular events was increased among those taking codeine. With hydrocodone as the reference point, risk of fracture was 79 percent lower among those taking tramadol and 46 percent lower among those taking propoxyphene. Compared with those taking hydrocodone, death from any cause was 2.4 times as likely among those taking oxycodone and twice as likely among those taking codeine.

"This study's findings do not agree with a commonly held belief that all opioids are associated with similar risk," the authors write. "The risks were not explained by the dosage being prescribed and did not vary across a range of sensitivity analyses. The risks were substantial and translated into numbers needed to treat that would be considered clinically significant. Our findings regarding cardiovascular risk were surprising and require validation in other data sets."

Proving a cause-and-effect relationship between types of opioids and adverse events requires an experimental rather than observation study design, they note, "but these results should prompt caution and further study."

In addition, a research letter, published in the same issue, found double the risk of cardiovascular events among patients followed for a median (midpoint) of 189 days after they stopped taking the analgesic drug rofecoxib during off-drug follow-up of a clinical trial. Joseph S. Ross, M.D., M.H.S., of Yale University School of Medicine, and colleagues analyzed data from a clinical trial that became available through litigation. Twenty-two cardiovascular events and 23 deaths occurred among patients who had taken rofecoxib in the trial, compared with six cardiovascular events and nine deaths among participants who took placebo.

The studies were funded by grants and contracts from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, as part of the Developing Evidence to Inform Decisions about Effectiveness (DECIDE) program.

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Journal Reference:

1. Joseph S. Ross et al. Persistence of Cardiovascular Risk After Rofecoxib Discontinuation. Arch Intern Med., 2010;170(22):2035-2036 DOI: 10.1001/archinternmed.2010.461

— A single injection of morphine to fight persistent pain in male rats is able to strongly reduce the hormone testosterone in the brain and plasma, according to a new paper published in the journal Molecular Pain.

The study, led by Anna Maria Aloisi, M.D., of the Department of Physiology — Section of Neuroscience and Applied Physiology at the University of Siena, Italy, Sbarro Institute for Cancer Research and Molecular Medicine at Temple University in Philadelphia, University of Siena, and the Human Health Foundation in Spoleto, Italy, showed that opioids had "long lasting genomic effects in body areas which contribute to strong central and peripheral testosterone levels" including the brain, the liver and the testis.

The study showed increases in aromatase, an enzyme that is responsible for a key step in the biosynthesis of estrogen. The findings are particularly important since testosterone is the main substrate of aromatase, which is involved in the formation of estradiol. Both testosterone and estradiol are important hormones, engaged in cognitive functions as well as in mood, motor control and in many other functions, such as bone structure remodeling.

"Our lab became interested in gonadal hormones several years ago when it became clear that there were many differences in pain syndromes between the sexes," says Dr. Aloisi. "In looking at differences, it was immediately apparent that these changes were introduced by different treatments, opioids in particular."

"The research findings are very relevant to the management of patients with chronic pain," said Marco Pappagallo, M.D., professor and director of pain research and development, Department of Anesthesiology, Mount Sinai School of Medicine, New York, NY. "Today, primary care physicians, pain specialists, and a variety of health care professionals are asked not only to treat pain but how to manage side effects of drugs and to strive for the best possible comprehensive care and wellness of patients who experience chronic pain. Opioid induced hypogonadism can cause health complications to which patients with pain can be overly susceptible, including chronic fatigue, loss of stamina, emotional and sexual disturbances, as well painful skeletal and muscular complications."

It has been known that patients treated with opioids for short or long periods show low levels of gonadal hormones. Hypogonadism was already described in opioid users and applied to pain patients as OPIAD (opioid induced androgen deficiency). It is also known that patients treated with opioids, including newer drugs (fentalyl, tramadol) have a high probability to be hypogonadic, with menopausal symptoms occurring in women and andropausal symptoms in men.

"The use of opioids puts a 'physiological' block on the reproductive system and can induce a long lasting absence of these essential hormones from the blood and the brain," says Dr. Aloisi. "The normal effect of opioids to restrict reproduction in stressed subjects is multiplied by the higher levels/ long duration of opioids in the body."

"Until a few years ago this condition was completely unrecognized by physicians although some reports clearly showed it in many kinds of patients," notes Dr. Aloisi. "Today there remains some ignorance on this condition but gonadal hormones are more commonly cited as responsible for many chronic degenerative pathologies."

Despite the side effects of opioids, Antonio Giordano, M.D., Ph.D., Director of the Sbarro Institute for Cancer Research and Molecular Medicine, warns that the study's message is not meant to limit the use of opioids for pain. Instead, he suggests that doctors should "take into consideration this side effect, since it is very easy to find hormone replacement therapies. Using HRTs, patients can get relief from their pain, and improve their quality of life."

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Journal Reference:

1. Anna Maria Aloisi, Ilaria Ceccarelli, Paolo Fiorenzani, Melinda Maddalena, Alessandra Rossi, Valentina Tomei, Giuseppina Sorda, Barbara Danielli, Michele Rovini, Andrea Cappelli, Maurizio Anzini, Antonio Giordano. Aromatase and 5-alfa Reductase Gene Expression: Modulation by Pain and Morphine Treatment in Male Rats. Molecular Pain, 2010; 6: 69 DOI: 10.1186/1744-8069-6-69

Helping to address the issue of medication adherence, persons with opioid dependence who had the medication buprenorphine implanted had less opioid use over 16 weeks, according to a study in the October 13 issue of JAMA.

Dependence on opioids, in the form of heroin or prescription pain medications, is a significant health concern. A treatment that has been increasing in usage is the medication buprenorphine, with numerous studies supporting the efficacy of sublingually (beneath the tongue) administered buprenorphine. However, poor treatment adherence, resulting in craving and withdrawal symptoms that increase the likelihood of relapse, is a concern, according to background information in the article. To address these problems with adherence and nonmedical use, an implantable formulation of buprenorphine was developed that delivers a constant and low level of buprenorphine. A preliminary open-label phase 2 study reported favorable results with this implant in opioid-dependent patients.

Walter Ling, M.D., of the University of California, Los Angeles, and colleagues conducted a phase 3 study of buprenorphine implants for treatment of opioid dependence at 18 sites in the United States between April 2007 and June 2008. The study included 163 adults, ages 18 to 65 years, diagnosed with opioid dependence. One hundred eight were randomized to receive buprenorphine implants and 55 to receive placebo implants. The implants were placed below the skin in the inner side of the nondominant arm. The 4 buprenorphine implants, each of which gradually released 80 mg of buprenorphine, and the 4 placebo implants, were removed after 6 months. Standardized individual drug counseling was provided to all patients. Opioid use was gauged via urine samples.

During the course of the study, the buprenorphine implant group had significantly more urine samples negative for illicit opioids during weeks 1 through 16. Patients with buprenorphine implants had an average percentage of urine samples that tested negative for illicit opioids of 40.4 percent and a median (midpoint) of 40.7 percent; those in the placebo group had an average of 28.3 percent and a median of 20.8 percent.

Treatment group differences were also evident on additional efficacy measures, with 65.7 percent of patients in the buprenorphine implant group remaining in the study for the full 24-week study period compared to 30.9 percent of patients in the placebo group. No patients in the buprenorphine implant group met the definition of treatment failure; 30.9 percent of placebo patients were classified as treatment failures.

"Those who received buprenorphine implants also had fewer clinician-rated and patient-rated withdrawal symptoms, had lower patient ratings of craving, and experienced a greater change on clinician global ratings of severity of opioid dependence and on the clinician global ratings of improvement than those who received placebo implants," the researchers write.

"In summary, this study found that the use of buprenorphine implants compared with placebo resulted in less opioid use over 16 weeks and also across the full 24 weeks."

Editorial: Advances in the Treatment of Opioid Dependence — Continued Progress and Ongoing Challenges

Patrick G. O'Connor, M.D., M.P.H., of the Yale University School of Medicine, New Haven, Conn., writes in an accompanying editorial that the study by Ling et al represents a potentially important step forward in the effort to improve and expand the treatment options for opioid dependence.

"Further research is needed to assess how this treatment compares with current opioid maintenance treatment prior to the widespread use of implant buprenorphine in clinical practice. If further research suggests that this buprenorphine implant is as good as or better than current treatment approaches, then the study by Ling et al would represent a major advance in the substantial and continued progress that has occurred in the treatment of opioid dependence since methadone maintenance began in the 1960s."

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Journal References:

1. P. G. O'Connor. Advances in the Treatment of Opioid Dependence: Continued Progress and Ongoing Challenges. JAMA: The Journal of the American Medical Association, 2010; 304 (14): 1612 DOI: 10.1001/jama.2010.1496
2. W. Ling, P. Casadonte, G. Bigelow, K. M. Kampman, A. Patkar, G. L. Bailey, R. N. Rosenthal, K. L. Beebe. Buprenorphine Implants for Treatment of Opioid Dependence: A Randomized Controlled Trial. JAMA: The Journal of the American Medical Association, 2010; 304 (14): 1576 DOI: 10.1001/jama.2010.1427

Thousands of infants each year have exposure to opioids before they are born. Over half of these infants are born with withdrawal symptoms severe enough to require opioid replacement treatment in the nursery. Such treatment is associated with long hospital stays which interferes with maternal/infant bonding.

Now, a team of researchers at Thomas Jefferson University has tested a semi-synthetic opioid they say has the potential to improve the treatment of these newborns, which could save hundreds of millions in healthcare costs annually if future tests continue to show benefit.

In the October 6th online issue of Addiction, the researchers say that using buprenorphine in a dozen addicted infants was both safe and successful and reduced days of treatment by 40 percent, compared to use of morphine in 12 other infants randomized to this treatment. The difference was 23 days of treatment versus 38 days.

"Given further study, such a beneficial drug could provide a new standard of treatment in a field where a well-defined therapeutic approach doesn't exist," says the study's lead author, Walter Kraft, M.D., associate professor in the Department of Pharmacology and Experimental Therapeutics at Jefferson.

"Not only do we think buprenorphine is an excellent choice to treat neonatal opioid withdrawal, but it may prove to also be cost effective," he says. "There are not good numbers to work with but we estimate up to 16,000 infants each year are at risk for the syndrome. If you assume the costs for this treatment are $2,000 a day over an average 30 days of hospitalization, annual charges for this treatment can be up to $1 billion."

"If we were to reduce hospital stay by just 20 percent, that would save $150 million," Dr. Kraft adds.

The investigative team, which includes experts in neonatology, addictions, clinical pharmacology and pediatric neurology are the first physicians to test buprenorphine in newborns. Buprenorphine is finding increased use in the treatment of adults with opioid dependence.

In infants, the agent was given sublingually — under the tongue — and to keep it there until it is absorbed, the physicians gave the babies pacifiers to suck. "This is the only report of a sublingual drug ever used in infants," Kraft says.

Many of the mothers of the infants receive care at the Family Center, which cares for the majority of pregnant opioid-addicted women in the Philadelphia area, Dr. Kraft says. The program is directed by co-author Karol Kaltenbach, Ph.D., who is a internationally known expert in the treatment of pregnant women with addiction.

In 2008, the research team published results from their first cohort using buprenorphine in infants. In this study, they enrolled 24 infants, half randomized to buprenorphine and half to standard of care oral morphine. The investigators found that infants treated with buprenorphine had a 23-day length of treatment, compared to 38 days for those treated with morphine. Length of hospital stay in the buprenorphine group was 32 days versus 42 in infants treated with morphine.

"They say that to truly know if buprenorphine is a better treatment for these infants, it will be necessary to conduct a double-blind randomized study in which physicians do not know which treatment has been administered. We are not using buprenorphine in infants who need treatment until we conduct this final step," Dr. Kraft says. "It is important to do the study in the most rigorous way possible, to prove the benefit of the therapy. We are currently in the planning stages of such a study."

Other co-authors include neonatologists Kevin Dysart, M.D.; Eric Gibson, M.D.; Jay Greenspan, M.D., chairman of the Department of Pediatrics; and Michelle Ehrlich, M.D., a pediatric neurologist.

The project was supported by the Commonwealth of Pennsylvania Tobacco Fund and the National Institute on Drug Abuse.

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Journal Reference:

1. Walter K. Kraft, Kevin Dysart, Jay S. Greenspan, Eric Gibson, Karol Kaltenbach, Michelle E. Ehrlich. Revised dose schema of sublingual buprenorphine in the treatment of the neonatal opioid abstinence syndrome. Addiction, 2010; DOI: 10.1111/j.1360-0443.2010.03170.x

— It is time to phase out the use of codeine as a pain reliever because of its significant risks and ineffectiveness as an analgesic, states an editorial in CMAJ (Canadian Medical Association Journal).

Although codeine has been used for pain relief for more than 200 years, it has never been subjected to the rigorous regulatory and safety requirements applied to all new drugs and its pharmacokinetics are unpredictable. Genetic variations in patients can mean very different responses to codeine, some with serious consequences. Infants and children are particularly vulnerable, and there have been several deaths due to different genetic responses. Serious, life-threatening effects have also been reported in adults.

"Because the need for oral pain control is so pervasive, the potential risk associated with codeine must be mitigated," write pediatricians Drs. Noni MacDonald, Section Editor, Public Health, CMAJ and Dr. Stuart MacLeod, University of British Columbia.

While limiting use of codeine, with minimum ages for codeine-based treatment, is one option, it is not ideal. Genetic testing prior to codeine use is expensive and impractical.

"Perhaps a more direct approach is now needed: to stop using the prodrug codeine altogether and instead use its active metabolite, morphine. Not only is the metabolism of morphine more predictable than that of codeine, but also it is cheaper," they write. They call for a warning to physicians and modifications to existing guidelines for codeine use and research to define safety parameters.

Patients who choose to spend their last days at home with specialized care and monitoring can safely be given opioids to control pain and other symptoms without reducing survival time, according to a study published in Journal of Palliative Medicine (JPM), a peer-reviewed journal from Mary Ann Liebert, Inc.

The use of high-dose opioids to relieve symptoms such as pain and shortness of breath in hospital- or hospice-based end-of-life care is proven to be effective but is available in only a few countries in the world. Many physicians around the world are afraid to prescribe opioids in sufficient doses to be effective in terminally ill patients in the home setting. Consequently, it is important that Itxaso Bengoechea, MD and colleagues from Galdakao-Usánsolo Hospital in Bizkaia, Spain, conducted a retrospective study on the safety and survival effects of increasing doses of opioids during end-of-life care at home. The study included 223 patients with terminal cancer who received specialized medical and nursing care and active monitoring in their homes.

The authors report that opioid use is both safe and effective and, in fact, patients who received a greater than two-fold increase in their initial dose had a longer median survival (22 days) than those who received lower doses (9 days). In the article entitled "Opioid Use at the End of Life and Survival in a Hospital at Home Unit," the authors conclude that opioid use in the home setting did not have a negative effect on patient survival time.

"Many worry that use of opioids in end-of-life care tacitly hastens death. Reassuringly, the results of this study show that higher doses were safe in the home and linked to longer survival," says Charles F. von Gunten, MD, PhD, Editor-in-Chief of Journal of Palliative Medicine and Provost, Institute for Palliative Medicine at San Diego Hospice.

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Journal Reference:

1. Itxaso Bengoechea, Susana Garcia Gutiérrez, Kalliopi Vrotsou, Miren Josune Onaindia, Jose Maria Quintana Lopez. Opioid Use at the End of Life and Survival in a Hospital at Home Unit. Journal of Palliative Medicine, 2010: 100828074323069 DOI: 10.1089/jpm.2010.0031

 If you want to know how people become addicted and why they keep using drugs, ask the people who are addicted.

Thirty-one of 75 patients hospitalized for opioid detoxification told University at Buffalo physicians they first got hooked on drugs legitimately prescribed for pain.

Another 24 began with a friend's left-over prescription pills or pilfered from a parent's medicine cabinet. The remaining 20 patients said they got hooked on street drugs.

However, 92 percent of the patients in the study said they eventually bought drugs off the street, primarily heroin, because it is less expensive and more effective than prescriptions.

They continued using drugs because they "helped to take away my emotional pain and stress," "to feel normal," "to feel like a better person."

Results of the study appear in the current issue of Journal of Addiction Medicine.

The information will be used to train medical students and residents at the UB School of Medicine and Biomedical Sciences and practicing physicians to screen for potential addiction among their patients, and to perform an intervention or refer for treatment before an addiction becomes life-threatening.

"We are seeing an increase in the number of patients addicted to prescription

drugs," says Richard Blondell, MD, professor of family medicine and senior author on the study, "so we wanted to better understand how they first got hooked.

"This information suggests that there is a progressive nature to opioid use, and that prescription opioids can be the gateway to illicit drug addiction. It also tells us that people who use prescriptions illegally may be at greater risk for subsequent heroin use than those who use prescriptions legally."

The study group was recruited from patients admitted to the detoxification unit in Erie County Medical Center in Buffalo who were addicted to opioids — defined as opiates that are made from the opium poppy (morphine, codeine and heroin) or medications that are developed artificially (methadone or fentanyl).

Researchers collected demographic and socioeconomic information from participants, plus the types of drugs they used, age of first use, preferred opioids and how they administered the drugs. They also asked participants how they got started and how their drug use progressed.

Replies showed that the average age of users was 32; that 65 percent were men, 77 percent considered themselves white, and 74 percent had a high school diploma or equivalent.

Why did they begin using? Slightly more than half — 51 percent — said they first used the drugs for pain — after surgery, for back pain or after an injury, and 49 percent said because they were curious and/or someone they were with had the drugs.

Those who became addicted from using drugs legally prescribed for pain were more likely to be older, female, have a college degree and more likely to take their drugs orally, rather than nasally or via injection.

Users' comments on how they got started using drugs other than for pain, and why they continued, were revealing. "Pill parties" were a common starting point. One person said the drug "was handed to me by my friend, this guy I know, someone who was at the party." Another patient said kids are using it "like Viagra."

Prescription drugs are available in high schools, "at the prom" and used by athletes "to make it through the game," and later to get high on weekends and during the off-season, according to the users.

When asked if any doctor had ever asked about a substance use problem before writing a prescription, of the 53 participants who answered the question, 74 percent said no.

Blondell emphasized that the prescribing physician is in the best position to prevent or address addiction in their patients.

"I tell patients that addiction can be an unintended side-effect that occurs occasionally with the use of these medications," says Blondell.

"Doctors need to be able to help them if this occurs, so doctors will need to monitor the use of these medications closely. I also tell patients to discard unused medication ASAP. to prevent addiction in themselves and those, such as teenage family members, who might get their hands on these leftover pills.

Marta C. Canfield, MD, who completed her residency in the UB Department of Family Medicine and now is in practice in Western New York, is first author on the study. Craig E. Keller, Lynne M. Frydrych, Lisham Ashrafioun and Christopher H. Purdy, all from UB, also contributed to the study.

The research was supported by a grant to Keller from the UB Foundation Family Medicine Endowment; by a grant to Blondell and Frydrych from the National Institute on Alcohol Abuse and Alcoholism, and by the UB Interdisciplinary Research Fund.

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Journal Reference:

1. Marta C. Canfield, Craig E. Keller, Lynne M. Frydrych, Lisham Ashrafioun, Christopher H. Purdy, Richard D. Blondell. Prescription Opioid Use Among Patients Seeking Treatment for Opioid Dependence. Journal of Addiction Medicine, 2010; 4 (2): 108 DOI: 10.1097/ADM.0b013e3181b5a713