Category: Opium

NewsPsychology (Aug. 23, 2011) — Action is needed to tackle the increasing number of deaths in the United States and Canada from prescription painkillers known as opioids, say experts in an article published online in the British Medical Journal.

Opioids are prescription painkillers that contain compounds derived from the opium poppy.

While they have long been used to control the symptoms of cancer and acute medical conditions, they are increasingly being used to control chronic pain, for example in patients suffering from osteoarthritis, say Dr Irfan Dhalla and colleagues at the University of Toronto.

They describe how in the US, deaths involving opioid painkillers increased from 4,041 in 1999 to 14,459 in 2007 and are now more common than deaths from skin cancer, HIV and alcoholic liver disease. They add that between 1.4 million and 1.9 million Germans are addicted to prescription drugs and that some authorities have suggested that the UK may face a similar epidemic to that of North America in five to ten years time. Indeed, the use of strong opioids for chronic non-cancer pain in the UK has been described as a “disaster in the making” by Dr. Des Spence previously on bmj.com.

Dr. Dhalla and colleagues add that “deaths involving methadone and codeine roughly doubled in England and Wales between 2005 and 2009, while deaths involving heroin or morphine remained unchanged.”

In order to tackle the crisis in the US and Canada, the authors put forward several strategies.

They say staff working for drug companies should not get commission for marketing prescription opioid drugs and that regulators should evaluate adverts for them before they are disseminated. Another initiative would be to introduce real-time electronic databases to reduce the frequency with which opioids are obtained from multiple doctors or pharmacies.

Dhalla and colleagues also call for educational outreach programmes for doctors to improve opioid prescribing, as well as more research to guide practice. They note that the evidence for the use of opioids to control chronic pain is very limited and the risks may outweigh the benefits.

In conclusion, they say that maintaining access to opioids for appropriately selected patients while striving for major reductions in overdose deaths must be a major priority for physicians and policymakers.

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The above story is reprinted (with editorial adaptations by UnknownBody.com staff) from materials provided by BMJ-British Medical Journal, via EurekAlert!, a service of AAAS.

Journal Reference:

1. I. A. Dhalla, N. Persaud, D. N. Juurlink. Facing up to the prescription opioid crisis. BMJ, 2011; 343 (aug23 1): d5142 DOI: 10.1136/bmj.d5142

NewsPsychology (Aug. 18, 2011) — Women and men experience pain, particularly chronic pain, very differently. The ability of some opioids to relieve pain also differs between women and men. While it has been recognized since the mid-nineties that some narcotic analgesics are more effective in women than men, the reason for this difference was largely unknown.

Narcotic analgesics decrease pain by activating opioid receptors, which are located on nerves that transmit painful sensations. Since levels of mu, delta, and kappa opiate receptors — the three main types of opioid receptor in the brain and spinal cord — are not thought to differ dramatically in men and women, it was difficult to understand why the effectiveness of some painkillers is dependent on sex.

Now, research supported by the National Institute of Drug Abuse (NIDA) has revealed that the same major types of opioid receptor interact differently, depending on sex. The spinal cord of female laboratory animals was found to contain almost five times more kappa-mu heterodimer — a complex of mu-opioid and kappa-opioid receptor — than the spinal cord of male animals. Furthermore, the amount of mu-kappa heterodimer in the spinal cord of the females was about four times higher when their levels of estrogen and progesterone were at their peak. Subsequently, researchers found that both estrogen and progesterone are critical for the formation of mu-kappa opioid receptor heterodimers.

This research was conducted by Alan Gintzler, PhD, professor of biochemistry, Department of Obstetrics and Gynecology, and his senior collaborators Sumita Chakrabarti, PhD, and Nai-Jiang Liu, PhD, at the State University of New York (SUNY) Downstate Medical Center

The discovery of a mu-kappa opioid receptor complex that is more prevalent in the spinal cord of females than males and that is synchronized with the ebb and flow of ovarian hormones could explain why drugs used to treat pain, such as pentazocine, nalbuphine, and butorphanol — which primarily act on mu-opioid and kappa-opioid receptors — are more effective in women than men. The activation of the kappa-opioid receptor within the kappa-mu-opioid receptor complex could provide a mechanism for recruiting the pain-relieving functions of spinal kappa-opioid receptors without also activating their pain-promoting functions.

The research by Drs. Gintzler, Liu, and Chakrabarti, which was recently published in the Proceedings of the National Academy of Sciences and the Journal of Neuroscience, suggests that kappa-mu opioid receptor heterodimers could function as a molecular switch that shifts the action of kappa-opioid receptors and endogenous chemicals that act on them from pain-promoting to pain-alleviating. Kappa-mu opioid receptor heterodimers could serve as a novel molecular target for pain management in women.

Dr. Gintzler’s research suggests that physicians should take the stage of the menstrual cycle into account before deciding which drugs to prescribe to treat pain in women. While some drugs might be very effective in treating pain at times when estrogen and progesterone levels are high, they could heighten pain when levels are low. “This consideration could become even more critical in managing pain in postmenopausal and elderly women,” said Dr. Gintzler. “Further research is needed to flesh out these possibilities.”

The Journal of Neuroscience paper appeared in the August 17, 2011 edition.

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The above story is reprinted (with editorial adaptations by UnknownBody.com staff) from materials provided by SUNY Downstate Medical Center.

Journal Reference:

1. N.-J. Liu, S. Chakrabarti, S. Schnell, M. Wessendorf, A. R. Gintzler. Spinal Synthesis of Estrogen and Concomitant Signaling by Membrane Estrogen Receptors Regulate Spinal κ- and μ- Opioid Receptor Heterodimerization and Female-Specific Spinal Morphine Antinociception. Journal of Neuroscience, 2011; 31 (33): 11836 DOI: 10.1523/JNEUROSCI.1901-11.2011

NewsPsychology (Aug. 4, 2011) — Fatal overdoses involving prescribed opioids tripled in the United States between 1999 and 2006, climbing to almost 14,000 deaths annually — more than cocaine and heroin overdoses combined. Hospitalizations and emergency room visits related to prescription opioid pain medicines such as oxycodone (brand name Oxycontin) and hydrocodone (Vicodin) also increased dramatically in the same period.

Now a report in the August issue of Health Affairs describes a major initiative at Group Health to make opioid prescribing safer while improving care for patients with chronic pain. Health Affairs is the nation’s premier health policy journal, and its August issue focuses on substance abuse.

In the Group Health initiative’s first nine months, clinicians at the Seattle-based integrated health system developed and documented care plans for almost 6,000 patients — 85 percent of those receiving long-term opioid therapy for chronic non-cancer pain.

Group Health’s initiative was implemented well before the White House Office of Drug Control Policy, the Food and Drug Administration, and the Drug Enforcement Administration announced a national action plan in April 2011 to stem the epidemic of prescription drug abuse. Scientists from Group Health Research Institute are evaluating the initiative’s effects on care, hoping Group Health’s experience can help guide national efforts.

Use of prescription opioids has increased sharply since the 1980s. Excluding people with cancer and those in end-of-life care, about 4 percent of U.S. adults now use prescription opioids long term. Pharmaceutical industry advocacy and education have fueled increased opioid prescribing for chronic non-cancer pain — despite limited scientific evidence supporting the drugs’ long-term effectiveness for chronic non-cancer pain.

In January 2010, Group Health Research Institute Senior Investigator Michael Von Korff, ScD, and colleagues published the first-ever study on overdose risk by dose among patients receiving prescribed opioids for chronic non-cancer pain. That study, published in the Annals of Internal Medicine, linked higher risk of fatal and nonfatal overdose to higher daily dose prescribed. His research also showed that Group Health, like other health systems nationwide, had been prescribing more opioids for chronic non-cancer pain over time — a twofold increase from 1997 to 2005.

Group Health launched a major primary care-based initiative to enhance opioid prescribing safety later in 2010. Led by Group Health Medical Director of Primary Care Claire Trescott, MD, the initiative aims to standardize use of opioids for chronic non-cancer pain, without creating undue restrictions on clinically appropriate opioid prescribing.

Using Lean management principles, Dr. Trescott worked with primary care doctors, nurses, pharmacists, pain specialists, and other clinical leaders to formulate new guidelines and related practice changes. These changes include creating standardized care plans for all patients receiving opioids long-term for chronic non-cancer pain.

“Our new opioid care plans specify one responsible prescribing physician, clarify expectations for monitoring and refills, outline treatment goals, and explain risks and side effects of long-term opioid use,” said Dr. Trescott.

The individualized plans are created for each patient receiving opioids for 90 days or more. The clinician actively involves patients in the plan development and education on the risks and potential benefits of long-term opioid use. Prescription refill processes are modified to avert problems when patients seek a refill on short notice or run out of medication over a weekend. Periodic monitoring visits with their providers are scheduled, depending on dosage level and risk factors.

Recognizing the importance of provider education, Group Health’s Chief of Physical Medicine and Rehabilitation Randi Beck, MD, partnered with Dr. Von Korff to develop an online clinician education course explaining the new guidelines. Funded by a Partnership for Innovation grant from the Group Health Foundation, the course aims to help primary care providers implement recommended practice changes.

By May 2011 — just 9 months after the new guideline was implemented — nearly 6,000 care plans were developed with patients receiving opioids for chronic non-cancer pain (85 percent of the target population).

“We see impressive changes when our delivery system, research institute, and foundation collaborate — pooling our knowledge, skills, and resources,” Dr. Von Korff said. “It’s a powerful example of how a learning health care system can act quickly to address important problems in health care.”

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The above story is reprinted (with editorial adaptations by UnknownBody.com staff) from materials provided by Group Health Research Institute.

Deaths related to prescription opioid therapy are under intense scrutiny, prompting those in pain medicine — clinicians, patient advocates, and regulators — to understand the causes behind avoidable mortality in legitimately treated patients. Studies reporting on statistics, causes, and adverse events involving opioid treatment are now available in a special supplement of Pain Medicine, a journal published by Wiley-Blackwell on behalf of the American Academy of Pain Medicine (AAPM).

Opioids are prescribed to treat moderate to severe pain and include extended-release opioid analgesic drugs such as methadone, morphine, and oxycodone. According to the Food and Drug Administration (FDA), 29 million Americans age 12 and older misused extended-release and long-acting opioids in 2002 climbing to more than 33 million in 2007. The FDA also estimates that opioids were responsible for nearly 50,000 emergency room visits in 2006.

"Preventing unnecessary deaths from opioid therapy should be a central focus for everyone working in the field of pain medicine," said Lynn R. Webster, MD, FACPM, FASAM, Medical Director and Founder of Lifetree Clinical Research and Pain Clinic in Salt Lake City, Utah, and officer for the AAPM. "Our primary objective is to increase understanding of the major risk factors associated with opioid-related deaths and exploring methods that mitigate the adverse effects involved in treating patients with analgesics that are potentially lethal."

One study in the Pain Medicine supplement on opioid mortality reports on the findings of epidemiologists at the Utah Department of Health (UDOH) who examined medication-related harm starting in 2004. The research team, led by Christina A. Porucznik, PhD, MSPH, of the Division of Public Health at the University of Utah analyzed several data sources including vital statistics, medical examiner records, emergency department diagnoses, and the state prescription registry. "Our analysis showed that prescription drug-related harm, including death, in Utah primarily involved opioids," commented Dr. Porucznik. "Additional studies are needed to identify risky prescribing patterns and individual-level risk factors which contribute to opioid-related injury or death."

In a related study, a panel of pain medicine experts, led by Dr. Webster, reviewed the medical literature and state and federal government sources to assess frequency, demographics and risk factors associated with overdose deaths caused by opioids. Analysis revealed a pattern of increasing opioid-related overdose deaths beginning in the early 2000s. While methadone represented less than 5% of opioid prescriptions dispensed, one third of opioid-related deaths in the U.S. were attributed to this drug.

Researchers determined that root causes of deaths from methadone included physician error due to knowledge deficits, patient non-adherence to prescribed medication regimen, and unanticipated medical or mental health comorbidities. Furthermore, some insurance companies require that methadone be used as first-line therapy to control pain over other opioid therapy. Forcing the use of methadone by health care providers who may not be aware of how to safely prescribe this drug may lead to greater mortality risk.

Additional contributors to overall opioid-related deaths included the presence of sleep-disordered breathing and use of other drugs that depress the central nervous system such as alcohol, benzodiazepines, and antidepressants. Approximately two thirds of opioid-related deaths are caused by opioids other than methadone. "Patients with depression, anxiety, or other mental illness who also have chronic pain need structured care that minimizes risks associated with opioid therapy," concluded Dr. Webster. "It is very difficult to safely treat chronic pain in patients who have serious mental health issues. We must strike a balance between treating pain and preventing harm."

Journal Reference:

1. Lynn R. Webster. Ending Unnecessary Opioid-Related Deaths: A National Priority. Pain Medicine, 2011; DOI: 10.1111/j.1526-4637.2011.01124.x

Scientists from the Florida campus of The Scripps Research Institute have for the first time accomplished a laboratory synthesis of a rare natural product isolated from the bark of a plant widely employed in traditional medicine. This advance may provide the scientific foundation to develop an effective alternative to commonly prescribed narcotic pain treatments.

The study, published May 23, 2011, in an advanced online edition of the journal Nature Chemistry, defines a chemical means to access meaningful quantities of the rare natural product conolidine. Based on data from mouse models, the study also suggests that synthetic conolidine is a potent analgesic as effective as morphine in alleviating inflammatory and acute pain, with few, if any, side effects.

In recent years, there has been significant interest in developing alternatives to opiate-based pain medications such as morphine. While widely prescribed for pain, morphine has a number of adverse side effects that range from the unpleasant to the lethal, including nausea, chronic constipation, addiction, and breathing depression.

The rare natural product central to the study is derived from the bark of a widely grown tropical flowering plant Tabernaemontana divaricata (also known as crepe jasmine). Long part of traditional medicine in China, Thailand, and India, extract from the leaves has been used as an anti-inflammatory applied to wounds, while the root has been chewed to fight the pain of toothache. Other parts of the plant have been used to treat skin diseases and cancer.

Conolidine belongs to a larger class of natural products, called C5-nor stemmadenines, members of which have been described as opioid analgesics, despite a substantial discrepancy between potent in vivo analgesic properties and low affinity to opiate receptors. Conolidine is an exceptionally rare member of this family for which no therapeutically relevant properties had ever been described. Despite the potential value of conolidine and related C5-nor stemmadenines as leads for therapeutics, efficient methods to prepare these molecules were lacking.

"This was a classic problem in chemical synthesis," said Glenn Micalizio, an associate professor in the Department of Chemistry, who initiated and directed the study, "which we were able to solve effectively and efficiently¬¬ — an achievement that made subsequent assessment of the potential therapeutic properties of this rare natural product possible."

Micalizio and his colleagues began working on the synthesis of the molecule after they arrived at Scripps Florida in 2008.

Testing For Potency

Once the synthesis was complete, research shifted to pharmacology for evaluation. The pharmacological assessment, performed in the laboratory of Scripps Florida Associate Professor Laura Bohn, showed that the new synthetic compound has surprisingly potent analgesic properties.

"Her pharmacological studies confirmed that while it's not an opiate, it's nearly as potent as morphine," Micalizio said.

In various models of pain, the new synthetic compound performed spectacularly, suppressing acute pain and inflammatory-derived pain, two key measures of efficacy. Not only that, but the new compound passed easily through the blood-brain barrier, and was present in the brain and blood at relatively high concentrations up to four hours after injection.

Bohn herself was surprised by the compound's potency and by the fact it so readily enters the brain.

"While the pain-relieving properties are encouraging, we are still challenged with elucidating the mechanism of action," she said. "After pursuing more than 50 probable cellular targets, we are still left without a primary mechanism."

So far, the compound has shown remarkably few, if any, side effects, but that is something of a double-edged sword.

"The lack of side effects makes it a very good candidate for development," Bohn said. "On the other hand, if there were side effects, they might provide additional clues as to how the compound works at the molecular level."

That remains a mystery. While the synthetic compound might be as effective as morphine, it doesn't act at any of the receptors associated with opiates. In fact, it misses most of the major neurotransmitter receptors completely, suggesting it may be highly tuned towards relieving pain while not producing multiple side effects. While still in the early stages of development, further characterizations of conolidine may suggest further development as a human therapeutic for the treatment of pain.

The first author of the study, "Synthesis of Conolidine, a Potent Non-Opioid Analgesic for Tonic and Persistent Pain," is Michael A. Tarselli of Scripps Research. Other authors include Kirsten M. Raehal, Alex K. Brasher, John M. Streicher, Chad Groer, and Michael D. Cameron, also of Scripps Research.

This research was made possible by Scripps Florida start-up funds, resulting from a one-time appropriation of federal economic development funds by the State of Florida, as well as support from Palm Beach County.

Journal Reference:

1. Michael A. Tarselli, Kirsten M. Raehal, Alex K. Brasher, John M. Streicher, Chad E. Groer, Michael D. Cameron, Laura M. Bohn, Glenn C. Micalizio. Synthesis of conolidine, a potent non-opioid analgesic for tonic and persistent pain. Nature Chemistry, 2011; 3 (6): 449 DOI: 10.1038/nchem.1050

Two reports by addiction researchers at the University of Pennsylvania School of Medicine and the National Institute on Drug Abuse show a drastic shift in prescribing patterns impacting the magnitude of opioid substance abuse in America. The reports, published in JAMA, recommend a comprehensive effort to reduce public health risks while improving patient care, including better training for prescribers, pain management treatment assessment, personal responsibility and public education.

The JAMA Research Report shows that there has been a drastic increase in opioid prescriptions while prescriptions for non-steroidal anti-inflammatory drugs (NSAIDs) have gone down. Prescriptions for hydrocodone and oxycodone account for 84.9 percent of opioid prescriptions. Over ten years, there has been a fivefold increase in admissions to substance abuse programs for opioid addiction.

While effective at reducing pain symptoms, opioid medications such as hydrocodone and oxycodone are associated with high rates of abuse, particularly among young adults. One in four 18-25 year olds will abuse prescription pain killers in their lifetime.

Researchers suggest targeting the relatively high rate of prescriptions to adolescents and young adults, who received 11.7 percent of the 202 million opioid prescriptions in the United States during 2009. A large share of the prescriptions to young adults was from dentists, and researchers believe there is a need for medical professionals to evaluate alternative pain medications in this particularly vulnerable age group.

"The scope of the problem is vast — opioid overdose is now the second leading cause of accidental death in the United States and the prevalence is second only to marijuana," said Thomas McLellan, PhD, co-author of the studies and director of the new Center for Substance Abuse Solutions, housed in the Department of Psychiatry at the University of Pennsylvania School of Medicine. "This study provides valuable information about factors contributing to the high rates of opioid analgesics, and identifies areas ripe for intervention."

In the accompanying Commentary, researchers offer recommendations to improve current pain management in primary care while simultaneously decreasing diversion, abuse and overdoses of opioid medication. These recommendations include:

• Comprehensive and contemporary training for pain management care providers -including physicians, nurses, dentists and pharmacists — covering the latest research advances on pain and addiction and new drug treatment options.
• Supporting the American Pain Society guidelines, which include plans to develop and roll out screening procedures for those at risk for abuse and dependence (e.g. adolescent or young adults, individual or family history of substance abuse history.)
• Increasing public awareness and responsibility of the addiction risks, to curb sharing or theft of the medication within families.

The research was conducted by The National Institute on Drug Abuse, of the National Institutes of Health, while Dr. McLellan was serving as Deputy Director of the United States Office of National Drug Control Policy.

Penn Medicine researchers are already looking into possible solutions to address these issues. Dr. McLellan leads the new Center for Substance Abuse Solutions that will translate addiction research into evidence-based practical applications to be used locally, nationally and globally.

Collaborators from the Penn Pain Medicine Center will partner with Penn's Center for Substance Abuse Solutions and Department of Internal Medicine to develop a "Patient-Centered Medical Home" care model for patients with chronic pain problems. This new process integrates care provided by primary care physicians and specialists in an effort to provide high-quality, comprehensive care to patients. New health care information technology, such as electronic health care records and Internet-based collection of patient outcomes, will be used to improve coordination of care. Researchers hope that Patient-Centered Medical Home model will improve pain care and lower the chances of diversion and abuse of pain medications.

"The research published today clearly demonstrates the risk of harm that pain medications can cause when used incorrectly," said Michael Ashburn, MD, MPH, MBA, professor of Anesthesiology and Critical Care and director of Pain Medicine at the University of Pennsylvania School of Medicine. "We hope our efforts will demonstrate that improvements can be made to the patient care process and lead to improved pain control and a lower risk of abuse and diversion of these medications."

Journal References:

1. Nora D. Volkow, Thomas A. Mclellan, Jessica H. Cotto, Meena Karithanom, Susan R. B. Weiss. Characteristics of Opioid Prescriptions in 2009. JAMA, 2011; 305 (13): 1299-1301 DOI: 10.1001/jama.2011.401
2. Nora D. Volkow, Thomas A. Mclellan. Curtailing Diversion and Abuse of Opioid Analgesics Without Jeopardizing Pain Treatment. JAMA, 2011; 305 (13): 1346-1347 DOI: 10.1001/jama.2011.369

 In an analysis of opioid prescription patterns and deaths, receiving higher prescribed doses is associated with an increased risk of opioid overdose death, but receiving both as-needed and regularly scheduled doses is not associated with overdose risk, according to a study in the April 6 issue of JAMA.

The rate of overdose death has increased sharply in the United States in the past decade and overdose death is a pressing public health problem, according to background information in the article. "Between 1999 and 2007, the rate of unintentional overdose death in the United States increased by 124 percent, largely because of increases in prescription opioid overdoses. Achieving a better understanding of the factors contributing to prescription opioid overdose death is an essential step toward addressing this troubling and dramatic increase in overdose mortality."

Amy S. B. Bohnert, Ph.D., of the Department of Veterans Affairs, Ann Arbor, Mich., and colleagues examined the relationship between opioid prescribing patterns (dose and schedule ["as needed," regularly scheduled, or both]) and risk of opioid-related deaths from 2004 through 2008 among diagnostic subgroups of patients (chronic pain, cancer, acute pain, and substance use disorders) in a national sample of Veterans Health Administration (VHA) patients. The study included data on all unintentional prescription opioid overdose decedents (n = 750) and a random sample of patients (n = 154,684) among those individuals who used medical services in 2004 or 2005 and received opioid therapy for pain.

The researchers approximated the rate of overdose among individuals treated with opioids to be 0.04 percent. Opioid overdose decedents were statistically significantly more likely to be middle-aged and white; more likely to have chronic or acute pain, substance use disorders, and other psychiatric diagnoses; and less likely to have cancer.

The authors found that the overdose rate was higher at higher maximum daily doses compared with lower maximum daily doses (100 mg/day or more vs. 1 mg/day to less than 20 mg/day) across all subgroups examined, including those with cancer, substance use disorders, chronic and acute pain.

Having as-needed opioids only compared with having regularly scheduled opioids was associated with an increase in risk of opioid overdose among patients with cancer. Receiving both as-needed and regularly scheduled doses was not associated with overdose risk after adjustment.

"The present findings highlight the importance of implementing strategies for reducing opioid overdose among patients being treated for pain," the authors write. "This study documents a relationship between opioid prescribing and opioid overdose in a large, national, prospective cohort of individuals receiving opioid therapy for a variety of medical conditions. The risk of opioid overdose should continue to be evaluated relative to the need to reduce pain and suffering and be considered along with other risk factors."

Journal Reference:

1. Amy S. B. Bohnert, Marcia Valenstein, Matthew J. Bair, Dara Ganoczy, John F. McCarthy, Mark A. Ilgen, Frederic C. Blow. Association Between Opioid Prescribing Patterns and Opioid Overdose-Related Deaths. JAMA, 2011; 305 (13): 1315-1321 DOI: 10.1001/jama.2011.370

 Some physicians are prescribing opioids such as OxyContin 55 times as often as others, according to a new study led by St. Michael's Hospital and the Institute for Clinical Evaluative Sciences (ICES). The study found most opioid-related deaths occur among patients treated by physicians who frequently prescribe opioids, suggesting doctors who prescribe a lot of opioids may not be doing so safely.

"We found that the 20 per cent of family doctors who are frequent prescribers wrote 55 times as many prescriptions as the 20 per cent of family doctors who prescribe opioids the least. This large variation in practice is concerning," says Dr. Irfan Dhalla, a general internist at St. Michael's Hospital and an adjunct scientist at ICES.

The study, published in the March edition of the journal Canadian Family Physician, examined opioid prescribing rates among family physicians in Ontario. Researchers found doctors who frequently prescribe opioids are also more likely to write the patient's final prescription before death.

"Family physicians are caught in the middle. On the one hand, there are many patients suffering terribly from chronic pain who can't get relief from other treatments. On the other hand, the evidence for long-term treatment with opioids is very weak," says St. Michael's family physician Dr. Philip Berger. "If the drugs were safe, it wouldn't be an issue. But unfortunately they do carry significant risks — most notably addiction and death from overdose. And it is important to recognize that one reason opioids are prescribed so often is that the pharmaceutical industry has marketed these drugs very aggressively."

Deaths related to opioids in Ontario have more than doubled — from 13.7 deaths per million residents in 1991 to 33.3 deaths per million residents in 2006. Of the 423 deaths that occurred in 2006, oxycodone — the active ingredient in OxyContin — was the opioid most frequently associated with an overdose death.

In 2010, the provincial government passed the Narcotics Safety and Awareness Act, which will enable the Ministry of Health and Long-Term Care to better track opioid prescribing in Ontario.

Poor expectations of treatment can override all the effect of a potent pain-relieving drug, a brain imaging study at Oxford University has shown.

In contrast, positive expectations of treatment doubled the natural physiological or biochemical effect of the opioid drug among the healthy volunteers in the study.

The study of the placebo effect — and its opposite the nocebo effect — is published in Science Translational Medicine. The findings suggest that doctors may need to consider dealing with patients' beliefs about the effectiveness of any treatment, as well as determining which drug might be the best for that patient.

'Doctors shouldn't underestimate the significant influence that patients' negative expectations can have on outcome,' says Professor Irene Tracey of the Centre for Functional Magnetic Resonance Imaging of the Brain at Oxford University, who led the research. '

For example, people with chronic pain will often have seen many doctors and tried many drugs that haven't worked for them. They come to see the clinician with all this negative experience, not expecting to receive anything that will work for them. Doctors have almost got to work on that first before any drug will have an effect on their pain.'

The placebo effect describes the improvements seen when patients — unknowingly — are given dummy pills or sham treatments but believe it will do them good. This is a very real physiological effect; it is not just about patients 'feeling' better. The nocebo effect is the opposite: patients see poorer outcomes as the result of doubts about a medical treatment.

Previous studies have investigated the basis of the placebo effect, when using sugar pills or saline injections for example, and confirmed it can elicit a real response.

This new research, funded by the Medical Research Council and German research funders, goes a step further by examining how manipulating participants' expectations can influence their response to an active drug.

The Oxford University team, along with colleagues from the University Medical Center Hamburg-Eppendorf in Germany, Cambridge University, and the Technische Universität München, set out to investigate these effects among 22 healthy adult volunteers by giving them an opioid drug and manipulating their expectations of the pain relief they might receive at different points.

The volunteers were placed in an MRI scanner and heat applied to the leg at a level where it begins to hurt — set so that each individual rated the pain at 70 on a scale of 1 to 100. An intravenous line for administration of a potent opioid drug for pain relief was also introduced.

After an initial control run, unknown to the participants, the team started giving the drug to see what effects there would be in the absence of any knowledge or expectation of treatment. The average initial pain rating of 66 went down to 55.

The volunteers were then told that the drug would start being administered, although no change was actually made and they continued receiving the opioid at the same dose. The average pain ratings dropped further to 39.

Finally, the volunteers were led to believe the drug had been stopped and cautioned that there may be a possible increase in pain. Again, the drug was still being administered in the same way with no change. Their pain intensity increased to 64. That is, the pain was as great as in the absence of any pain relief at the beginning of the experiment.

The researchers used brain imaging to confirm the participants' reports of pain relief. MRI scans showed that the brain's pain networks responded to different extents according to the volunteers' expectations at each stage, and matching their reports of pain.

This showed the volunteers really did experience different levels of pain when their expectations were changed, although the administration of pain relief remained constant.

Professor Tracey notes that these results have been seen in a small, healthy group of volunteers, and that these are short-term, not sustained, manipulations of the participants' beliefs about the treatment.

But she says it's important not to underestimate the strength of the effect of such expectations on any treatment, and that clinicians need to know how to manage that.

Professor Tracey says there may also be lessons for the design of clinical trials. These are often carried out comparing a candidate drug against a dummy pill to see if there is any effect of a drug above and beyond that of the placebo.'We should control for the effect of people's expectations on the results of any clinical trial. At the very least we should make sure we minimize any negative expectations to make sure we're not masking true efficacy in a trial drug.'

Journal Reference:

1. U. Bingel, V. Wanigasekera, K. Wiech, R. Ni Mhuircheartaigh, M. C. Lee, M. Ploner, I. Tracey. The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid Remifentanil. Science Translational Medicine, 2011; 3 (70): 70ra14 DOI: 10.1126/scitranslmed.3001244

NewsPsychology (Feb. 17, 2011) — A new treatment using naltrexone implants could lead to a significant reduction in heroin dependency. According to the researchers responsible for a recent Norwegian study, this should have major implications for the treatment options offered to heroin-dependent patients.

Today, the most common way to become heroin-free is through treatment with methadone or Subutex. These substances resemble morphine and are also addictive, but reduce heroin use and criminality among patients.

The new treatment is targeted towards people who wish to overcome their heroin addiction without using other addictive substances. The researchers have been using naltrexone, a substance that works by completely blocking the effect of heroin and other morphine substances. This reduces the likelihood of overdose, physical dependency and other drug cravings.

“This blockage effect induces a feeling of calm and allows the patients to escape from their heroin addiction and stressful, drug-dependent lives. They are able to concentrate on getting a new start,” explains Nikolaj Kunøe, who, with the help of Research Council funding, completed his doctorate on this topic at the Norwegian Centre for Addiction Research (SERAF) at the University of Oslo.

Satisfied users

Some 56 heroin-dependent patients who had undergone detoxification treatment and were particularly motivated to remain heroin-free took part in the study. Half of the participants were implanted with a total of 20 subcutaneous pellets containing naltrexone, which was gradually released from a saline solution with the aim of producing a six-month blockage effect. All the participants continued their normal follow-up treatments while the study was ongoing.

After six months, over twice as many in the group receiving naltrexone as in the control group (11 out of 23 as opposed to 5 out of 26) managed to refrain from using heroin and other morphine substances. Heroin use among those patients receiving naltrexone who did not manage to discontinue using heroin altogether was more than halved compared with their level of heroin use before they started treatment. In the control group the majority of patients relapsed to daily heroin use.

Satisfaction with the naltrexone implants was high. On a scale from 0 to 100 the participants gave the capsules a score of 85.

Clear-cut findings

Helge Waal, Professor emeritus at SERAF, would like to see the naltrexone implant included as one of the treatment options offered to heroin-dependent patients in Norway.

“Although this is a relatively small-scale study, the findings are so clear-cut that we think this should become an important treatment option for substance abusers.”

SERAF is seeking to obtain more detailed documentation of the effects of naltrexone in order to provide a basis for the approval of the naltrexone implant or depot by the Norwegian Medicines Agency (NoMA).

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The above story is reprinted (with editorial adaptations by newsPsychology staff) from materials provided by The Research Council of Norway.

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