Advocates for Prescription Opioid Reform
prescriptionopioidreform.com

Families, Patients, and Doctors, Hoping for Change

DOCS RESEARCH & STUDIES

Below is a collection of various research references and medical opinions involved in prescription opioids.

It is an extensive list, yet incomplete. However, we believe the accumulation of these documents and studies point out, at the very least, that the use of opioids for chronic non cancer pain is a practice that is being employed within an environment that lacks the appropriate support and training. Medical experts, are and have been, warning about a lack of science based evidence for the use of opioids for long term therapy. They have also been concerned with the lack of education and training, within the medical community, for the appropriate use of opioids for chronic non-malignant pain.

Please feel free to visit our library of articles and guidelines for the use of opioids for chronic pain, in our research pages. APOR recognizes that there are many excellent pain management practitioners. Unfortunately, we also recognize that there are many physicians, who do not specialize in this area, who are in need of training and information, if they want to treat their patients with opioids for chronic pain. Please help us in our effort to get that training, which we believe will reduce the unintended overdose and addiction that can come from mis-informed practitioners.

J Manag Care Pharm. 2010 Feb;16(1 Supp B):26-27.

Practice Strategies to Improve Compliance and Patient Self-Management.

Ruetsch C.

Health Analytics, LLC, 9250 BendixnRd. N., Ste. 240, Columbia, MD 21045, USA. Charles.Ruetsch@healthanalytic.com.

Background: Failure in treating opioid dependence is costly to the patient, the employer, managed care organizations, and the overall health care system. Opioid dependent patients tend to be less productive at work and in society and utilize a great many health care resources. Optimizing outcomes is essential. Objective: To introduce the benefit of integrated strategies and patient support in the treatment of opioid dependence. Summary: Health Analytics is currently studying the benefit of HereToHelp, a behavioral support program in which registered nurses or addiction treatment counselors with specialized training in addiction education provide information and encouragement to patients receiving pharmacologic treatment for opioid dependence. A total of 470 physicians in 41 states have been enlisted to participate in this patient support study. The study hypothesis is that patients who receive behavioral support and encouragement will be more compliant with their opioid replacement therapy, leading to better outcomes. Additional treatment strategies are also being developed to minimize the risk of abuse and diversion. Prodrugs and vaccines are also being investigated. Conlusion: A coordinated team approach is essential in treating pain patients and opioid-dependent patients. Offering behavior modification in addition to pharmacotherapy and utilizing strategies such as prescription monitoring programs, pain contracts, and screening are all vital components necessary for positive outcomes.

PMID: 20146552 [PubMed - as supplied by publisher]

Tentative identification of novel oxycodone metabolites in human urine.

Moore KA, Ramcharitar V, Levine B, Fowler D.

Office of the Chief Medical Examiner, State of Maryland, 111 Penn Street, Baltimore, Maryland 21201-1020, USA.

Oxycodone is a semisynthetic codeine derivative that has been used both as an analgesic and antitussive. In the mid 1990s, OxyContin was introduced as a slow-release formulation of oxycodone for use in patients with moderate to severe chronic pain from such ailments as arthritis, vertebral disc disease, and cancer. Doctors wrote 6.9 million prescriptions for OxyContin from May 2000 through May 2001. Thus, it is no surprise that hospitals and medical examiners' offices across the country have seen an increasing number of admissions and deaths resulting from oxycodone abuse and overdose. The laboratory identifies oxycodone as part of its routine abused and therapeutic drug-testing procedures. Routine gas chromatographic analysis of bile or urine in many of these cases revealed unidentified peaks in the region of oxycodone that appeared to be oxycodone metabolites. In humans, the only documented metabolites of oxycodone are oxymorphone and N-desmethyloxycodone (noroxycodone). This study attempts to characterize these compounds as "presumptive" metabolites based on circumstantial evidence from known metabolic pathways of oxycodone in other species, as well as of other opiates and narcotic analgesics.

Eur J Clin Pharmacol. 2010 Aug 10. [Epub ahead of print]

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir.

Nieminen TH, Hagelberg NM, Saari TI, Neuvonen M, Neuvonen PJ, Laine K, Olkkola KT.

Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital and University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, 20521, Turku, Finland, tuija.nieminen@utu.fi.

Abstract

PURPOSE: This study aimed to investigate the effect of antivirals ritonavir and lopinavir/ritonavir on the pharmacokinetics and pharmacodynamics of oral oxycodone, a widely used opioid receptor agonist used in the treatment of moderate to severe pain.

METHODS: A randomized crossover study design with three phases at intervals of 4 weeks was conducted in 12 healthy volunteers. Ritonavir 300 mg, lopinavir/ritonavir 400/100 mg, or placebo b.i.d. for 4 days was given to the subjects. On day 3, 10 mg oxycodone hydrochloride was administered orally. Plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Pharmacokinetic parameters were calculated with standard noncompartmental methods. Behavioral effects and experimental cold pain analgesia were assessed for 12 h. ANOVA for repeated measures was used for statistical analysis.

RESULTS: Ritonavir and lopinavir/ritonavir increased the area under the plasma concentration-time curve of oral oxycodone by 3.0-fold (range 1.9- to 4.3-fold; P <0.001) and 2.6-fold (range 1.9- to 3.3-fold; P <0.001). The mean (+/- SD) elimination half-life increased after ritonavir and lopinavir/ritonavir from 3.6 +/- 0.6 to 5.6 +/- 0.9 h (P <0.001) and 5.7 +/- 0.9 h (P <0.001), respectively. Both ritonavir (P <0.001) and lopinavir/ritonavir (P <0.05) increased the self-reported drug effect of oxycodone.

CONCLUSIONS: Ritonavir and lopinavir/ritonavir greatly increase the plasma concentrations of oral oxycodone in healthy volunteers and enhance its effect. When oxycodone is used clinically in patients during ritonavir and lopinavir/ritonavir treatment, reductions in oxycodone dose may be needed to avoid opioid-related adverse effects.

PMID: 20697700 [PubMed - as supplied by publisher]

Officials Warn of Rising Fatalities From Painkiller Abuse Epidemic

By Matthew Heller on February 23, 2011

Public health officials are warning of an epidemic of prescription painkiller abuse, pointing to a five-fold increase in fatal overdoses since 1990.

More than 27,000 people, a record high, died from overdoses of such powerful drugs as Oxycontin and Vicodin in 2007, according to data presented by the Centers for Disease Control and Prevention at a forum last week in Atlanta. “Just about the only mortality statistic that is getting worse is death from prescription opioid abuse,” said CDC director Dr. Thomas Frieden.

The featured panelist at the “Grand Rounds” CDC event was U.S. drug czar Gil Kerlikowske, who said the Obama administration has made combating prescription painkiller abuse a top priority. In its proposed National Drug Control Strategy, the administration has called for a 15 percent reduction in drug-induced deaths over five years.

Nationwide, the overall number of drug-induced deaths — which are, in large part, attributable to prescription painkillers — is approaching the number of deaths from motor vehicle crashes.

In some states, the problem is particularly severe. In Ohio, more than 1,300 people died from accidental drug overdoses in 2009, overtaking the fatality toll from car wrecks. Gov. John Kasich announced Monday that former Attorney General Betty Montgomery will advise a new, multi-agency task force tackling the issue of prescription drug abuse.

Mac McArthur, executive director of the Transitions Inc. substance abuse rehabilitation center in nearby northern Kentucky, said he has witnessed a surge in the problem, too. “We see a lot more young people overdosing than we did even five years ago,” he told WLWT, a Cincinnati TV station.

At the CDC event, MedPage Today reports, officials called for more help from states, citing a new Washington state law that requires physicians to contact a pain specialist if patients exceed a certain dosage of a painkiller and still aren’t feeling better.

Posted in News & Notes, Pharmaceutical Industry and Drugs

Pharmacogenomics. 2011 Feb;12(2):215-33.

Absorption, distribution, metabolism and excretion pharmacogenomics of drugs of abuse.

Meyer MR, Maurer HH.

Department of Experimental & Clinical Toxicology, Institute of Experimental & Clinical Pharmacology & Toxicology, Saarland University, D 66421 Homburg (Saar), Germany.

Abstract

Pharmacologic and toxic effects of xenobiotics, such as drugs of abuse, depend on the genotype and phenotype of an individual, and conversely on the isoenzymes involved in their metabolism and transport. The current knowledge of such isoenzymes of frequently abused therapeutics such as opioids (oxycodone, hydrocodone, methadone, fentanyl, buprenorphine, tramadol, heroin, morphine and codeine), anesthetics (γ-hydroxybutyric acid, propofol, ketamine and phencyclidine) and cognitive enhancers (methylphenidate and modafinil), and some important plant-derived hallucinogens (lysergide, salvinorin A, psilocybin and psilocin), as well as of nicotine in humans are summarized in this article. The isoenzymes (e.g., cytochrome P450, glucuronyltransferases, esterases and reductases) involved in the metabolism of drugs and some pharmacokinetic data are discussed. The relevance of such data is discussed for predicting possible interactions with other xenobiotics, understanding pharmacokinetic behavior and pharmacogenomic variations, assessing toxic risks, developing suitable toxicological analysis procedures, and finally for interpretating drug testing results.

PMID: 21332315 [PubMed - in process]

Opioids and Deaths

N Engl J Med 2011; 364:686-687February 17, 2011

Article

To the Editor:

We applaud the article by Okie (Nov. 18 issue)1 on the increasing number of overdose deaths, since we have seen far too many patients die prematurely of opioid overdoses. One topic was missing from this article: the usefulness of providing access to naloxone to be administered by laypersons to prevent death from an opioid overdose. Several studies involving illicit-drug users have confirmed that training laypeople to recognize and respond appropriately to an overdose situation is feasible, safe, and effective.2-4 Thousands of lives have been saved with either intramuscular injection or intranasal spray of naloxone.5 If it were the standard of care for physicians who prescribe long-acting opiates to also prescribe accompanying naloxone and provide access to brief training on its use, there would be far fewer overdose deaths. Improving access to prescribed naloxone is one fundamental lifesaving response within a clinician's reach to directly address the unprecedented “flood of opioids” and “rising tide of deaths.”

Josiah D. Rich, M.D., M.P.H.
Traci C. Green, Ph.D.
Brown University Medical School, Providence, RI
jrich@lifespan.org

Michelle S. McKenzie, M.P.H.
Miriam Hospital, Providence, RI

No potential conflict of interest relevant to this letter was reported

Pain Medicine: Repairing a Fractured Dream

Posted on January 28, 2011 by Gilbert Fanciullo| 1 Comment

Jane C. Ballantyne, MD, FRCA

Quick on the heels of Allen Burton’s opioid post comes this Editorial just published in Anesthesiology written by my friend and colleague Jane Ballantyne who is in transition relocating from The U of Penn Pain Medicine Center to the University of Washington Pain Center. Those who know Dr Ballantyne recognize her as one of the great thinkers and leaders in our field. She is incredibly bright, passionate in her beliefs, articulate, and thoughtful. I cannot do better than to quote

“How many multidisciplinary pain centers have to be closed, and how many academic pain programs have had to focus on interventional approaches to the near exclusion of all else to meet the production metrics expected by their hospitals and bean counters. The model for economic survival is not the model for good care”.

There is much room for discussion here between “interventionalists” and the multidisciplinary pain center caregivers. I will not criticize interventionalists who may rely on others, less highly remunerated , to provide the pharmacological, behavioral, and physical medicine care our patients need. Nor will I chastise the academic pain medicine leaders for succumbing, so often, to the pressures of the changing landscape of academic medicine, possibly in the interest of maintaining their salaries. I have been slowly watching this happen for 20 years now and I deserve as much blame as anyone else.

Dr Ballantyne states “This is not intended as a message of doom and gloom”. She is optimistic. Maybe that is too strong a word. Maybe hopeful. Once before, in the 1940′s or 50′s, pain medicine died as a specialty because of a lack of commitment of institutional leaders to support good pain care; a lack of science supporting our ability to actually help people; and lack of adequate reimbursement to pay for good pain medicine. Roy Van Dam wrote about this but it was so long ago I was unable to locate his paper, written so long ago- maybe someone else can find it. Our institutions want procedural pain medicine. I have been waiting my whole career for a big scientific discovery in pain medicine and all I see is another opioid, anticonvulsant or antidepressant. There is inadequate reimbursement for everything in pain medicine except for procedures. Dr. Ballantyne may be more optimistic than I am. History may be repeating itself.

We can only do our best to try to help our patients in a very limiting and unsupportive environment. We can only speak out when we see our patients access to care threatened. Anesthesiology based pain medicine salaries, according to the latest MGMA surveys, are declining. Dr. Ballantyne concludes by stating:

“I would like to be able to hold my head high and say that what I am doing, and what my specialty is doing, is helping to relieve the burden of chronic pain”.

I think we all agree. Leroy D. Vandam, M.D., once quoted Alexander Slater, M.D., who stated that: “Without vision and research, the professions die.” The model for economic survival is not the model for good care. I am worried about the future of pain medicine. ”

Opioids, Opioids: To prescribe?, to wean?, to increase?, to screen?: When did it all get so crazy-complicated ???

Posted on January 24, 2011 by Gilbert Fanciullo| 1 Comment

Allen Burton, MD

This is a guest post from Allen Burton, MD. Dr. Burton is the Chair, Department of Pain Medicine, at MD Anderson Cancer Center in the Great State of Texas, USA.

“To prescribe or not to prescribe (COT), that is the question…”

A perfect storm has developed involving prescription opioid medications. Throughout the last few decades there has been an increased awareness of untreated/unrecognized pain with subsequent efforts enlisting doctors to assess and treat pain more aggressively. This frequently translated into increased prescribing of opioids.

More than 10 years ago, both the American Pain Society and the American Academy of Pain Medicine wrote formal position statements endorsing and formally legitimizing the prescription and use of chronic opioid therapy (COT) for the treatment of pain.

These efforts have succeeded in increasing the assessment of pain, and in the prescribing of opioids-both by specialists and primary care providers. An editorial in Pain put it this way “Increased opioid prescribing: A reason for celebration- or alarm? Are we flying blind.” As a result of the increased availability of opioids, many serious, unanticipated problems have arisen. These problems include an explosion in non-therapeutic opioid use. Deaths from prescription opioids currently exceed deaths from heroin and cocaine overdoses. A recent JAMA publication found hydrocodone to be the drug of choice for 9^th graders experimenting with drugs-over marijuana. The United States represents 5% of the world’s population but consumes 99% of the world’s hydrocodone production.

In Houston, where I practice, “pill-mills” have run amuck further complicating the issue. (See article from today’s Houston Chronicle http://www.chron.com/disp/story.mpl/headline/metro/7385695.html ) These are basically store front sham-“medical practices” which sell prescriptions for cash; the most popular combination being vicodin/soma/xanax- sometimes called “the holy trinity” or “the party pack.” The pill mill problem has led to massive outpouring of these medications into the streets with predictable results- increased use/abuse by drug experimenting adolecents/teens/adults…with overdoses fairly commonplace. It seems that the reputation of the “pain clinic” is in the gutter as the specialty of pain medicine too often gets lumped in with “pill mills.”

The pain community in Texas worked, via the Texas Pain Society (www.texaspain.org) with the legislature last session to craft “pain clinic” rules for clinics that largely prescribe controlled substances as part of their practice. This upcoming session, we at the TPS are trying to strengthen and enhance Texas’ prescription monitoring program to enhance a physician’s ability to scrutinize a patient’s prescriptions real-time, not relying on patient report. The role of urine drug screening needs clarification; third party payors, including medicare push back on paying for routine screening, while medical boards mandate this.

Finally, it becomes increasingly challenging to seek clarity on the basic medical question of efficacy- are chronic opioids indicated to treat chronic pain? Do they improve function? Improve pain quality/intensity/other features? Improve psychological well-being? Some good quality studies show that they do improve pain in refractory chronic pain conditions- for example for shingles pain from 2002, Raja and colleagues showed good pain relief and low side effects for 8 weeks duration (Raja SN, et al. Neurology 2002; 59(7):1015-21). Other studies show disappointing results in the long term (Eriksen J, et al. Pain 2006; 125(1):172-79). In my own practice, I remain confused over the role of COT, but am beginning to see a little clarity. The issue of chronic opioid prescribing is very polarizing-within the pain community- which “team“ are you on “opioid advocates” or “opioid nihilists?” I would like to be on the side of the truth- but where can I find that ?? There is so much bias in so much of the information we receive.

As a practicing pain physician, I have many duties: to relieve pain and suffering in my patients, to cause them no harm, to practice safe medicine for the community at large-among them. Personally, my goals include staying out of trouble from a regulatory perspective-while “doing the right thing” for my patients. I have evolved, in the current climate to a somewhat bi-modal patient population who may be candidates for chronic opioid therapy (COT). Opioid candidates (in my opinion) include those with fairly recent injury and the likelihood of improving with multi-modal approaches- including perhaps PT/OT/injections/surgery/psychological support and/or time- still this requires a judicious approach with risk assessment, and perhaps monitoring. Those patients developing the more refractory chronic pain conditions, in my opinion, need extensive time to try other non-COT regimens, including pharmaceutical options, in combination with extensive rehabilitation, and numerous attempts at non-COT treatment options before “settling” with COT…. These are the patients where I frequently decide that this is “the best I can do for them” at this point. In all my patients receiving opioids, I do now require detailed risk assessment, urine screening periodically, written informed consent, and regular reassessment including “Passick’s 4-As” ((1)Analgesia, (2)Activity or ADLs, (3)Adverse effects, and (4)Aberrant behaviors or addiction). But this is a very labor intensive process, for in many cases, very little actual functional gain, and limited pain relief- at relatively large expense- both for the medication directly, and for all the listed medical costs above.

I must say in all honesty the longer I practice, it seems that my long-term chronic opioid “success” stories have become fewer and fewer. I think this must be the experience of others as well?

So, to prescribe or not to prescribe (COT)… that is the question….It is a very, very difficult situation, and I am hoping for some clarity soon?!!?

Am J Addict. 2010 Nov;19(6):515-22. doi: 10.1111/j.1521-0391.2010.00080.x. Epub 2010 Sep 21.

Prescription use disorders in older adults.

Kalapatapu RK, Sullivan MA.

Department of Psychiatry, Division on Substance Abuse, New York State Psychiatric Institute, Columbia University, New York, New York 10032, USA. kalapat@pi.cpmc.columbia.edu

Abstract

The number of older adults needing substance abuse treatment is projected to rise significantly in the next few decades. This paper will focus on the epidemic of prescription use disorders in older adults. Particular vulnerabilities of older adults to addiction will be considered. Specifically, the prevalence and patterns of use of opioids, stimulants, and benzodiazepines will be explored, including the effects of these substances on morbidity and mortality. Treatment intervention strategies will be briefly discussed, and areas for future research are suggested.

PMID: 20958847 [PubMed - indexed for MEDLINE]

Pain. 2011 Feb;152(2):397-402. Epub 2010 Dec 21.

Identifying prescription opioid use disorder in primary care: diagnostic characteristics of the Current Opioid Misuse Measure (COMM).

Meltzer EC, Rybin D, Saitz R, Samet JH, Schwartz SL, Butler SF, Liebschutz JM.

Department of Medicine, Boston University School of Medicine, Boston, MA, USA.

Abstract

The Current Opioid Misuse Measure (COMM), a self-report assessment of past-month aberrant medication-related behaviors, has been validated in specialty pain management patients. The performance characteristics of the COMM were evaluated in primary care (PC) patients with chronic pain. It was hypothesized that the COMM could identify patients with prescription drug use disorder (PDD). English-speaking adults awaiting PC visits at an urban, safety-net hospital, who had chronic pain and had received any opioid analgesic prescription in the past year, were administered the COMM. The Composite International Diagnostic Interview served as the "gold standard," using DSM-IV criteria for PDD and other substance use disorders (SUDs). A receiver operating characteristic (ROC) curve demonstrated the COMM's diagnostic test characteristics. Of the 238 participants, 27 (11%) met DSM-IV PDD criteria, whereas 17 (7%) had other SUDs, and 194 (82%) had no disorder. The mean COMM score was higher in those with PDD than among all others (ie, those with other SUDs or no disorder, mean 20.4 [SD 10.8] vs 8.4 [SD 7.5], P<.0001). A COMM score of⩾13 had a sensitivity of 77% and a specificity of 77% for identifying patients with PDD. The area under the ROC curve was 0.84. For chronic pain patients prescribed opioids, the development of PDD is an undesirable complication. Among PC patients with chronic pain-prescribed prescription opioids, the COMM is a promising tool for identifying those with PDD. Among primary care patients with chronic pain-prescribed opioids, the validated Current Opioid Misuse Measure (COMM) is a promising tool for identifying patients with prescription opioid use disorder.

PMID: 21177035 [PubMed - in process]PMCID: PMC3027065 [Available on 2012/2/1]

J Urol. 2011 Feb;185(2):551-5. Epub 2010 Dec 18.

Overprescription of postoperative narcotics: a look at postoperative pain medication delivery, consumption and disposal in urological practice.

Bates C, Laciak R, Southwick A, Bishoff J.

University of Utah Health Sciences Center, Salt Lake City, Utah, USA. cory.bates@hsc.utah.edu

Abstract

PURPOSE: Prescription narcotic abuse is a significant social problem. Surplus medication following surgery is 1 source of prescription diversion. We assessed prescribing practices, consumption and disposal of prescribed narcotics after urological surgery.

MATERIALS AND METHODS: Surveys were administered to a 3-month consecutive sample of adult patients who underwent surgery performed by full and adjunct University of Utah Urology faculty. Surveys were performed 2 to 4 weeks postoperatively. With the exception of the investigators, prescribing physicians had no prior knowledge of the study. Data collected included perception of pain control, type and quantity of medication prescribed, quantity of leftover medication, refills needed, disposal instructions and surplus medication disposition.

RESULTS: Overall 47% of 586 patients participated in the study. Hydrocodone was prescribed most commonly (63%), followed by oxycodone (35%), and 86% of the patients were satisfied with pain control. Of the dispensed narcotics 58% was consumed and 12% of patients requested refills. A total of 67% of patients had surplus medication from the initial prescription and 92% received no disposal instructions for surplus medication. Of those patients with leftover medication 91% kept the medication at home while 6% threw it in the trash, 2% flushed it down the toilet and less than 1% returned it to a pharmacy.

CONCLUSIONS: Overprescription of narcotics is common and retained surplus medication presents a readily available source of opioid diversion. It appears that no entity on the prescribing or dispensing ends of prescription opioid delivery is fulfilling the responsibility to accurately educate patients on proper surplus medication disposal. Surgeons should analyze prescribing practices and consider decreasing the quantity of postoperative narcotics prescribed.

PMID: 21168869 [PubMed - in process

Background Information for the Washington Academy of Family Physicians

Pertaining to “Cautious, Evidence-based Opioid Prescribing”

Contact:

Michael Von Korff Sc.D.

Senior Investigator

Group Health Research Institute

1730 Minor Avenue, Suite 1600

Seattle, WA 98101

206-287-2874 vonkorff.m@ghc.org

The attached materials were developed by "Physicians for Responsible Opioid Prescribing". This group formed due to concerns about:

The national epidemic of fatal drug overdose involving prescription opioids;
Increasing rates of prescription opioid addiction and misuse;
Widespread use of diverted opioids by adolescents;
And, increasing patient care problems that have arisen around prescribing opioids for chronic pain.

Physicians for Responsible Opioid Prescribing is an ad hoc group that includes physicians and researchers with expertise in addiction medicine, pain medicine, pharmacoepidemiology, and public health. The “Cautious, Evidence-based Opioid Prescribing” document was externally reviewed by leading experts on the use of opioids for management of chronic non-cancer pain and addiction medicine.

We are pleased that the Washington Academy of Family Physicians is considering use of our materials. You may decide that Cautious, Evidence-based Opioid Prescribing would be useful information to share with your members, either in written form, or by placing it on your website. You may decide that you wish to modify some parts of this document to meet specific needs of your organization. You do not need permission to use or modify these materials. Physicians for Responsible Opioid Prescribing is seeking non-profit organization status, and has no industry support for its work—our efforts are entirely voluntary.

Cautious Evidence-based Opioid Prescribing is NOT a guideline for chronic opioid therapy. Rather, the intent is to provide simple, practical information grounded in available evidence regarding steps that primary care physicians can take to reduce risks when considering use of opioid analgesics, particularly for management of chronic non-cancer pain. These brief materials are intended to counter two decades of pharmaceutical industry supported physician education about use of opioids for chronic non-cancer pain that has spread information that is often incomplete, misleading or out of date. Cautious, Evidence-based Opioid Prescribing reflects results of new studies published over the last five years that have shed light on risks and harms associated with increased prescribing of opioids for chronic non-cancer pain. It attempts to clarify where there are major gaps in information regarding the effectiveness of chronic opioid therapy.

The written materials are organized as "Myths and Facts" and "Do's and Don’ts" (see pdf). The New York City Health Department is planning to use the “Myths and Facts” as a basis for a communication to all physicians in the New York City area. Seattle’s SAMA (Science and Management of Addictions) Foundation has endorsed these materials and is working with us on making this information widely available. Several professional associations are currently considering either endorsement or dissemination.

The stance of Physicians for Responsible Opioid Prescribing towards chronic opioid therapy for chronic non-cancer pain is as follows:

“While chronic opioid therapy at lower doses may be a useful treatment for some patients, it should only be considered for carefully evaluated, closely monitored patients when a cautious, structured and selective approach is employed, and clear benefits for pain and function are documented. COT always entails risks for patients, their families and the community, so vigilance and caution are essential.”

As a supplement to Cautious, Evidence-Based Opioid Prescribing, we have developed brief videos to illustrate three of the myths and facts. These videos include segments with various experts including Jane Ballantyne, Thomas Kosten, and others. These videos are strikingly different than industry-generated information that has been widely disseminated about the low risks and effectiveness of chronic opioid therapy for chronic non-cancer pain.

We believe it has been a mistake to let standards for opioid prescribing for chronic non-cancer pain be defined unilaterally by pain specialists, generally with substantial industry funding. Family physicians and general internists, along with experts in addiction medicine, pharmacoepidemiology, and public health, need to be at the table to consider what can be done to stem the current epidemic of prescription opioid addiction and overdose fatalities, in ways that preserve cautious use of opioids for the sub-set of chronic pain patients who sometimes benefit.

We hope you find the materials we have developed useful. Michael Von Korff, Andrew Kolodny, and other members of Physicians for Responsible Opioid Prescribing will be happy to answer any questions you may have about these educational materials, or about use of these materials by the Washington Academy of Family Practitioners. Please keep us informed of the outcome of your deliberations.

Video clip one: Risk of Addiction and Opioid Therapy for Chronic Non-Cancer Pain

http://www.youtube.com/watch?v=BhUqHQdcY_U

Video clip two: High Dose Opioid Therapy for Chronic Non-Cancer Pain

http://www.youtube.com/watch?v=P1pBghrB6X8

Video clip three: Discontinuing Chronic Opioid Therapy

http://www.youtube.com/watch?v=bY5ZOCmx40M

Pain Physician. 2011 Jan;14(1):71-82.

Feasibility study of rapid opioid rotation and titration.

Korkmazsky M, Ghandehari J, Sanchez A, Lin HM, Pappagallo M.

Mount Sinai Hospital and School of Medicine, Department of Anesthesiology, New York, NY; Maimonides Medical Center, Brooklyn, NY.

Abstract

BACKGROUND: Opioid guidelines recommend opioid rotation and switching for patients who do not achieve adequate pain relief or who experience intolerable adverse events (AEs) with their current opioid. However, specific recommendations and protocols for opioid rotation are lacking, making the practice time consuming and difficult for primary care physicians to accomplish independently or coordinate with a pain specialist.

OBJECTIVES: To assess the safety and feasibility of using 24-hour intravenous patient-controlled analgesia (IV-PCA) to achieve rapid opioid rotation and titration (RORT).

STUDY DESIGN: Open-label pilot study.

SETTING: Hospital research center.

METHODS: At admission, patients (aged ≥ 18 years) with treatment-refractory chronic pain who were taking morphine or oxycodone for ≥ 3 months and had pain scores ≥ 4 on a 10-point scale, underwent opioid rotation to oral oxymorphone extended release (ER). They also received IV-PCA oxymorphone for 24 hours as needed. At discharge, the participants were taking oral oxymorphone ER with oxymorphone immediate release (IR) as needed based on their total 24-hour oral plus IV-PCA oxymorphone use. During a 2-week follow-up, their oxymorphone usage was titrated as needed. Main outcome measures were AEs, Patient Global Impression of Change (PGIC), Brief Pain Inventory (0 = no pain/interference, 10 = worst pain/complete interference), treatment satisfaction, and change in oxymorphone dose.

RESULTS: Twelve patients enrolled and completed the 24-hour IV-PCA; 10 completed the 2-week follow-up post-24-hour IV-PCA. PGIC status improved by 12 hours (odds ratio [OR], 0.19, 95% CI, 0.08 - 0.44; P < 0.001), and both PGIC status and activity scores improved by 24 hours (OR, 0.23, 95% CI, 0.09 - 0.55; P = 0.001; OR, 0.49, 95% CI, 0.25 - 0.96; P = 0.04, respectively) and 2 weeks (OR, 0.14, 95% CI, 0.04 - 0.46; P = 0.001; OR, 0.21, 95% CI, 0.06 - 0.72; P = 0.01) versus 6 hours. During the 24-hour IV-PCA time period, 6 of 10 patients accomplished ≥ 50% of their overall dose titration. At 2 weeks, 8 of 10 participants were Greatly Satisfied or Somewhat Satisfied with the overall RORT procedure. RORT was well tolerated, with no serious AEs.

LIMITATIONS: This was a pilot open-label study in a small number of participants. A larger randomized study with long-term follow-up and comparison to traditional protocols is necessary.

CONCLUSIONS: Preliminary data suggest that RORT can be performed safely and effectively by incorporating IV-PCA during the first 24 hours. Further investigations are needed to determine whether RORT can become an ambulatory treatment intervention in pain practice.

PMID: 21267044 [PubMed - in process]

Ugeskr Laeger. 2010 Nov 15;172(46):3173-8.

[The licit opioid consumption in Denmark].

[Article in Danish]

Jarlbaek L, Kehlet H, Sjøgren P.

Herlev Hospital, Onkologisk Afdeling R, Denmark.

Abstract

To identify users and use of opioids in Denmark three databases were combined. The latest fifteen years an increase in users has been noted, and the costs of opioids have increased from 175 million DKK (1994) to 540 million DKK (2008). Oxycodone and transdermal fentanyl constitute 60% of the total annual costs, and together with the increasing costs of buprenorphine, the three opioids constitute 70% of the total costs in the primary health care sector. The largest group of users is individuals with acute pain, however, the highest consumption is generated by individuals with chronic non-malignant pain.

PMID: 21073831 [PubMed - indexed for MEDLINE]

Drug Alcohol Depend. 2010 Dec 3. [Epub ahead of print]

Epidemiologic trends and geographic patterns of fatal opioid intoxications in Connecticut, USA: 1997-2007.

Green TC, Grau LE, Carver HW, Kinzly M, Heimer R.

The Warren Alpert Medical School of Brown University, Box G-1, Providence, RI 02912, USA.

Abstract

BACKGROUND: The leading cause of injury death among adults in Connecticut (CT), USA is drug poisonings. We analyzed the epidemiology and geographic distribution of opioid-involved accidental drug-involved intoxication deaths ("overdoses") in CT over an 11-year period.

METHODS: We reviewed data from 1997 to 2007 on all adult accidental/undetermined drug intoxication deaths in CT that were referred to the Office of the Chief Medical Examiner (OCME). Regression analyses were conducted to uncover risk factors for fatal opioid-involved intoxications and to compare heroin- to prescription opioid- and methadone-involved deaths. Death locations were mapped to visualize differences in the geographic patterns of overdose by opioid type.

RESULTS: Of the 2900 qualifying deaths, 2231 (77%) involved opioids. Trends over time revealed increases in total opioid-related deaths although heroin-related deaths remained constant. Methadone, oxycodone and fentanyl, the most frequently cited prescription opioids, exhibited significant increases in opioid deaths. Prescription opioid-only deaths were more likely to involve other medications (e.g., benzodiazepines) and to have occurred among residents of a suburban or small town location, compared to heroin-involved or methadone-involved deaths. Heroin-only deaths tended to occur among non-Whites, were more likely to involve alcohol or cocaine and to occur in public locations and large cities.

CONCLUSIONS: The epidemiology of fatal opioid overdose in CT exhibits distinct longitudinal, risk factor, and geographic differences by opioid type. Each of these trends has implications for public health and prevention efforts.

PMID: 21131140 [PubMed - as supplied by publisher]

N Engl J Med. 2010 Nov 18;363(21):1981-5.

A flood of opioids, a rising tide of deaths.

Okie S.

Georgetown University School of Medicine, Washington, DC, USA.

Erratum in:

N Engl J Med. 2011 Jan 20;364(3):290.

PMID: 21083382 [PubMed - indexed for MEDLINE]Free Article

Arch Intern Med. 2010 Dec 13;170(22):1979-86.

The comparative safety of opioids for nonmalignant pain in older adults.

Solomon DH, Rassen JA, Glynn RJ, Garneau K, Levin R, Lee J, Schneeweiss S.

Division of Pharmacoepidemiology, Brigham and Women's Hospital, Boston, MA 02115, USA. dsolomon@partners.org

Comment in:

Arch Intern Med. 2010 Dec 13;170(22):1986-8.

Abstract

BACKGROUND: Severe nonmalignant pain affects a large proportion of adults. Optimal treatment is not clear, and opioids are an important option for analgesia. However, there is relatively little information about the comparative safety of opioids. Therefore, we sought to compare the safety of opioids commonly used for nonmalignant pain.

METHODS: We devised a propensity-matched cohort analysis that used health care utilization data collected from January 1, 1996, through December 31, 2005. Study participants were Medicare beneficiaries from 2 US states who were new initiators of opioid therapy for nonmalignant pain, including codeine phosphate, hydrocodone bitartrate, oxycodone hydrochloride, propoxyphene hydrochloride, and tramadol hydrochloride; none had a cancer diagnosis, and none were using hospice or nursing home care. Our main outcome measures were incidence rates and rate ratios (RRs) with 95% confidence intervals (CIs) for cardiovascular events, fractures, gastrointestinal events, and several composite end points.

RESULTS: We matched 6275 subjects in each of the 5 opioid groups. The groups were well matched on baseline characteristics. The risk of cardiovascular events was similar across opioid groups 30 days after the start of opioid therapy, but it was elevated for codeine (RR, 1.62; 95% CI, 1.27-2.06) after 180 days. Compared with hydrocodone, after 30 days of opioid exposure the risk of fracture was significantly reduced for tramadol (RR, 0.21; 95% CI, 0.16-0.28) and propoxyphene (0.54; 0.44-0.66) users. The risk of gastrointestinal safety events did not differ across opioid groups. All-cause mortality was elevated after 30 days for oxycodone (RR, 2.43; 95% CI, 1.47-4.00) and codeine (2.05; 1.22-3.45) users compared with hydrocodone users.

CONCLUSIONS: The rates of safety events among older adults using opioids for nonmalignant pain vary significantly by agent. Causal inference requires experimental designs, but these results should prompt caution and further study.

PMID: 21149754 [PubMed - indexed for MEDLINE]

Inj Prev. 2011 Jan 7. [Epub ahead of print]

Increasing deaths involving oxycodone, Victoria, Australia, 2000-09.

Rintoul AC, Dobbin MD, Drummer OH, Ozanne-Smith J.

Department of Forensic Medicine, Monash University, Australia.

Abstract

Objective In light of an emerging epidemic identified in the United States and Canada, to identify trends in fatal drug toxicity involving oxycodone and the demographic characteristics and indicators of socioeconomic disadvantage of the deceased. Study design Population-based observational study in Victoria, Australia. Population Decedents whose death was reported to the Victorian Coroner between 2000 and 2009 and where oxycodone was detected. Main outcome measures Association between supply of oxycodone and deaths. Demographic characteristics of decedents. Rate ratios of the rural or metropolitan location and socioeconomic indicators of disadvantage of the deceased. Results Supply to Victoria has increased nine-fold from 7.5&emsp14;mg per capita in 2000 to 67.5&emsp14;mg per capita in 2009. Detection of oxycodone in deaths reported to the Victorian Coroner has increased from 4 (0.08/100 000 population) in 2000 to 97 (1.78/100 000 population) in 2009-a 21-fold increase in deaths. Of the 320 cases described, 53.8% (172) were the result of drug toxicity. Of these, 52.3% were unintentional and 19.8% intentional self-harm; the remaining 27.9% are either still under investigation by the coroner or intent is unknown. Drug toxicity deaths were overrepresented in both rural areas and areas indexed with high levels of disadvantage. Conclusions The substantial increase in the number of deaths involving oxycodone is strongly and significantly associated with the increase in supply. Most drug toxicity deaths involving oxycodone were unintentional. This newly identified trend in fatalities in Victoria supports concerns that a pattern of increasing deaths involving oxycodone is emerging globally.

PMID: 21164159 [PubMed - as supplied by publisher]

J Urol. 2011 Feb;185(2):551-5. Epub 2010 Dec 18.

Overprescription of postoperative narcotics: a look at postoperative pain medication delivery, consumption and disposal in urological practice.

Bates C, Laciak R, Southwick A, Bishoff J.

University of Utah Health Sciences Center, Salt Lake City, Utah.

Abstract

PMID: 21168869 [PubMed - in process]

Pain. 2011 Feb;152(2):397-402. Epub 2010 Dec 21.

Identifying prescription opioid use disorder in primary care: Diagnostic characteristics of the Current Opioid Misuse Measure (COMM).

Meltzer EC, Rybin D, Saitz R, Samet JH, Schwartz SL, Butler SF, Liebschutz JM.

Clinical Addiction Research and Education (CARE) Unit, Section of General Internal Medicine, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, MA, USA.

Abstract

PMID: 21177035 [PubMed - in process]PMCID: PMC3027065 [Available on 2012/2/1]

Eur J Clin Pharmacol. 2011 Feb;67(2):165-8. Epub 2010 Nov 6.

Trends in opioid analgesics consumption, Israel, 2000-2008.

Ponizovsky AM, Marom E, Zeldin A, Cherny NI.

Mental Health Services, Ministry of Health, 2 Ben Tabai Street, 93591, Jerusalem, Israel, alexander.ponizovsky@moh.health.gov.il.

Abstract

OBJECTIVE: To describe trends in opioid consumption in Israel (morphine, methadone, oxycodone, pethidine, fentanyl, buprenorphine, codeine, and dextropropoxyphene) over the 9 years, 2000-2008, and to explore explanations for changes in consumption, in amounts and the pattern.

METHODS: Data for the 2000-2008 period (all treatment settings, private and public) were drawn from the database maintained by the Israel Ministry of Health's Pharmaceutical Administration. The data were converted into a defined daily dose (DDD)/1,000 inhabitants/day.

RESULTS: Consumption of the five strong opioids (requiring a special prescription form) increased by 47%, from 2.46 DDD/1,000 inhabitants per day in 2000 to 3.61 DDD/1,000 inhabitants per day in 2008. This rise was mainly the result of a 4-fold increase in fentanyl consumption from 0.32 DDD/1,000 inhabitants per day in 2000 to 1.28 DDD/1,000 inhabitants per day in 2008. Oxycodone and methadone consumption levels increased moderately, and buprenorphine and dextropropoxyphene consumption rose drastically, whereas morphine, pethidine, and codeine use significantly fell.

CONCLUSION: There has been a modest increase in opioid consumption in the years 2000-2008. This has been associated with substantial changes in the pattern of differential opioid prescribing characterized by increased prescription of oxycodone, fentanyl, buprenorphine, and dextropropoxyphene, and decreases in morphine, pethidine, and codeine.

PMID: 21057940 [PubMed - in process]

Curr Top Med Chem. 2010 Nov 4. [Epub ahead of print]

Opioid Analgesics and P-glycoprotein Efflux Transporters: A Potential Systems-Level Contribution to Analgesic Tolerance.

Mercer SL, Coop A.

Department of Pharmaceutical Sciences, Lipscomb University College of Pharmacy, One University Park Drive, Nashville, TN 37204, USA. Susan.Mercer@Lipscomb.edu.

Abstract

Chronic clinical pain remains poorly treated. Despite attempts to develop novel analgesic agents, opioids remain the standard analgesics of choice in the clinical management of chronic and severe pain. However, mu opioid analgesics have undesired side effects including, but not limited to, respiratory depression, physical dependence and tolerance. A growing body of evidence suggests that P-glycoprotein (P-gp), an efflux transporter, may contribute a systems-level approach to the development of opioid tolerance. Herein, we describe current in vitro and in vivo methodology available to analyze interactions between opioids and P-gp and critically analyze P-gp data associated with six commonly used mu opioids to include morphine, methadone, loperamide, meperidine, oxycodone, and fentanyl. Recent studies focused on the development of opioids lacking P-gp substrate activity are explored, concentrating on structure-activity relationship development to develop an optimal opioid analgesic lacking this systems-level contribution to tolerance development. Continued work in this area will potentially allow for delineation of the mechanism responsible for opioid-related P-gp up-regulation and provide further support for evidence based medicine supporting clinical opioid rotation.

PMID: 21050174 [PubMed - as supplied by publisher]

Time. 2010 Sep 13;176(11):46-9.

The new drug crisis; addiction by prescription.

Kluger J.

PMID: 20873408 [PubMed - indexed for MEDLINE]

Neuropsychopharmacology. 2011 Jan;36(2):411-22. Epub 2010 Oct 27.

The subjective, reinforcing, and analgesic effects of oxycodone in patients with chronic, non-malignant pain who are maintained on sublingual buprenorphine/naloxone.

Jones JD, Sullivan MA, Manubay J, Vosburg SK, Comer SD.

Division on Substance Abuse, New York State Psychiatric Institute/College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

Abstract

Some sources suggest that significant misuse of opioid drugs exists among patients with chronic pain. However, the risk factors and motivation behind their abuse may differ from those of other opioid abusers. This study sought to examine the abuse liability of oxycodone among patients with chronic, non-malignant pain who met the DSM-IV criteria for opioid abuse. Eighteen opioid-dependent patients with chronic pain lived on an in-patient unit of the New York State Psychiatric Institute during the 7-week study. Participants were given oral oxycodone (0, 10, 20, 40, and 60 mg/70 kg) while maintained on various doses of sublingual buprenorphine/naloxone (Bup/Nx; 2/0.5, 8/2, and 16/4 mg/day). Doses of both medications were administered under double-blind conditions. Oxycodone produced an overall positive, but less robust, subjective profile than previously reported in recreational opioid users without pain. Furthermore, unlike our findings in recreational opioid users and more similar to effects in non-drug-abusing individuals, oxycodone failed to serve as a reinforcer. As for the maintenance drug, Bup/Nx produced a dose-related reduction in some of the effects of acutely administered oxycodone. These data suggest that sublingual Bup/Nx has the potential as an analgesic medication and further research should investigate its use in treating patients with chronic pain who abuse opioids.

PMID: 20980992 [PubMed - in process]

Clin Pharmacokinet. 2010 Dec 1;49(12):817-27. doi: 10.2165/11536610-000000000-00000.

A pharmacokinetic and pharmacodynamic study of oral oxycodone in a human experimental pain model of hyperalgesia.

Olesen AE, Upton R, Foster DJ, Staahl C, Christrup LL, Arendt-Nielsen L, Drewes AM.

Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aarhus, Denmark.

Abstract

BACKGROUND AND OBJECTIVE: Oxycodone is not as well characterized, with respect to its pharmacokinetic/pharmacodynamic properties, as other opioids. Moreover, the pharmacodynamic profile of oxycodone can be affected by changes in the pain system, e.g. hyperalgesia. Therefore, the aim of this study was to investigate the pharmacokinetic/pharmacodynamic profiles of oxycodone in a human experimental pain model of hyperalgesia.

METHODS: Twenty-four healthy subjects received oral oxycodone (15 mg) or placebo. Pharmacodynamics were assessed utilizing a multimodal, multi-tissue paradigm where pain was assessed from skin (heat), muscle (pressure) and viscera (heat and electricity) before and 30, 60 and 90 minutes after induction of generalized hyperalgesia evoked by perfusion of acid and capsaicin in the oesophagus. Venous blood samples were obtained for quantification of oxycodone plasma concentrations before and 5, 10, 15, 30, 45, 60, 90 and 120 minutes after drug administration.

RESULTS: Oxycodone blood concentrations could be described by a one-compartment model but, given the necessarily short timescale of the study, the concentrations were represented by linear interpolation for subsequent pharmacodynamic models. Time-dependent changes in the pain measures in the placebo arm of the study were represented by linear or quadratic functions. The time course of the pain measures in the oxycodone arm was taken to be the time course for the placebo arm plus a concentration-effect relationship that was either zero (no drug effect), linear or a maximum effect (E(max)) model. For three of the four pain measures, there was a time-dependent change after administration of placebo (e.g. due to the development of generalized hyperalgesia).

CONCLUSION: There was a measurable effect of oxycodone, compared with placebo, on all pain measures, and a linear concentration-effect relationship without an effect delay was demonstrated. This could indicate an initial peripheral analgesic effect of oxycodone.

PMID: 20873879 [PubMed - in process]

Aust Fam Physician. 2010 Aug;39(8):540-6.

Prescription drug misuse.

Monheit B.

Southcity Clinic, Monash University, The Alfred, Melbourne, Victoria. bmonheit@southcityclinic.com.au

Comment in:

Aust Fam Physician. 2010 Oct;39(10):715.

Abstract

BACKGROUND: Recognising and dealing with patients who seek drugs for nonmedical purposes can be a difficult problem in general practice. 'Prescription shoppers' and patients with chronic nonmalignant pain problems are the main people who constitute this small but problematic group. The main drugs they seek are benzodiazepines and opioids.

OBJECTIVE: To provide data on current trends in prescription drug abuse and to discuss different strategies on how to deal with this issue in the clinic setting.

DISCUSSION: Misuse of prescription drugs can take the form of injecting oral drugs, selling them on the street, or simply overusing the prescribed amount so that patients run short before the due date and then request extra prescriptions from the doctor. Currently oxycontin and alprazolam are the most abused drugs in Australia. Adequate prescription monitoring mechanisms at the systems level are lacking so we need to rely on our clinical skills and the patient's behaviour pattern over time to detect problematic prescription drug misuse. Management strategies may include saying 'no' to patients, having a treatment plan, and adopting a universal precaution approach toward all patients prescribed drugs of addiction. Among patients with chronic nonmalignant pain, requests for increasing opioid doses need careful assessment to elucidate any nonmedical factors that may be at play.

PMID: 20877745 [PubMed - indexed for MEDLINE]

J Opioid Manag. 2010 Jul-Aug;6(4):300-3.

Acute opioid withdrawal precipitated by ingestion of crushed embeda (morphine extended release with sequestered naltrexone): case report and the focused review of the literature.

Ruan X, Chen T, Gudin J, Couch JP, Chiravuri S.

Physicians' Pain Specialists of Alabama, Mobile, USA.

Abstract

BACKGROUND: The introduction of newly formulated extended release (ER) morphine with sequestered naltrexone (Embeda) has provided another treatment option for moderate to severe persistent pain. Embeda was designed to be an abuse-deterrent opioid formulation. Naltrexone is a centrally acting opioid receptor antagonist that blocks the action of opioid. When taken as directed, insignificant amount of sequestered naltrexone would reach systemic circulation, but upon tampering, the released naltrexone may blunt the euphoria of opioids, and possibly precipitate opioid withdrawal in opioid-dependent patient. OBJECTIVE: To describe a case report ofa 50-year-old opioid-dependent male who developed acute opioid withdrawal after taking crushed Embeda. CASE REPORT: A 50-year-old male with severe, chronic low back pain due to degenerative disc disease was referred to our clinic for pain management. He was taking ER oxycodone 80 mg tid and Roxicodone 30 mg qid prn, with inadequate pain relief A trial of ER oxymorphone was decided, at 40 mg 1-2 doses bid. The patient returned to the clinic 1 week early, out of his ER oxymorphone. At this time, the decision to switch him to Embeda was made, at 80 mg/3.2 mg, 1-2 doses bid. The patient and his family members were counseled about risk involved with tampering with Embeda. A few hours later, our clinic was informed that the patient was brought to emergency room by ambulance, in severe opioid withdrawal. He was treated with IV fluid, antiemetics, clonidine, and IV hydromorphone. His condition improved and he was discharged home the next morning. Later on, the patient admitted that he took two prescribed Embeda within half an hour, the 1st one whole and the 2nd one crushed. He further admitted that he did so against our medical advice. CONCLUSION. Taking tampered Embeda may precipitate opioid withdrawal in opioid-tolerant patient. To the best of our knowledge, this is the first report of induced opioid withdrawal following consumption of crushed Embeda.

PMID: 20862910 [PubMed - indexed for MEDLINE]

Pain Physician. 2010 Sep-Oct;13(5):401-35.

Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective.

Manchikanti L, Fellows B, Ailinani H, Pampati V.

Pain Management Center of Paducah, Paducah, KY, USA. drlm@thepainmd.com

Abstract

The treatment of chronic pain, therapeutic opioid use and abuse, and the nonmedical use of prescription drugs have been topics of intense focus and debate. After the liberalization of laws governing opioid prescribing for the treatment of chronic non-cancer pain by state medical boards in the late 1990s, and with the introduction of new pain management standards implemented by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) in 2000, opioids, in general, and the most potent forms of opioids including Schedule II drugs, in particular, have dramatically increased. Despite the escalating use and abuse of therapeutic opioids, nearly 15 to 20 years later the scientific evidence for the effectiveness of opioids for chronic non-cancer pain remains unclear. Concerns continue regarding efficacy; problematic physiologic effects such as hyperalgesia, hypogonadism and sexual dysfunction; and adverse side effects - especially the potential for misuse and abuse - and the increase in opioid-related deaths. Americans, constituting only 4.6% of the world's population, have been consuming 80% of the global opioid supply, and 99% of the global hydrocodone supply, as well as two-thirds of the world's illegal drugs. Retail sales of commonly used opioid medications (including methadone, oxycodone, fentanyl base, hydromorphone, hydrocodone, morphine, meperidine, and codeine) have increased from a total of 50.7 million grams in 1997 to 126.5 million grams in 2007. This is an overall increase of 149% with increases ranging from 222% for morphine, 280% for hydrocodone, 319% for hydromorphone, 525% for fentanyl base, 866% for oxycodone, to 1,293% for methadone. Average sales of opioids per person have increased from 74 milligrams in 1997 to 369 milligrams in 2007, a 402% increase. Surveys of nonprescription drug abuse, emergency department visits for prescription controlled drugs, unintentional deaths due to prescription controlled substances, therapeutic use of opioids, and opioid abuse have been steadily rising. This manuscript provides an updated 10-year perspective on therapeutic use, abuse, and non-medical use of opioids and their consequences.

PMID: 20859312 [PubMed - indexed for MEDLINE]

Am J Prev Med. 2010 Oct;39(4):357-63.

Increase in unintentional medication overdose deaths: Oklahoma, 1994-2006.

Piercefield E, Archer P, Kemp P, Mallonee S.

CDC, CDC/OWCD/CDD/PMR, 1600 Clifton Road NE, Mailstop E-92, Atlanta GA 30333, USA. epiercefıeld@cdc.gov

Abstract

BACKGROUND: During 1999-2006, rates of unintentional drug-related deaths increased 120% in the U.S.

PURPOSE: This report describes demographics and trends of unintentional medication overdose deaths among Oklahoma residents to target prevention strategies.

METHODS: Oklahoma medical examiner data regarding fatal unintentional poisonings involving at least one prescription or over-the-counter medication during 1994-2006 and opioid retail sales data during 1997-2006 were analyzed during 2008-2009 to determine demographic-specific rates of overdose deaths and changes in 3-year mean death rates.

RESULTS: A total of 2112 fatal unintentional medication overdoses were identified (4.7 deaths/100,000 population) involving a median of two substances/decedent. The highest fatality rates occurred among men (5.9/100,000) and people aged 35-54 years (11/100,000). Crude overdose death rates increased sevenfold during the investigation period, peaking at 11/100,000 in 2006. Death rates increased more for women (ninefold) than men (sixfold); rates among residents of rural counties increased more (eightfold) than urban county rates (sixfold). Leading drug types involved in fatalities were opioids and anxiolytics. The individual drugs contributing most frequently included methadone (31%); hydrocodone (19%); alprazolam (15%); and oxycodone (15%). During 1997-2006, Oklahoma prescription opioid sales increased fourfold. Methadone was associated with the highest number of deaths per equianalgesic dose sold (23.3), whereas hydrocodone and oxycodone had the highest increases in deaths per equianalgesic dose sold (threefold increase each).

CONCLUSIONS: Unintentional medication-related deaths are increasing in Oklahoma and often involve multiple substances. Substances most frequently contributing to deaths were prescription opioid analgesics. Prevention strategies should target people aged 35-54 years and emphasize the dangers of coingesting substances and misusing prescription pain medications.

Published by Elsevier Inc.

PMID: 20837287 [PubMed - indexed for MEDLINE]

Narcotic Painkillers May Raise Risks for Older Patients, Study Says

By Jessica Roberts on December 14, 2010

Older patients with arthritis who take narcotic or opioid-based painkillers appear to face a higher risk for bone fractures, heart attacks and death, compared to those using other, non-narcotic painkillers, according to a study published in the Archives of Internal Medicine.

“Doctors should not assume that opioids are a safer alternative,” to other painkillers, Dr. Daniel H. Solomon, the study’s lead researcher, told The New York Times.

The Times said the study appears to be the first large-scale effort to look at the comparative risks for the elderly of taking different classes of painkillers. The use of narcotic or opiod painkillers–a category including codeine, Vicodin and Oxycontin–has increased in recent years because of a belief that they were safer for older patients than non-narcotic drugs such as Advil and Motrin.

Researchers at Brigham and Women’s Hospital in Boston reviewed the records of Medicare recipients in New Jersey and Pennsylvania, treated from 1999 through 2005, who were diagnosed with osteoarthritis or rheumatoid arthritis. Using statistical methods they divided the mostly female patients, whose average age was 80, into three painkiller groups.

The groups were: narcotic-based drugs; nonsteroidal anti-inflammatory drugs, or NSAIDs, such as Advil or Aleve; and another class of pain drugs called coxibs, including Celebrex as well as Vioxx, which has been pulled from the market.

Although the researchers could not identify all the factors that may have contributed to adverse effects, they found that patients taking narcotic painkillers faced twice as high a risk of death compared to those taking a nonsteroidal anti-inflammatory drug. Patients on narcotics-based painkillers were also four times more likely to experience a compound bone fracture, apparently as a result of a fall, and twice as likely to have a heart attack. The painkillers in the coxibs group carried the same cardiovascular risk as the narcotic drugs.

One of the primary reasons doctors have advocated the use of narcotics-based painkillers is that they were believed to reduce gastrointestinal bleeding, but the review also found that the rate was the same for patients taking narcotic painkillers as for those taking Advil or Aleve.

The Times noted that two physicians at Yale University Medical School, Dr. William C. Becker and Dr. Patrick G. O’Connor, wrote in a commentary accompanying the study that the study’s findings could be skewed by undocumented patient use of over-the-counter painkillers. But they added that the high incidence of bone fractures, which often lead to fatal complications in the elderly, was troublesome.

Posted in News & Notes, Product Hazards and Recalls

The Comparative Safety of Analgesics in Older Adults With Arthritis

Daniel H. Solomon, MD, MPH; Jeremy A. Rassen, ScD; Robert J. Glynn, PhD; Joy Lee, BA; Raisa Levin, MS; Sebastian Schneeweiss, MD, ScD

Arch Intern Med. 2010;170(22):1968-1978. doi:10.1001/archinternmed.2010.391

Background The safety of alternative analgesics is unclear.We examined the comparative safety of nonselective NSAIDs (nsNSAIDs),selective cyclooxygenase 2 inhibitors (coxibs), and opioids.

Methods Medicare beneficiaries from Pennsylvania and NewJersey who initiated therapy with an nsNSAID, a coxib, or anopioid from January 1, 1999, through December 31, 2005, werematched on propensity scores. We studied the risk of adverseevents related to analgesics using incidence rates and adjustedhazard ratios (HRs) from Cox proportional hazards regression.

Results The mean age of participants was 80.0 years, andalmost 85% were female. After propensity score matching, the3 analgesic cohorts were well balanced on baseline covariates.Compared with nsNSAIDs, coxibs (HR, 1.28; 95% confidence interval[CI], 1.01-1.62) and opioids (1.77; 1.39-2.24) exhibited elevatedrelative risk for cardiovascular events. Gastrointestinal tractbleeding risk was reduced for coxib users (HR, 0.60; 95% CI,0.35-1.00) but was similar for opioid users. Use of coxibs andnsNSAIDs resulted in a similar risk for fracture; however, fracturerisk was elevated with opioid use (HR, 4.47; 95% CI, 3.12-6.41).Use of opioids (HR, 1.68; 95% CI, 1.37-2.07) but not coxibswas associated with an increased risk for safety events requiringhospitalization compared with use of nsNSAIDs. In addition,use of opioids (HR, 1.87; 95 CI, 1.39-2.53) but not coxibs raisedthe risk of all-cause mortality compared with use of nsNSAIDs.

Conclusions The comparative safety of analgesics variesdepending on the safety event studied. Opioid use exhibits anincreased relative risk of many safety events compared withnsNSAIDs.

High doses, frequency of opioid prescribing are 'troubling': Ontario study

TORONTO - Researchers are raising new concerns about opioids, in particular some of the high doses of strong painkillers being prescribed to socially disadvantaged people in Ontario.

A study by the Institute for Clinical Evaluative Sciences finds that Canadian guidelines for opioid therapy are not always being followed. And preliminary data indicate that patients who receive high opioid doses have a much greater likelihood of dying than a member of the general population.

"While prescribing has been increasing of opioids, as expected, the daily dose that people are receiving is also increasing over time, and that increase is most pronounced among people who are being prescribed long-acting oxycodone - so this is drugs like OxyContin," said Tara Gomes, a researcher and epidemiologist at the institute.

"About a third of people who are receiving prescriptions for long-acting oxycodone are in fact receiving doses that are considered to be high or very high dose, based on published clinical guidelines."

The term opioid covers powerful painkillers like morphine, codeine and oxycodone.

Researchers looked at prescriptions for patients aged 15 to 64 under Ontario's public drug plan over a six-year period from 2003 to 2008, and found opioid prescribing rates rose 16.2 per cent. By 2008, 180,974 people were receiving nearly 1.5 million opioid prescriptions annually. The findings are published Tuesday in the journal Open Medicine.

Patients with cancer and in palliative care who were taking opioids were not included in the study.

Gomes said several guidelines define an upper dose, or watchful dose, at about 200 milligrams per day. In 2008, 32.6 per cent of people treated with OxyContin received daily doses equivalent to more than 200 mg of oral morphine per day.

"People who were receiving high or very high doses of opioids were 10 times more likely to die within two years (compared to) the general population," she said in an interview.

Among patients who had prescriptions filled for high or very high doses of opioids in 2004, almost 20 per cent of the deaths during the subsequent two-year period were related to opioids.

The Office of the Chief Coroner for Ontario classified 302 deaths as opioid-related, including 45 confirmed as suicides, the study showed.

Gomes described the findings as troubling. The median age of people who were dying of opioid-related causes was 46 years.

"So these are young people that are either being treated with opioids for pain, or have begun to abuse these drugs and become addicted to them, and are dying as a result of that," she said.

Multi-doctoring, in which addicts visit more than one doctor for a painkiller prescription, is considered to be part of the problem, experts say.

Gomes said more education is needed for the public about the risks associated with these drugs, and for physicians and pharmacists about the dangers of prescribing high doses.

Having real-time access to electronic records that show the prescribing history of patients could help address problems of drug dependency and addiction, she said.

Dr. Philip Berger, chief of the family medicine department at St. Michael's Hospital in Toronto, said the study is an extension of earlier findings, looking more closely at deaths and prescribing rates in a socially disadvantaged group.

He said the Ontario Ministry of Health, the regulatory body - the College of Physicians and Surgeons of Ontario - and the University of Toronto have "utterly failed until very recently to confront an epidemic of opioid deaths which has been known for a long time."

But he said the ministry has finally responded with its plan for real-time monitoring that would allow a pharmacist to ascertain whether a patient received a similar prescription on the same day or recently, inappropriately and from more than one doctor.

"That's good," he said, "but the system's not implemented yet."

And he noted that regulatory bodies have issued new guidelines.

"I'm not sure how much that is penetrating the consciousness of Canadian doctors. I hope so. But we're not going to know until there's more studies done."

Open Medicine, Vol 5, No 1 (2011)

Home > Vol 5, No 1 (2011) > Gomes

Research

Trends in opioid use and dosing among socio-economically disadvantaged patients

Tara Gomes, David N Juurlink, Irfan A Dhalla, Angela Mailis-Gagnon, J Michael Paterson, Muhammad M Mamdani

ABSTRACT

Background: Opioid therapy for patients with chronic nonmalignant pain remains controversial, primarily because of safety concerns and the potential for abuse. The objective of this study was to examine trends in opioid utilization for nonmalignant pain among recipients of social assistance and to explore the relation between dose of analgesic and mortality.

Methods: Using a cross-sectional study design, we characterized annual trends in prescriptions for and daily dose of opioid analgesics between 2003 and 2008 for beneficiaries (aged 15 to 64 years) of Ontario’s public drug plan. We defined moderate, high and very high dose thresholds as daily doses of up to 200, 201 to 400, and more than 400 mg oral morphine (or equivalent), respectively. In an exploratory cohort study, we followed, over a 2-year period, patients who received at least one prescription for an opioid in 2004 to investigate the relation between opioid dose and opioid-related mortality.

Results: Over the study period, opioid prescribing rates rose by 16.2%, and 180 974 individuals received nearly 1.5 million opioid prescriptions in 2008. Also by 2008, the daily dose dispensed exceeded 200 mg morphine equivalent for almost a third (32.6%) of recipients of long-acting oxycodone but only 20.3% of those treated with fentanyl or other long-acting opioids. Among patients for whom high or very high doses of opioids were dispensed in 2004, 19.3% of deaths during the subsequent 2 years were opioid-related, occurring at a median age of 46 years. Two-year opioid-related mortality rates were 1.63 per 1000 population (95% confidence interval [CI] 1.42–1.85) among people with moderate-dose prescriptions, 7.92 per 1000 population (95% CI 5.25–11.49) among those with high-dose prescriptions, and 9.94 per 1000 population (95% CI 2.78–25.12) among those with very-high-dose prescriptions.

Interpretation: Among socio-economically disadvantaged patients in Ontario, the use and dose of opioids for nonmalignant pain has increased substantially, driven primarily by the use of long-acting oxycodone and, to a lesser extent, fentanyl. The findings of our exploratory study suggested a strong association between opioid-related mortality and the dose of opioid dispensed.

Expert Opin Pharmacother. 2011 Jan 22. [Epub ahead of print]

Opioids in chronic non-cancer pain.

Chan BK, Tam LK, Wat CY, Chung YF, Tsui SL, Cheung CW.

The University of Hong Kong, Queen Mary Hospital, Department of Anaesthesiology, Room 424, Block K, 102 Pokfulam Road, Hong Kong, China.

Abstract

Introduction: The use of chronic opioid therapy for chronic non-cancer pain is growing and is now accepted as an effective treatment modality. Areas covered: Although there are guidelines and reviews for chronic opioid therapy for chronic non-cancer pain patients, physicians may still have concerns and be reluctant to prescribe strong opioids for chronic non-cancer pain. Common issues and concerns when prescribing opioid for chronic pain management are reviewed and discussed. The literature search was done using Medline with key words 'chronic non-cancer pain', 'chronic opioid therapy', 'effectiveness', 'opioid tolerance', 'opioid-induced hyperalgesia', 'adverse effect', 'opioid dependency', 'addiction', 'monitoring', 'opioid contract' and various combinations with these key words. Studies from 1990 - 2010 have been included. This article helps readers to update, clarify and understand the common concerns when using opioid for chronic non-cancer pain. Clinical effectiveness and adverse effects with chronic opioid therapy, opioid tolerance and opioid-induced hyperalgesia, opioid dependency and addiction, monitoring during chronic opioid use, and opioid contact are discussed in detailed. Expert opinion: Not much strongly positive data supports the long-term use of opioids for pain relief, and the evidence for an improvement in functional activity is inconclusive. With careful selection of patients, meticulous prescription and monitoring protocol, chronic non-cancer pain patients who are likely to benefit from potent opioids should not be prevented from obtaining this treatment.

PMID: 21254859 [PubMed - as supplied by publisher]

Perspective

A Flood of Opioids, a Rising Tide of Deaths

NEJM | November 17, 2010 | Topics: Drugs, Devices, and the FDA, Public Health

Susan Okie, M.D.

Faced with an epidemic of drug abuse and overdose deaths involving prescription opioid pain relievers, the Food and Drug Administration (FDA) plans to require opioid makers to provide training for physicians and patient-education materials on the appropriate prescribing and use of extended-release and long-acting versions of these drugs. But since July, FDA officials have been scrambling to revise their proposed Risk Evaluation and Mitigation Strategy (REMS), after an advisory panel (the agency’s Anesthetic and Life Support Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee) voted 25 to 10 against the FDA’s plan, saying it didn’t go far enough. Advisors urged that training in appropriate use of opioids be made mandatory for all physicians who prescribe them.

In the eyes of many patients, these opioids “are essentially legal heroin,” advisory committee member Lewis Nelson of New York University School of Medicine commented during the panel’s discussion. “We need to think about how we would construct a REMS if we were going to be marketing heroin.” With more than a million prescribers of controlled substances registered with the Drug Enforcement Administration (DEA) and about 4 million U.S. patients receiving long-acting or extended-release opioids each year, the FDA’s opioid REMS will affect far more people than any existing REMS for high-risk medications. Any discussion of restricting the use of pain medicines provokes emotional debate, with some advocates warning that people in chronic pain may be undertreated or stigmatized and others arguing that access to powerful painkillers leads to thousands of deaths each year.

Figure 1: U.S. Rates of Death from Unintentional Drug Overdoses and Numbers of Deaths, According to Major Type of Drug.

There is ample evidence that action is needed. According to the Centers for Disease Control and Prevention (CDC), deaths from unintentional drug overdoses in the United States have been rising steeply since the early 1990s (see bar graph) and are the second-leading cause of accidental death, with 27,658 such deaths recorded in 2007. That increase has been propelled by a rising number of overdoses of opioids (synthetic versions of opium), which caused 11,499 of the deaths in 2007 — more than heroin and cocaine combined (see line graph). Visits to emergency departments for opioid abuse more than doubled between 2004 and 2008,¹ and admissions to substance-abuse treatment programs increased by 400% between 1998 and 2008, with prescription painkillers being the second most prevalent type of abused drug after marijuana.²

These escalations parallel an increase by a factor of 10 in the medical use of opioids since 1990, spurred in part by aggressive marketing of OxyContin, an extended-release form of oxycodone approved in 1995, and by efforts to encourage clinicians to become more proactive in identifying and treating chronic pain. Between 1997 and 2002, sales of oxycodone and methadone nearly quadrupled. Although both per capita opioid sales and death rates from the drugs vary widely among the 50 states, studies have found a strong correlation between states with the highest drug-poisoning mortality and those with the highest opioid consumption; per capita sales are most strongly linked with methadone- and oxycodone-related mortality.³ “In some ways, this is an unintended consequence of an intent to treat pain better,” said Robert Rolfs, Utah’s state epidemiologist.

The increase in opioid deaths has been accompanied by a striking shift in the prevalence of fatal drug overdoses from urban to rural counties. The highest rates now occur in predominantly rural states, including West Virginia, New Mexico, Utah, Louisiana, Oklahoma, Nevada, Kentucky, and Tennessee — although some other rural states have low rates. Leonard Paulozzi, a medical epidemiologist with the CDC’s Division of Unintentional Injury Prevention, said that the increases in opioid prescribing and sales during the 1990s brought “abusable” drugs into rural areas where no distribution network had existed for illicit drugs, such as heroin or cocaine. “Everybody’s within a few miles of a pharmacy,” he said, though he admits that increased availability is not the only relevant factor.

States’ systems for investigating deaths vary in comprehensiveness, and Paulozzi said the CDC’s figures underestimate the total number of overdose deaths. Nevertheless, certain patterns seem clear. For example, although rates of suicide caused by drug overdoses have also increased somewhat, most opioid-overdose deaths are accidental. More often than not, laboratory tests reveal the presence of one or more substances in addition to the opioid, suggesting that the depressant effects of alcohol or other drugs on the central nervous system were additive with those of the pain reliever in causing death.

In almost every age group, men have higher death rates from drug overdoses than women. The highest mortality for both sexes occurs among people 45 to 54 years of age, although young adults abuse opioids and other drugs more frequently and are more likely to be seen with drug-related symptoms in emergency rooms. Whites and Native Americans have higher death rates from drug overdoses than blacks. National prescription-tracking data show that more than 40% of opioid prescriptions are written by general or family practitioners, osteopaths, or internists, most commonly for diseases of the musculoskeletal system and connective tissue. More than 3% of U.S. adults currently receive long-term opioid therapy for chronic noncancer pain, and patients taking high daily doses appear to be at increased risk for overdose.⁴

Reducing deaths from opioid overdoses is challenging because such deaths stem from multiple factors, including providers’ inappropriate prescribing or inadequate counseling and monitoring, patients’ misuse or abuse of drugs, sharing of pain pills with relatives or friends, “doctor shopping” to obtain multiple prescriptions, and diversion of opioids leading to illicit sales and abuse. A study of unintentional-overdose deaths during 2006 in West Virginia (the state with the highest rate of death from such overdoses) showed that almost everyone who died had one or more indicators of drug or substance abuse; additional risk factors included having a low level of education and living in one of the state’s poorest counties.⁵ About half of those who died had a medical history of pain treatment. Opioids were involved in 93% of deaths, with methadone implicated far more often than any other drug. Methadone sales for chronic pain have increased partly in response to pressure from insurers and Medicaid programs, because the medication has been viewed as a cheaper and potentially less abusable alternative to other long-acting pain relievers. However, its very long half-life makes it tricky to manage and especially dangerous when combined with other drugs.

Experts said that tracing the sources of drugs that are implicated in individual overdose deaths is difficult. “It’s really impossible to say with any certainty, `This death obviously was a therapeutic error,’ or `This death was misuse of the drug,’ or `This death was obviously abuse,’” said Edward Boyer, chief of the division of medical toxicology at the University of Massachusetts and an advisory committee member.

“Clearly, getting [prescription pain relievers] from doctors” is common in such cases, added Utah’s Rolfs. “Many of these people have chronic pain, and you might want to consider prescribing an opioid for them, but they also tend to be people, at least in retrospect, who have a lot of risk factors” for abuse.

John Jenkins, director of the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research, said the opioid REMS will use training programs and educational materials to try to ensure that physicians prescribe the drugs only for appropriate patients and indications, prescribe them properly, and counsel patients on their safe use and disposal. He said the agency proposed limiting the REMS to long-acting and extended-release opioids because the “unique pharmacology and delivery system” of these formulations make them riskier than immediate-release opioids. For patients with no previous exposure to such drugs, 80 mg of OxyContin “might be a fatal dose, even if you take it correctly,” Jenkins said. In addition, fewer health care providers prescribe long-acting opioids than immediate-release ones, so limiting the REMS to the longer-acting drugs would reduce the burden on the health care system. However, many advisory committee members argued that the REMS should cover all opioids, and some suggested that methadone deserved special attention.

Under the proposed REMS, companies marketing opioids would develop training content (subject to FDA approval), recruit doctors, and assess their programs’ effectiveness, but training would be voluntary. The FDA could require such training, but officials said doing so would be costly and would duplicate the DEA’s registration system for prescribers of controlled substances. To make pain-management training mandatory for obtaining a DEA number, a change supported by the advisory committee, Congress would have to pass legislation. Alternatively, state medical licensing boards could require such training (California, Rhode Island, and West Virginia already do to some extent), but each state sets its own licensing requirements.

In its proposed REMS, the FDA also opted not to require registration of persons receiving long-acting opioids or signed patient–provider agreements regarding proper use. Though such measures might strengthen the program, critics predicted they would create barriers to treatment and stigmatize people with chronic pain. Once the agency notifies manufacturers of its REMS requirements, they’ll have up to 120 days to submit a program for approval, so details of the final plan will probably not become public until early next year.

Meanwhile, other federal agencies, state and local governments, and private entities are striving to reduce opioid abuse and overdose deaths. The DEA prosecutes doctors accused of illegally prescribing opioids at bogus pain clinics and recently tightened its regulation of online pharmacies. In September, it oversaw the first 1-day prescription-drug take-back program, encouraging consumers to turn in unused pain medications. Florida, Texas, and Louisiana recently passed laws to crack down on “pill mills,” imposing state registration and other restrictions on pain clinics. Forty-one states have established programs allowing physicians and other authorized users to check a patient’s history of receiving controlled-substance prescriptions, but some of these programs are unfunded or nonoperational, and few prescribers have signed up to use them. Next June, the country’s most sweeping law aimed at regulating opioid use and improving pain-management practices will become effective in Washington State (see below), and health officials nationwide will be watching closely.

Ultimately, “we probably need a complicated, multifaceted solution” to the problem of opioid abuse and overdose, said Utah’s Rolfs. “I don’t think we have the answer.”

Regulating Opioid Use in Washington State

Once a new law goes into effect in mid-2011, opioid prescribers in Washington State will have to enter their patients’ clinical responses to treatment in a statewide database and consult a pain specialist if a patient’s daily dose goes above a specified threshold.

Deaths by poisoning (90% of them caused by drug overdoses) surpassed motor vehicle crashes several years ago as the commonest cause of accidental death in the state. The law that was passed earlier this year, which also mandates uniform pain-management guidelines and the use of a prescription-monitoring program, is the first state-government effort to require assessment of doctors’ outcomes in managing chronic pain. The new rules will not apply to cancer pain, pain treated as part of palliative or end-of-life care, or acute pain after an injury or surgery.

Dr. Alex Cahana, chief of the Division of Pain Management at the University of Washington and an architect of the measure, said physicians have not substantially changed their practices in response to treatment guidelines and voluntary educational programs. However, they will do so “if they know their success in treating patients is being measured,” he predicted. At the time that patients initially present with pain, they will be asked to complete a confidential computerized questionnaire assessing factors such as daily pain level, mood, quality of life, and history of mental illness or substance abuse. At each subsequent visit, they will complete a brief follow-up questionnaire. Health care providers can review each patient’s longitudinal record in making treatment decisions, and studies of de-identified patient data can be used to measure population-wide outcomes and set policy. Cahana hopes that clinical feedback will help shift practitioners away from an “overreliance on pills, devices, and surgical procedures” and toward the use of nondrug treatments, such as graded exercise or behavior-modification programs.

A working group drawn from Washington’s boards of health care professionals is drafting rules to implement the law. Critics predict that there will be too few pain specialists to meet the consultation demands and that some providers may opt out of prescribing opioids altogether. The new requirements “may lead practitioners to be far more hesitant to treat,” said Dr. Perry Fine, a professor of anesthesiology at the University of Utah School of Medicine and president-elect of the American Academy of Pain Medicine.

Still, Fine added, Washington’s new law may provide “the opportunity for measurable, monitorable” results of policies aimed at “getting the outcomes we all want.”

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

Source Information

Dr. Okie is a medical journalist and a clinical assistant professor of family medicine at Georgetown University School of Medicine, Washington, DC

J Fam Pract. 2010 Nov;59(11):628-33.

Is it time to drug test your chronic pain patient?

McBane S, Weigle N.

University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92023, USA. smcbane@ucsd.edu

PMID: 21060901 [PubMed - indexed for MEDLINE

Year in Review: Mitigating Opioid Risk

By Kristina Fiore, Staff Writer, MedPage Today

Published: December 30, 2010

As part of the Year in Review series, MedPage Today reporters are revisiting major news stories and following up with an analysis of the impact of the original report, as well as subsequent news generated by the initial publication. Here's what's happened on the opioid use front since we published the first 2010 piece on the topic.

Last summer, an FDA advisory panel rejected the agency's proposed risk evaluation and mitigation strategy (REMS) for long-acting opioids, arguing that the plan lacked teeth to curb the growing epidemic of addiction to prescription painkillers.

The panel called for stronger education requirements for doctors prescribing opioids and warned that drugmakers shouldn't be in charge of that education.

Now, the FDA is reworking its plan and expects to announce the final program in early 2011, according to an agency spokesperson. Drug companies will then have 120 days to submit their own REMS and implement relevant programs.

In the meantime, some groups have launched their own initiatives to prevent inappropriate prescribing and abuse of extended-release opioid painkillers -- trends made evident by increasing overdoses and hospital emergency department admissions that parallel a 10-fold rise in the use of medical opioids since 1990, experts say. An estimated four million patients in the U.S. receive long-acting opioids each year.

Washington state, for instance, passed a law that will require doctors to consult with pain specialists if patients aren't responding to higher doses of opioids. And a number of addiction specialists -- along with some respected patient advocates -- have formed a work group to champion better education for physicians who prescribe opioids.

"It was a shame that FDA hadn't proposed anything that would be effective," Andrew Kolodny, MD, chair of psychiatry at Maimonides Medical Center in Brooklyn, N.Y., told MedPage Today. Kolodny is among the leadership of Physicians for Responsible Opioid Prescribing and is joined by other experts like Michael Von Korff, ScD, of GroupHealth in Seattle, and Len Paulozzi, MD, MPH, of the CDC.

But the group also extends to patient advocates -- some of whom lead their own groups as well -- including Betts Tully, a pain patient who ended up addicted and has shared her story with the FDA and in a letter in the Annals of Internal Medicine, and Pete Jackson, a biologist who lost his daughter to an accidental overdose of Oxycontin.

Kolodny says everyone in the group shares a common concern about "the way we are prescribing opioids for pain."

One of their first initiatives is an educational brochure for physicians, complete with citations and peer review, on the "myths and facts" about opioid therapy, as well as a list of do's and don't's when prescribing. The group will soon distribute the pamphlet to New York City physicians via its Department of Health and Mental Hygiene.

The group also plans to approach the CDC and other professional medical associations for an endorsement as well.

Ultimately, they hope to be involved in other educational efforts if the final FDA long-acting opioid REMS requires it -- offering an alternative to the "same key opinion leaders who made themselves wealthy through pharmaceutical marketing," Kolodny says. (Kolodny has no conflicts of interest.)

Washington state is beefing up its educational resources for when the new law takes effect in June 2011. At that time, opioid prescribers will have to enter their patients' clinical responses to treatment in a state-wide database and consult a pain specialist if a patient's daily dose exceeds 120 mg.

Researchers there are developing a program in which University of Washington pain specialists will train physicians and nurse practitioners in appropriate prescribing, according to Gary Franklin, MD, MPH, medical director of the state's department of Labor and Industries, who was extensively involved in the legislation.

"What we've done here is where this country needs to go," Franklin told MedPage Today. He said the foundations for the law were set in 2007 with the creation of the first guideline on opioid dosing, which was expanded just last year.

The final bill was signed into law last spring, and committees are now hammering out the final pattern rules, which will be published as preliminary rules this winter.

"I was extremely proud that our legislators stepped up," Franklin said. "I could see that people generally do not recognize this problem. Most of the people in that hearing were unaware that so many people die every year from unintentional overdose."

Kolodny's group is focused on illuminating the gaps in the evidence base for opioid treatment. The first topic in its myths and facts brochure is the lack of evidence for long-term prescribing (greater than 16 weeks) of opioids for chronic pain. There's also no evidence that long-acting drugs are better than their short-acting counterparts, or that high-dose regimens are safe or effective, the brochure states.

The brochure also cites some of Von Korff's most recent evidence that it's not just stereotypical drug abusers who overdose on opioids. In an Annals of Internal Medicine study, Von Korff and colleagues showed an almost nine-fold increased risk of death among those on 100 mg of opioids per day or more.

"We don't have the data on the long-term health effects that we need," Von Korff said, "and we really need to be thinking about how much benefit the patient gets relative to the risk."

Am J Prev Med. 2010 Oct;39(4):357-363.

Increase in Unintentional Medication Overdose Deaths Oklahoma, 1994-2006.

Piercefield E, Archer P, Kemp P, Mallonee S.

Epidemic Intelligence Service Officer, assigned to the CDC, Atlanta, Georgia.

Abstract

BACKGROUND: During 1999-2006, rates of unintentional drug-related deaths increased 120% in the U.S.

PURPOSE: This report describes demographics and trends of unintentional medication overdose deaths among Oklahoma residents to target prevention strategies.

PMID: 20837287 [PubMed - as supplied by publisher]

Sonoma Medicine Magazine: Controversies in Therapeutics
Volume 60, Number 4 - Fall 2009

Are we making pain patients worse?

By Andrea Rubinstein, MD
Opioids are among the most frequently prescribed medications in the United States. With only 4% of the world’s population, we use 80% of all opioids and 99% of all hydrocodone.[1] The medical literature and the media are ripe with conflicting opinions, as in “pain is undertreated” vs. “doctors are over-prescribing,” or “deaths are up” vs. “opioids are safe,” or “we are making a society of addicts” vs. “addiction is very rare.” Opioid prescribing practices vary widely among physicians, indicating a lack of consensus on best use. Two and one-half millennia after Hippocrates described the use of opium for medical purposes, we are still asking the question: Do these drugs work, and are they safe?

Make no mistake, these questions are difficult to answer, primarily because opioids and their use have always been part medicine, part emotion, and part politics. The pendulum swings, and opioids are used liberally for a while. Then there is some form of backlash, and use is sharply curtailed. This phenomenon has been documented repeatedly over hundreds of years. During the 20th century, for example, opiates were legally available in the United States until the Harrison Act of 1914. Heroin wasn’t outlawed until 1924, when opioid use became restricted primarily to patients with cancer. The 1970s saw the introduction of the methadone treatment act, and the 1990s witnessed a significant push to be more aggressive in the treatment of pain. Pain became “the fifth vital sign,” and some states, including California, legislated a “bill of rights for pain patients.” These actions sent the pendulum swinging back the other way, leading to a 300% increase in the number of opioid prescriptions since 1990. With almost 20 years of increasingly liberal use of these medications, can the literature and our experience tell us anything new?

Let’s begin by examining efficacy. Put simply, do these medications work? In the short term, and for acute and postoperative pain, the answer is a resounding yes. But can we extrapolate from this that they continue to be efficacious over time? Unfortunately, there have only been a few randomized controlled trials regarding opioid efficacy for chronic non-cancer pain. Even fewer are double-blind, and none look at long-term use. Most studies are small and just four to 16 weeks long. Yet, almost daily, we see patients who have been on opioids for years, sometimes decades.

A 2004 meta-analysis of the literature between 1996 and 2003 found that, for periods of up to eight weeks (the longest study included), opioid doses ≤120 mg oral morphine or equivalent provided at least a 30% reduction in pain over placebo for diabetic peripheral neuropathy, phantom limb pain, and post-herpetic neuralgia.[2] “Success” in this case is defined as a 30% reduction in pain or a two-point drop on a scale of 1 to 10. This is a far cry from the “complete relief” expected by many patients. Second, even phantom limb pain and post-herpetic neuralgia, two very painful conditions, were treated with less than 120 mg morphine equivalents per day. In other conditions—including osteoarthritis, musculoskeletal pain and mixed pain pictures—opioids provided either an insignificant reduction over placebo or failed to provide at least a 30% reduction in pain.

When endpoints other than analgesia—such as mood, function, and general health—are considered, the efficacy findings are even more mixed. In one study, investigators observed patients on opioids over six months and found that higher doses of opioids (over 40 mg of morphine per day) correlated with poorer physical function and poorer general health as self-reported by patients.[3]

In 2006, Danish epidemiologists studied chronic pain patients on opioids, chronic pain patients not on opioids, and healthy controls. Patients were asked to self-assess body pain, physical function, mental function, social function, and vitality, among other criteria. The study found that across every criterion, including pain, patients on opioids self-scored lower than pain patients not on opioids.[4]

These results confirm a common experience for patients with chronic pain: opioids may work acceptably well for a while, but over the long term, function generally declines, as does general health, mental health, and social functioning. Over time, even high doses of potent opioids often fail to control pain, and these patients are unable to function normally.

Whether we look at randomized control trials, retrospective studies, or epidemiologic data, there is growing evidence that opioids may not work as well as we thought or as well as our patients would like, when used over the long term. These studies do not definitively answer the question of opioid efficacy, but they do challenge the current dogma that opioids are generally efficacious for patients with chronic pain and that higher doses lead to better relief.

If efficacy is not a slam dunk, let’s look at safety. Many doctors who prescribe opioid medications consider respiratory depression and addiction to be the biggest patient safety issues and diversion to be the biggest public safety issue. We monitor for these, and if they do not appear to be of concern, we assume we are using these drugs safely. But let’s put aside addiction and diversion, which already garner the lion’s share of the media’s attention, and consider some safety issues that are equally if not more medically significant.

Several recent studies have looked at the effect of opioids on the endocrine system, particularly testosterone levels in men. One study found that 74% of male opioid users had testosterone levels below 300.[5] This data is surprising but hardly new. In an 1839 report on the tea trade in India, the trader Charles Alexander Bruce observed that, “Opium has kept, and does now keep down the population: the women have fewer children than those of other countries … the feeble opium smokers of Assam … are more effeminate than women.”[6] In the pain clinic at Kaiser Santa Rosa, I routinely screen all men on opioids for hypogonadism. Over 50% are below 300, and it is not uncommon to have men with testosterone levels less than 100. Among men on methadone in our population, 80% are hypogonadal.

To put this finding in some perspective, Vioxx was taken off the market in 2004 because it was associated with a relative risk of myocardial infarction somewhere between 2.4 and 5.0.[7] We can calculate the relative risk of hypogonadism from opioids by beginning with the estimated 2.7% of American men who are hypogonadal. Let’s assume that none of these men are hypogonadal due to opioids. If 30% of the men on opioids are hypogonadal, the relative risk of hypogonadism from opioids is 11. If 70% are hypogonadal, the relative risk jumps to 25! Admittedly, this is an apples-to-oranges comparison, but the sequelae from hypogonadism, especially osteoporosis, may lead to morbidity and mortality rates that approach those of myocardial infarction.

The endocrine effect of opioids occurs in women as well, although it is not as clear-cut or as easy to diagnose. Symptoms may include depression and sexual dysfunction and may involve dysmenorrhea.[8] Unfortunately, none of these symptoms are specific to opioid use. Physicians with significant numbers of patients on long-term opioid therapy will probably see pre-menopausal women with some or all of these symptoms, so it is important to consider opioid-induced endocrinopathy as part of the differential diagnosis.

Low testosterone also increases fasting blood glucose and lipids and leads to anhedonia, depression, cognitive difficulties, erectile dysfunction and even anemia.[9] Additionally, there is evidence in animals that low testosterone both lowers pain tolerance and decreases the effectiveness of opioid analgesia, which may play a role in spiraling doses and decreased efficacy.[9]

In the pain clinic, I often see men on methadone or some other opioid for low back pain. Their other medications often include Lipitor, Metformin, Prozac and Viagra. I cannot help but wonder how many of the associated “comorbidities” are iatrogenic from the medication being used to treat their chronic pain—which, by the way, they almost always say is not working well.

Perhaps the biggest concern in hypogonadal patients is the development of osteoporosis. A recent retrospective study looked at 81 men on opioids and found that 50% had bone densities in the osteopenic or osteoporotic range.[10] Hypogonadism is certainly linked to osteoporosis; but in this study, bone density was low even in men with normal testosterones.

I order bone-density studies on all patients who are on intrathecal opioids, high-dose oral opioids, or methadone, or are clinically hypogonadal. Roughly 25% have frank osteoporosis and 75% have osteopenia or osteoporosis. This effect is not limited to the elderly. In the last six months, I have seen two men under 40 with vertebral osteoporosis, presumably from the opioids they were taking for chronic pain.

In addition to the endocrine risk, evidence is mounting that patients on opioids are hypoxemic at night. In two separate studies looking at patients on opioids with overnight polysomnography, the incidence of some form of apnea was 85% in one and 75% in the other.[11,12] In our pain clinic, two-thirds of the sleep studies ordered are positive for OSA, central apnea, or both.

With the best of intentions, we use opioids to treat pain, yet we create the problems of hypogonadism, osteoporosis and sleep apnea in a significant number of patients. The ultimate irony is that we might actually be making pain worse. The concept of opioid-induced hyperalgesia has been documented in animals, methadone patients, and healthy volunteers. It is marked by decreasing effectiveness of medication without disease progression and decreased tolerance to new or acute injuries.

A recent observational study tested patients with chronic pain on methadone or morphine and found that their pain tolerance was significantly reduced compared to controls.[13] Further studies are needed to refine the parameters under which this phenomenon occurs, but those of us who treat these patients regularly know that their pain tolerance tends to be very low; that new injuries are perceived as extremely painful; and that postoperative pain is often difficult to control. If the very medication we are using to treat pain is causing pain, or worsening the perception of pain, where do we go from here?

The media seem concerned that we as physicians are making “addicts” of our patients. Addiction is certainly an issue, but there is less data to support claims of addiction than to support the proposition that we are making hypogonadal, osteoporotic patients with worse pain than when they came to us.

This proposition is not to say that opioids should not be used or that they have no place in the treatment of pain. Quite the contrary, opioids do work to treat pain in many cases, and there are countless patients who have benefited greatly from them; they will likely have a place in the management of chronic pain for some time.

Our job as physicians is to perform good patient selection, monitor the use of these medications, and screen for the known complications of their continued use. We need to constantly perform a risk-benefit analysis when using these medications. When the risk outweighs the benefit, we need to discuss this result with the patient and make the correct medical decision regarding continued use or discontinuation of pain medication.

References

1. Manchikanti L, Singh A, “Therapeutic opioids,” Pain Physician, 11:S63-88 (2008).

2. Kalso E, et al, “Opioids in chronic non-cancer pain: systematic review of efficacy and safety,” Pain, 21:372-380 (2004).

3. Dillie KS, et al, ”Quality of life associated with daily opioid therapy in a primary care chronic pain sample,” J Am Bd Fam Med, 21:108-117 (2008).

4. Eriksen J, et al, “Critical issues on opioids in chronic non-cancer pain,” Pain, 125:172-179 (2006).

5. Daniell HW, “Hypogonadism in men consuming sustained-action oral opioids,” J Pain, 3:377-384 (2002).

6. Bruce CA, Report on the manufacture of tea: and on the extent and produce of the tea plantations in Assam, Bishop’s College Press (1839).

7. Bombardier C, et al, “Response to expressions of concern regarding VIGOR study,” NEJM, 354:1196-99 (2006).

8. Daniell HW, “Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain,” J Pain, 9:28-36 (2008).

9. Katz N, Mazer M, ”Impact of opioids on the endocrine system,” Clin J Pain, 25:170-175 (2009).

10. Fortin JD, et al, “Does opioid use for pain warrant routine bone density screening in men?” Pain Physician, 11:539-541 (2008).

11. Mogri M, et al, “Hypoxemia in patients on chronic opiate therapy with and without sleep apnea” Sleep Breath, 13:49-57 (2008).

12. Webster L, et al, “Sleep-disordered breathing and chronic opioid therapy,” Pain Med, 9:425-432 (2008).

13. Chu L, et al, “Opioid-induced hyperalgesia in humans,” Clin J Pain, 24:479-496 (2008).

14.

Study: PCPs Often Underestimate Opioid Abuse Risk

Gabriel Miller

Most primary care patients who are taking opioids for chronic pain are at moderate risk for prescription opioid abuse, according to a new study.

Among other significant findings: A majority of primary care physicians (PCPs) do not use formal risk assessment or monitoring tools when prescribing opioids; when they do, they are more likely to underestimate, rather than overestimate, the risk for abuse by these patients.

Results of the study, which was sponsored by King Pharmaceuticals, were presented at the 2010 annual meeting of the American Pain Society, in Baltimore (abstract 236).

“We were interested in two different things,” said Beatrice Setnik, PhD, a research scientist at King in Cary, N.C., and lead investigator of the study. “There is little known about what pain patients are doing when they are receiving chronic opioids [in primary care settings], so the questions became how much abuse is happening and how are physicians mitigating that risk?”

Because the risk assessment analysis was one part of an efficacy and safety trial of King’s extended-release morphine pill (Avinza), the study benefited from a large group of both patients completing the study (N=561) and PCPs involved (N=281).

Patients in the study had to have chronic pain lasting longer than three months, and a pain intensity (PI) score of 4 or greater or unacceptable side effects from other opioids.

In the study, PCPs prescribing extended-release morphine used a “universal precautions” approach to pain management. During the first baseline visit, patients signed an opioid treatment agreement; were given a prescription card to document prescription-filling times and locations; underwent urine drug screening (UDS); were assessed by the PCP for any aberrant behaviors, such as frequent requests for early refills; and completed the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), a validated, 24-item, risk assessment questionnaire.

From visits 2 through 5, physicians also used pill counts and PI scores, in addition to continuing to use UDS and checking for any aberrant behaviors.

Finally, at the end of the study, investigators completed a survey rating the usefulness of each risk assessment tool.

At the beginning of the study period, 52% of patients were considered at moderate risk for misuse or abuse based on SOAPP-R score, UDS and presence of aberrant drug-related behavior. Furthermore, 47% were considered at low risk and 1% were considered at high risk for opioid misuse and abuse.

Questions About Risk Assessment

One “alarming” baseline finding, according to Dr. Setnik, was the high rate of positive drug screens in the patient population: 16% for marijuana, 10% for cocaine and 6% for both ecstasy and phencyclidine.

“I found that very disturbing, because the majority [of patients with a positive UDS for cocaine and marijuana] were deemed low risk,” Dr. Setnik said.

At the initial visit, for example, of 152 patients who screened positively for cocaine, 52% were rated as low risk. At the third visit, 42 patients screened positively for cocaine and 71% were reassessed as low risk for opioid misuse or abuse.

“It gets at the question of what is driving the decisions of risk assessment at the clinic,” said Dr. Setnik. “For most physicians, [a positive] UDS would have an influence; they would assess the risk level differently. Clearly, there is a group of physicians that didn’t take it seriously enough.”

In their practices before the trial began, the overwhelming majority of PCPs reported that they used “clinical insight alone” to assess risk prior to prescribing opioids (79%) or to monitor risk during treatment (86%).

Two additional trends seen in the study also seemed to indicate that most PCPs underestimate risk.

At baseline, 45% of patients were given a risk assessment level lower than their validated SOAPP-R score would indicate, even though these physicians were using three objective tools to assess risk, including the SOAPP-R itself.

Furthermore, for patients who were initially assessed as “moderate risk” at the beginning of the study (N=699), 28% were downgraded to a low-risk level by the end of the study, despite the fact that, per protocol, patients could not be moved down to a lower risk level throughout the study.

“It’s obviously challenging to identify risk in a patient, particularly when physicians have a relationship with their patients,” said Dr. Setnik. “Sometimes physicians may be in denial, thinking, ‘These things don’t happen in my clinic.’”

“What this tells you is that, regardless of the population that you see—whether you are in an area where you see a high-risk population or an affluent area where you see a low-risk population—you cannot tell a book by its cover,” said Howard Heit, MD, assistant clinical professor of medicine at Georgetown University School of Medicine in McLean, Va., who specializes in pain medicine and addiction. “You cannot observe a patient and then predict aberrant behavior.”

One positive note, Dr. Setnik said, was that at three and six months post-study, 95% and 93%, respectively, of PCPs in the study continued to use at least one of the objective risk assessment tools; most commonly it was the treatment agreement or the UDS.

“These two tools were likely picked up by primary care physicians because they are easy to incorporate into a standard practice; however, they may also have been used for medicolegal reasons for appropriate documentation in medical records,” Dr. Heit said.

“Your medical records are your best defense against any malpractice allegations,” he added. “What you find is that you get comfortable with a particular protocol and then you stick with it for consistency.”

Br J Clin Pharmacol. 2010 Aug;70(2):189-200.

Different effects of morphine and oxycodone in experimentally evoked hyperalgesia: a human translational study.

Olesen AE, Staahl C, Arendt-Nielsen L, Drewes AM.

Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark. aeolesen@hst.aau.dk

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Previous studies using short-lasting experimental pain stimulations in healthy volunteers have shown differences in opioid effects regarding visceral pain stimulations. However, these differences can be more pronounced in patients due to a sensitized pain system. Therefore, the aim of the present study was to mimic the clinical situation by investigating opioid effects on experimental pain in healthy volunteers after experimentally evoked hyperalgesia. WHAT THIS STUDY ADDS? * We now know that morphine and oxycodone exerts different effects in the sensitized pain system as we found a greater analgesic effect of oxycodone in response to skin, muscle and oesophageal pain stimulation. This supports clinicians' experiences that oxycodone can be superior to morphine in the treatment of some pain conditions. The evoked hyperalgesia bridged findings from studies in healthy volunteers to patients, and new fundamental knowledge on different analgesic effects in hyperalgesia was found. AIM Similar analgesics may have different analgesic potencies especially in patients in whom the pain system is sensitized. The aim was to investigate different opioid effects on experimental pain after the sensitized pain system was mimicked evoking hyperalgesia in healthy volunteers. METHODS Twenty-four healthy volunteers were randomized to treatment with morphine (30 mg orally) and oxycodone (15 mg orally) or placebo in a double-blind crossover study. Hyperalgesia was induced by oesophageal perfusion with acid and capsaicin. Several exploratory endpoints were studied using skin heat, muscle pressure and oesophageal mechanical, heat and electrical stimulation. Effects on pain from deeper structures were considered most important. RESULTS Different analgesic potencies were found. Oxycodone had a greater analgesic effect than morphine attenuating pain from: (i) heat stimulation of skin (P= 0.016); difference between the means of 0.39 degrees C, 95% CI 0.22, 2.09. (ii) muscle pressure (P < 0.001); difference between the means of 11.93kPa, 95% CI 5.4, 18.5. (iii) oesophageal heat stimulation (P < 0.001); difference between the means of 38.54 cm(2), 95% CI 15.37, 61.71 and (iv) oesophageal electrical stimulation (P= 0.016); difference between the means of 6.69mA, 95% CI 1.23, 12.13. CONCLUSION After sensitization of the pain system different analgesic potencies of morphine and oxycodone were found in response to skin, muscle and oesophageal pain stimulation, in which oxycodone had a greater effect. As similar differential analgesic potencies of the two opioids have been found in patients with chronic pain, the experimental hyperalgesia model bridged findings from studies in healthy volunteers to patients.

PMID: 20653672 [PubMed - in process]

Pain Med. 2010 Mar;11(3):425-34. Epub 2009 Dec 9.

Opioid analgesics for pain control: wisconsin physicians' knowledge, beliefs, attitudes, and prescribing practices.

Wolfert MZ, Gilson AM, Dahl JL, Cleary JF.

University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin WI 53792, USA. mwolfert@uic.edu

Abstract

OBJECTIVE: Opioid analgesics are the drugs of choice for the treatment of moderate to severe acute and cancer pain. Although their role in the management of chronic pain not related to cancer is controversial, there is increasing evidence for their benefit in certain patient populations.

DESIGN: A 32-item survey to assess Wisconsin physicians' knowledge, beliefs, and attitudes toward opioid analgesic use was mailed to 600 randomly selected licensed physicians, resulting in a 36% response rate.

RESULTS: Half of the respondents considered diversion a moderate or severe problem in Wisconsin. A majority considered addiction to be a combination of physiological and behavioral characteristics, rather than defining it solely as a behavioral syndrome. Most physicians felt it lawful and acceptable medical practice to prescribe opioids for chronic cancer pain, but only half held this view if the pain was not related to cancer. Fewer physicians considered such prescribing as lawful and generally accepted medical practice if the patient had a history of substance abuse. About two-thirds of physicians were not concerned about being investigated for their opioid prescribing practices, but some admitted that fear of investigation led them to lower the dose prescribed, limit the number of refills, or prescribe a Schedule III or IV rather than a Schedule II opioid.

CONCLUSION: Wisconsin physicians who responded to this survey held many misconceptions about the prescribing of opioids. Such views, coupled with a lack of knowledge about laws and regulations governing the prescribing of controlled substances, may result in inadequate prescribing of opioids with resultant inadequate management of pain.

PMID: 20002590 [PubMed - indexed for MEDLINE

J Arthroplasty. 2010 Apr;25(3):410-5. Epub 2010 Feb 9.

A prospective evaluation of 2 different pain management protocols for total hip arthroplasty.

Post ZD, Restrepo C, Kahl LK, van de Leur T, Purtill JJ, Hozack WJ.

Rothman Institute of Orthopaedics at Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA.

Abstract

Pain management after total hip arthroplasty has improved dramatically in the past decade. However, most protocols use opioid medications for pain control. In the current study, 100 patients were prospectively selected to receive a traditional narcotic-based patient-controlled analgesia protocol or a nonnarcotic oral protocol for pain management after primary total hip arthroplasty. Therapy programs were similar for both groups. Postoperatively, patients were followed daily for opioid use, medication adverse effects, pain control, and overall satisfaction. The nonnarcotic oral group showed lower mean pain scores during the first 24 hours after surgery. The satisfaction rate was high in both groups. Both protocols provided adequate pain control after total hip arthroplasty; the nonnarcotic pain management protocol resulted in significantly decreased opioid consumption and fewer adverse effects.

PMID: 20149582 [PubMed - indexed for MEDLINE]

Anaesthesia. 2010 Aug 16. [Epub ahead of print]

A comparison of the respiratory effects of oxycodone versus morphine: a randomised, double-blind, placebo-controlled investigation*

Chang SH, Maney KM, Phillips JP, Langford RM, Mehta V.

Consultant Anaesthetist, St Bartholomews Hospital, London, UK.

Abstract

Summary Oxycodone's respiratory profile (particularly the extent of respiratory depression in comparison to morphine) remains to be fully characterised in the peri-operative period. We randomly assigned ASA 1-2 adults for elective surgery under general anaesthesia to receive saline, morphine 0.1 mg.kg(-1), or oxycodone 0.05 mg.kg(-1), 0.1 mg.kg(-1), or 0.2 mg.kg(-1). Results were obtained from six patients in the saline group, 12 patients in the groups receiving morphine 0.1 mg.kg(-1), oxycodone 0.05 mg.kg(-1) and 0.1 mg.kg(-1), and from 10 patients who received oxycodone 0.2 mg.kg(-1). Patients were breathing spontaneously and minute ventilation monitored with a wet wedge spirometer for 30 min. All active groups demonstrated significant respiratory depression compared to saline (p < 0.0001 for all groups). The mean (SD) reduction in minute volume from baseline was 22.6% (10.4%) for the morphine 0.1 group and 53.3% (27.2%), 74.4% (12.9%) and 88.6% (13.5%) for the oxycodone 0.05, 0.1 and 0.2 groups, respectively, with significant dose dependent differences between oxycodone groups (p = 0.0007). The extent and speed of onset of oxycodone induced respiratory depression was dose dependent and greater than an equivalent dose of morphine.

PMID: 20712805 [PubMed - as supplied by publisher

Eur J Pain. 2010 Aug 27. [Epub ahead of print]

Dissociation of rewarding, anti-aversive and anti-nociceptive effects of different classes of anti-nociceptives in the rat.

Rutten K, Vry JD, Robens A, Tzschentke TM, van der Kam EL.

Grünenthal GmbH, Global Preclinical Research and Development, Department of Pharmacology, Zieglerstrasse 6, 52078 Aachen, Germany.

Abstract

It was previously shown that morphine more potently reduces the affective as compared to the sensory component of nociception, and this effect is independent of morphine's rewarding properties. Here we investigated whether this finding can be generalized to other classes of anti-nociceptive drugs. The effect of oxycodone (0-10mg/kg, i.p.), tramadol (0-10mg/kg, i.p.), ibuprofen (0-300mg/kg, i.p.) and pregabalin (0-31.6mg/kg, i.p.) on negative affect and mechanical hypersensitivity accompanying carrageenan-induced (0.5% intraplantar) inflammatory nociception was assessed using conditioned place aversion (CPA) and Randall Selitto paw pressure test, respectively. The rewarding effect of these drugs was assessed using conditioned place preference (CPP). All four anti-nociceptive drugs dose-dependently reduced carrageenan-induced CPA and mechanical hypersensitivity. Furthermore all drugs induced CPP, except for ibuprofen. Similar to morphine, oxycodone and tramadol showed a large dissociation of anti-aversive versus anti-nociceptive potency, i.e. 10 times more potent against the affective versus the sensory component of nociception. Oxycodone and tramadol were 30 and 10 times more potent to produce CPP in animals under normal versus painful conditions. Ibuprofen and pregabalin also showed a dissociation of anti-aversive and anti-nociceptive potency, but less pronounced (i.e. three times more potent against the affective component). However, pregabalin showed no dissociation between rewarding potency under normal versus painful conditions. Taken together, these data suggest that the dissociation of rewarding potency in animals under normal versus painful conditions is limited to drugs with an opioid mechanism of action, while the dissociation of anti-aversive and anti-nociceptive potency applies to anti-nociceptive drugs with different mechanisms of action.

PMID: 20801699 [PubMed - as supplied by publisher]

Pol Arch Med Wewn. 2009 Jul-Aug;119(7-8):469-77.

2009 Clinical Guidelines from the American Pain Society and the American Academy of Pain Medicine on the use of chronic opioid therapy in chronic noncancer pain: what are the key messages for clinical practice?

Chou R.

Department of Medicine, Oregon Health & Science University, Portland OR, United States. chour@ohsu.edu

Abstract

Safe and effective chronic opioid therapy (COT) for chronic noncancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and in the assessment and management of risks associated with opioid abuse, addiction, and diversion. The American Pain Society and the American Academy of Pain Medicine commissioned a systematic review of the evidence on COT for chronic noncancer pain and convened a multidisciplinary expert panel to review the evidence and formulate recommendations based on the best available evidence. This article summarizes key clinical messages from this guideline regarding patient selection and risk stratification, informed consent and opioid management plans, initiation and titration of COT, use of methadone, monitoring of patients, use of opioids in high-risk patients, assessment of aberrant drug-related behaviors, dose escalations and high-dose opioid therapy, opioid rotation, indications for discontinuation of therapy, prevention and management of opioid-related adverse effects, driving and work safety, identifying a medical home and when to obtain consultation, and management of breakthrough pain.

PMID: 19776687 [PubMed - indexed for MEDLINE]Free Article

J Pain. 2009 Feb;10(2):131-46.

Opioids for chronic noncancer pain: prediction and identification of aberrant drug-related behaviors: a review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline.

Chou R, Fanciullo GJ, Fine PG, Miaskowski C, Passik SD, Portenoy RK.

The Oregon Evidence-based Practice Center, Department of Medicine, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, Oregon, USA. chour@ohsu.edu

Comment in:

J Pain. 2010 Feb;11(2):195; author reply 196.

Abstract

Optimal methods to predict risk of aberrant drug-related behaviors before initiation of opioids for chronic noncancer pain and to identify aberrant behaviors after therapy is initiated are uncertain. We systematically reviewed published literature identified through searches of Ovid MEDLINE and the Cochrane databases through July 2008. Diagnostic test characteristics and accompanying confidence intervals were calculated with data extracted from the studies. Four prospective studies evaluated diagnostic accuracy of risk prediction instruments. Two higher-quality derivation studies found that high scores on the Screener and Opioid Assessment for Patients with Pain (SOAPP) Version 1 and the Revised SOAPP (SOAPP-R) instruments weakly increased the likelihood for future aberrant drug-related behaviors (positive likelihood ratios [PLR], 2.90 [95% CI, 1.91 to 4.39] and 2.50 [95% CI, 1.93 to 3.24], respectively). Low scores on the SOAPP Version 1 moderately decreased the likelihood for aberrant drug-related behaviors (negative likelihood ratio [NLR], 0.13 [95% CI, 0.05 to 0.34]) and low scores on the SOAPP-R weakly decreased the likelihood (NLR, 0.29 [95% CI, 0.18 to 0.46]), but estimates are too imprecise to determine if there is a difference between these instruments. One lower-quality study found that categorization as high risk using the Opioid Risk Tool strongly increased the likelihood for future aberrant drug-related behaviors (PLR, 14.3 [95% CI, 5.35 to 38.4]) and classification as low risk strongly decreased the likelihood (PLR, 0.08 [95% CI, 0.01 to 0.62]). Nine studies evaluated monitoring instruments for identification of aberrant drug-related behaviors in patients on opioid therapy. One higher-quality derivation study found higher scores on the Current Opioid Misuse Measure (COMM) weakly increased the likelihood of current aberrant drug-related behaviors (PLR, 2.77 [95% CI, 2.06 to 3.72]) and lower scores weakly decreased the likelihood (NLR, 0.35 [95% CI, 0.24 to 0.52]). In 8 studies of other monitoring instruments, diagnostic accuracy was poor, results were difficult to interpret due to methodological shortcomings, or standard diagnostic test characteristics were not reported. Definitions for aberrant drug-related behaviors were not standardized across studies and did not account for seriousness of identified behaviors. No reliable evidence exists on accuracy of urine drug screening, pill counts, or prescription drug monitoring programs; or clinical outcomes associated with different assessment or monitoring strategies. PERSPECTIVE: Evidence on prediction and identification of aberrant drug-related behaviors is limited. Although several screening instruments may be useful, evidence is sparse and primarily based on derivation studies, and methodological shortcomings exist in all studies. Research that performs external validation, uses standardized definitions for clinically relevant aberrant drug-related behaviors, and evaluates clinical outcomes associated with different assessment and monitoring strategies is needed.

PMID: 19187890 [PubMed - indexed for MEDLINE]

South Med J. 2010 Aug;103(8):738-47.

Pain management by primary care physicians, pain physicians, chiropractors, and acupuncturists: a national survey.

Breuer B, Cruciani R, Portenoy RK.

Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, NY 10003, USA. bbreuer@chpnet.org

Abstract

OBJECTIVES: Chronic pain is a serious public health problem and is treated by diverse health care providers. In order to enhance policies and programs to improve pain care, we collected information about the distribution of pain patients among four major groups of pain management providers: primary care physicians (PCPs), pain physicians, chiropractors, and acupuncturists, and the variation in the attitudes and practices of these providers with respect to some common strategies used for pain.

METHODS: National mail survey of PCPs, pain physicians, chiropractors, and acupuncturists (ntotal = 3,000).

RESULTS: Eight hundred seventeen responses were usable (response rate, 29%). Analyses weighted to obtain nationally representative data showed that PCPs treat approximately 52% of chronic pain patients, pain physicians treat 2%, chiropractors treat 40%, and acupuncturists treat 7%. Of the chronic pain patients seen for evaluation, the percentages subsequently treated on an ongoing basis range from 51% (PCPs) to 63% (pain physicians). Pain physicians prescribe long-acting opioids such as methadone, antidepressants or anti-convulsants, and other nontraditional analgesics approximately 50-100% more often than PCPs. Twenty-nine percent of PCPs and 16% of pain physicians reported prescribing opioids less often than they deem appropriate because of regulatory oversight concerns. Of the four groups, PCPs are least likely to feel confident in their ability to manage musculoskeletal pain and neuropathic pain, and are least likely to favor mandatory pain education for all PCPs.

CONCLUSIONS: There is substantial variation in attitudes and practices of the various disciplines that treat chronic pain. This information may be useful in interpreting differences in patient access to pain care, planning studies to clarify patient outcomes in relation to different providers and treatment strategies, and designing a system that matches chronic pain patients to appropriate practitioners and treatments.

Annu Rev Pharmacol Toxicol. 2009;49:97-121.

Progress in genetic studies of pain and analgesia.

Lacroix-Fralish ML, Mogil JS.

Department of Psychology and Center for Research on Pain, McGill University, Montréal, Quebec, H3A1B1 Canada.

Abstract

Interindividual variability in pain sensitivity and the response to analgesic manipulations remains a considerable clinical challenge as well as an area of intense scientific investigation. Techniques in this field have matured rapidly so that much relevant data have emerged only in the past few years. Our increasing understanding of the genetic mediation of these biological phenomena have nonetheless revealed their surprising complexity. This review provides a comprehensive picture and critical analysis of the field and its prospects.

PMID: 18834308 [PubMed - indexed for MEDLINE]PMCID: PMC2730377

Expert Opin Pharmacother. 2007 Oct;8(14):2235-45.

The pharmacogenetics of analgesia.

Stamer UM, Stüber F.

Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Anaesthesiology and Intensive Care Medicine, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. ulrike.stamer@ukb.uni-bonn.de

Abstract

Genomic variations influencing response to pharmacotherapy of pain are under investigation. Candidate genes such as (opioid)-receptors, transporters and other molecules important for pharmacotherapy are discussed. Drug metabolising enzymes represent a further major target of ongoing research in order to identify associations between an individual's genetic profile and drug response (pharmacogenetics). Polymorphisms of the cytochrome P450 enzymes influence analgesic efficacy of codeine, tramadol and tricyclic antidepressants (CYP2D6). Blood levels of some NSAIDs are dependent on CYP2C9 activity, whereas opioid-receptor polymorphisms are discussed for differences in opioid mediated analgesia and side effects. Pharmacogenetics as a diagnostic tool has the potential to improve patient therapy and care, and it is hoped that pharmacogenetics will individualise drug treatment to a greater extent in the near future.

PMID: 17927480 [PubMed - indexed for MEDLINE]

APS Bulletin • Volume 17, Number 2, 2007

Research Update

Norman Harden, MD, Department Editor

Where’s the Long-Term in Opioid Research?

Jane Martinsons, Staff Writer

Collisions tend to spur questions and nowhere is that more evident than with opioids where there’s a collision of minds over how best to treat noncancer chronic pain (NCCP) patients without increasing their risk of abuse or addiction. Toss in the fact that both the rate of abuse and the number of opioid prescriptions continue to climb nationwide, and questions abound. Here, for example, are what a few pain experts say are their top concerns with opioid therapy:

· What’s the risk of prescribing opioids to a patient who may abuse, divert, or become addicted to these medications, and will that lead to undertreating NCCP patients who are unlikely to abuse opioids?

· How do you determine who’s at risk of abuse? Are physicians’ judgments on risk reliable? Should physicians select patients for treatment to minimize behavioral problems? Is that ethical?

· How do you measure pain reduction, as well as mood and function improvement? Do opioids actually provide pain relief and improve functionality and quality of life?

· Should ceilings on doses be instituted?

· Does continuous use of opioids compromise the ability to treat new onset pain?

· Does opioid tolerance wear off with time?

· With more than half of NCCP patients on opioids having hypogonadism, why isn’t more being done on the part of the Federal Drug Administration (FDA), pharmaceutical companies, and the National Institutes of Health (NIH) to study the condition and its impact on pain control and treatment?

· Can abuse-deterrent formulations impact the problem of prescription drug abuse?

· Will rapid-onset opioids get used—and used safely?

· How do we treat negative side effects associated with opioid use, which may include constipation, hypogonadism, hyperanalgesia, increased susceptibility of infection, and even increased risk of death?

Long-Term, Human Trials Needed

And this is just a sample of concerns. Still, most experts who recently spoke to APS Bulletin contend that the core issue around which all these questions revolve is the lack of longterm or human data on opioid therapy.

“The greatest controversy is what is the long-term safety and efficacy of chronic opioid therapy in patients with nonmalignant pain. Do they work? How long do they work for? Who is the right candidate for it?” says Kathleen Foley, MD, of Memorial Sloan-Kettering Cancer Center in New York. “What surrounds this whole issue is we don’t have good data,” she says, and “we don’t have any long-term trials.”

Foley stresses that concerns over addiction may only serve to co-opt discussions over much needed research, and may even divert new monies away from finding better drugs and advancing the scientific basis for pain treatment.

Other pain experts say that the studies that do exist are either flawed or are short-term trials that don’t address long-term use of opioids for chronic pain. Gilbert Fanciullo, MD MS, of Dartmouth Hitchcock Medical Center in Lebanon, NH, says that the dozen or so often-cited “big” studies demonstrating that opioids are useful for NCCP are “seriously flawed” and leave open the queston of whether opioids provide long-term benefits.

Meanwhile, Dennis Turk, PhD, of the University of Washington in Seattle, says that most studies are 35-day randomized controlled trials conducted by pharmaceutical firms that base their research on their own agenda. Frequently these studies exclude people believed to at high risk for abuse or are beset by high participant drop-out rates because of the negative side effects associated with taking opioids.

“Although randomized studies are supposed to be so-called ‘gold standard,’ in the case of chronic opioid therapy they have a limited role because you can only conduct them at months at the most, usually weeks,” says Jane Ballantyne, MD, MGH Pain Center in Boston. “They don’t really tell you what’s happening either in the long term or in the wider population.” Ballantyne points out that some research currently underway includes broader epidemiological studies that, unlike smaller studies, are showing that opioid-treated patients do not fare as well, or fare worse, than nonopioid-treated patients in terms of pain, quality of life, and function.

Others say the focus should be on clinical trials rather than lab trials. Nathaniel Katz, MD MS, of Analgesic Research in Needham, MA, and Tufts University in Boston, says that for the past 50 years research has been conducted “completely in the wrong direction,” with laboratory studies driving clinical research instead of the other way around. However, he adds that initiatives such as the NIH Roadmap, FDA’s Critical Path Initiative, and APS’s Translational Research Task Force could help reverse the trend and lead to the development of more effective and safe therapies.

What’s needed are “naturalistic studies so that you get around some of the immense problems of selection bias in the existing opioid literature,” says Steve Passik, PhD, of Sloan-Kettering, who acknowledges that finding funding for such studies poses a challenge. He contends that these studies would involve “real time patients treated by real time doctors,” with study participants who show signs of substance abuse either going off-study or receiving structured management.

Lack of Funding

But several pain experts say that the real heart of the issue is the underfunding of pain research. “NIH and other agencies just have not prioritized pain as an issue strongly enough,” says Fanciullo.

Katz says that a “huge part of the problem has been the lack of adequate funding by any of the stakeholders of research on the fundamental and critical questions regarding prescription opioid abuse. If you peel away all the layers [of this issue], the final nucleus of all these problems comes down to the same thing—effective advocacy of key policy makers at a federal level. NIH and the FDA have not yet demonstrated that they will foster the necessary clinical research, suggesting that policy approaches may be needed. If you can’t get it funded, it isn’t going to happen.” Both Katz and Fanciullo are hopeful that the funding outlook will improve with APS’s current lobby efforts and position statements. At the APS Annual Meeting in May, board members visited their representatives in the House and Senate to discuss APS’s legislative agenda. Details of this agenda can be found on the APS Web site at http://www.ampainsoc.org/advocacy/.

Meanwhile, APS and the American Academy of Pain Medicine are developing opioid guidelines to develop specific, actionable recommendations for clinicians to optimally manage their patients. Draft recommendations are slated for release in August and final recommendations are expected by year’s end.

Upcoming Trends

What can we expect in long-term opioid therapy in the next 1 to 3 years? These experts say that we’ll see more focus on:

Objective measures of pain and risk of abuse

Increasingly, objective measures like urine toxicology screenings are revealing just how unreliable clinicians are at judging who’s at risk for addiction and abuse, Turk says. Upwards of 40% of patients taking opioids are not doing so as prescribed, either by not taking them, taking too much of them, or taking them in combination with other drugs, he says.

However, several initiatives are underway to develop objective measures to assess that risk. Among them is the patient questionnaire. Fanciullo is one of a handful of pain physicians who have patients fill out an extensive questionnaire—in his practice, using a computer touchpad. He also uses a variety of tools to measure patients’ pain and display these scores graphically. “Let’s say I’m prescribing an opioid to my patient for 7 months,” he says. “That’s all I have to do is glance at graphs to see if a patient’s pain has diminished or if their function has improved. It takes me 5 seconds using validated instruments. It’s extremely useful. We can show it to the patients and say, ‘Look, you think you feel better, but this is what this shows.’”

According to Katz, there is a growing awareness that opioids cannot be prescribed safely without external outcomes measures, including urine toxicology screening and prescription monitoring. He says that prescription monitoring is likely to be particularly useful because it allows practitioners to increase access to opioids for those who do well on therapy, and reduce it for those who don’t.

Abuse-deterrent opioids

Look for more studies on reducing the abuse potential of existing opioids. Turk predicts more systematic human studies on hyperalgesia to identify whether it’s a significant problem and, if so, how to measure and assess it.

Likewise, Ballantyne says that basic science research will provide “further insight into the neuroadaptations that underpin the clinical phenomena of opioid tolerance, hyperalgesia, dependence, and addiction.” This, she says, “may open up the possibility of pharmacological manipulations to alter these adaptations and reduce their adverse clinical consequences.” Ballantyne says also to expect advances in genetics to tailor opioids to people’s unique metabolic and psychological makeup.

Passik, meanwhile, acknowledges that abuse-deterrent opioids will help reduce prescription drug abuse, but cautions that pain doctors receive intensive medical education on addiction medicine. “Relying on the drug delivery system to substitute for getting more savvy about addiction medicine could lull people into a false sense of security,” he says. “Ultimately someone will figure out how to tamper with them, and it will blow up in our faces.”

Combination therapies

Look for more focus on using opioids in combination with other medications, such as anticonvulsants, or in conjunction with physical or psychological therapies. Several pain physicians expect that, as a consequence, open-ended dose escalation of a particular opioid for chronic pain management may be on the way out.

Increased scrutiny of potential patients

Expect ethical concerns to mount in coming years as physicians continue to grapple with determining which patients are good candidates for opioid therapy. Not only will there be more emphasis placed on finding validated screening instruments, but physicians may face the prospect of having to select patients for treatment, Ballantyne says.

On the flip side, Passik foresees the spread of a mass media ad campaign to educate consumers on how to properly store and monitor their drugs, including opioids. Either way, clinicians will be looking at ways to avoid the head-on collision between patients and the wall of addiction

Clin J Pain. 2007 Feb;23(2):103-18.

Foundations of opioid risk management.

Katz NP, Adams EH, Benneyan JC, Birnbaum HG, Budman SH, Buzzeo RW, Carr DB, Cicero TJ, Gourlay D, Inciardi JA, Joranson DE, Kesslick J, Lande SD.

Tufts University School of Medicine, Boston, MA, USA. nkatz@analgesicresearch.com

Abstract

Increased abuse and diversion of prescription opioids has been a consequence of the increased availability of opioids to address the widespread problem of undertreated pain. Opioid risk management refers to the effort to minimize harms associated with opioid therapy while maintaining appropriate access to therapy. Management of these linked public health issues requires a coordinated and balanced effort among a disparate group of stakeholders at the federal, state, industry, practitioner, and patient levels. This paper reviews the principles of opioid risk management by examining the epidemiology of prescription opioid abuse in the United States; identifying key stakeholders involved in opioid risk management and their responsibilities for managing or monitoring opioid abuse and diversion; and summarizing the mechanisms currently used to monitor and address prescription opioid abuse. Limitations of current approaches, and emerging directions in opioid risk management, are also presented.

PMID: 17237659 [PubMed - indexed for MEDLINE]

J Addict Med. 2010 Jun 1;4(2):108-113.

Prescription Opioid Use among Patients Seeking Treatment for Opioid Dependence.

Canfield MC, Keller CE, Frydrych LM, Ashrafioun L, Purdy CH, Blondell RD.

State University of New York, University at Buffalo, Department of Family Medicine, Family Medicine Research Institute, SUNY Clinical Center, 462 Grider Street, Buffalo, New York 14215.

Abstract

OBJECTIVE: This study was designed to assess non-medical prescription opioid use among a sample of opioid dependent participants. METHODS: A cross-sectional survey was conducted with a convenience sample of patients hospitalized for medical management of opioid withdrawal. We collected data related to participant demographics, socio-economic characteristics, the age of first opioid use, types of opioids preferred, and routes of administration. We also asked participants to describe how they first began using opioids and how their use progressed over time. RESULTS: Among the 75 participants, the mean age was 32 years (SD: +/- 11, range: 18-70), 49 (65%) were men, 58 (77%) considered themselves to be "white," 55 (74%) had a high school diploma or equivalent, and 39 (52%) were unemployed. All of these participants considered themselves to be "addicted." Thirty-one (41%) felt that their addiction began with "legitimate prescriptions," 24 (32%) with diverted prescription medications, and 20 (27%) with "street drugs" from illicit sources; however, 69 (92%) had reported purchasing opioids "off the street" at some point in time. Thirty-seven (49%) considered heroin to be their current preferred drug, and 43 (57%) had used drugs intravenously. CONCLUSIONS: We found that many treatment-seeking opioid dependent patients first began using licit prescription drugs before obtaining opioids from illicit sources. Later, they purchased heroin, which they would come to prefer because it was less expensive and more effective than prescription drugs.

PMID: 20543897 [PubMed]PMCID: PMC2882311 [Available on 2011/6/1]

Pain Physician. 2010 Mar;13(2):167-86.

Importance of urine drug testing in the treatment of chronic noncancer pain: implications of recent medicare policy changes in kentucky.

Gilbert JW, Wheeler GR, Mick GE, Storey BB, Herder SL, Richardson GB, Watts E, Gyarteng-Dakwa K, Marino BS, Kenney CM, Siddiqi M, Broughton PG.

Spine and Brain Neurosurgical Center, Lexington, KY, USA.

Abstract

BACKGROUND: Urine drug testing has become a widely used tool in American society for deterring illicit drug use. In the practice of medicine, urine drug testing is commonly used to help diagnose substance misuse, abuse, or addiction. OBJECTIVE: This narrative review provides an informed perspective on the importance of urine drug testing in the medical treatment of chronic noncancer pain. The history and current uses of urine drug tests in the United States are reviewed, the prevalence and nature of prescription drug misuse is described as is related to chronic noncancer pain, and implications and considerations for practitioners are presented related to the noncancer pain diagnosis and treatment. DISCUSSION: Practitioners are confronted with the ethical and legal dilemma of being called to adequately treat chronic pain in a culture with a high prevalence of prescription drug abuse. Yet the symptoms of drug abuse are nonspecific and therefore of limited value to the practitioner in determining patient compliance to drug treatment regimens. In contrast, urine drug testing has a reliable history, both in and out of medicine, as an independent sign of drug misuse. This sign can be used to aid in the diagnosis and treatment of drug misuse and underlying addictions to improve patient outcomes. CONCLUSION: Regular urine drug testing should be a part of acute and chronic pain management whether or not the patient has any signs or symptoms of drug misuse.

PMID: 20309383 [PubMed - indexed for MEDLINE]

Br J Pharmacol. 2010 Jun;160(4):919-30.

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety.

Samer CF, Daali Y, Wagner M, Hopfgartner G, Eap CB, Rebsamen MC, Rossier MF, Hochstrasser D, Dayer P, Desmeules JA.

Clinical Pharmacology and Toxicology and Multidisciplinary Pain Centre, Department of Anaesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland. Caroline.Samer@hcuge.ch

Abstract

BACKGROUND AND PURPOSE: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. EXPERIMENTAL APPROACH: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg x kg(-1)) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. KEY RESULTS: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone C(max) was correlated with SPT assessment (rho(S)= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. CONCLUSIONS AND IMPLICATIONS: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism.

PMID: 20590588 [PubMed - in process]

Research

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Open Medicine, Vol 5, No 1 (2011)

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Regulating Opioid Use in Washington State

Source Information

Different effects of morphine and oxycodone in experimentally evoked hyperalgesia: a human translational study.

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A prospective evaluation of 2 different pain management protocols for total hip arthroplasty.

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A comparison of the respiratory effects of oxycodone versus morphine: a randomised, double-blind, placebo-controlled investigation*

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Dissociation of rewarding, anti-aversive and anti-nociceptive effects of different classes of anti-nociceptives in the rat.

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2009 Clinical Guidelines from the American Pain Society and the American Academy of Pain Medicine on the use of chronic opioid therapy in chronic noncancer pain: what are the key messages for clinical practice?

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Pain management by primary care physicians, pain physicians, chiropractors, and acupuncturists: a national survey.

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Progress in genetic studies of pain and analgesia.

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The pharmacogenetics of analgesia.

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Foundations of opioid risk management.

Abstract

Prescription Opioid Use among Patients Seeking Treatment for Opioid Dependence.

Abstract

Importance of urine drug testing in the treatment of chronic noncancer pain: implications of recent medicare policy changes in kentucky.

Abstract

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety.