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Opioid Prescriptions for Chronic Pain and Overdose: A Cohort Study

Kate M. Dunn, PhD; Kathleen W. Saunders, JD; Carolyn M. Rutter, PhD; Caleb J. Banta-Green, MSW, MPH, PhD; Joseph O. Merrill, MD, MPH; Mark D. Sullivan, MD, PhD; Constance M. Weisner, DrPH, MSW; Michael J. Silverberg, PhD, MPH; Cynthia I. Campbell, PhD; Bruce M. Psaty, MD, PhD; and Michael Von Korff, ScD
[+] Article and Author Information

From Group Health Research Institute and University of Washington, Seattle, Washington; Arthritis Research Campaign National Primary Care Centre, Keele University, Keele, United Kingdom; and Northern California Kaiser Permanente, Oakland, and University of California, San Francisco, California.


Disclaimer: Dr. Von Korff had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Grant Support: This research was supported by a grant to Dr. Von Korff from the National Institute of Drug Abuse (DA022557). Dr. Dunn participated in this work with Dr. Von Korff at the Group Health Research Institute through a grant from the Wellcome Trust (083572).

Potential Conflicts of Interest:Consultancies: M.D. Sullivan (Eli Lilly, ABT Bio-Pharma). Stock ownership or options (other than mutual funds): K.W. Saunders (Merck & Co.). Grants received: M.D. Sullivan (Wyeth, Eli Lilly, Aetna, Johnson & Johnson, Ortho-McNeil). Grants pending: M. Von Korff (Johnson & Johnson).

Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. Von Korff (e-mail, vonkorff.m@ghc.org).

Corresponding Author: Michael Von Korff, ScD, Group Health Research Institute, Group Health Cooperative, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101; e-mail, vonkorff.m@ghc.org.

Current Author Addresses: Dr. Dunn: Arthritis Research Campaign National Primary Care Centre, Primary Care Sciences, Keele University, Keele ST5 5BG, United Kingdom.

Ms. Saunders and Dr. Rutter: Group Health Research Institute, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101-1448.

Dr. Banta-Green: Alcohol and Drug Abuse Institute, University of Washington, 1107 Northeast 45th Street, Suite 120, Box 354805, Seattle, WA 98105-4631.

Dr. Merrill: Department of Medicine, RR-512, Health Sciences Building, University of Washington, Box 356420, Seattle, WA 98195-6420.

Dr. Sullivan: Department of Psychiatry & Behavioral Sciences, University of Washington, 1959 Northeast Pacific Street, Box 356560, Room BB1644, Seattle, WA 98195-6560.

Drs. Weisner, Silverberg, and Campbell: Kaiser Permanente Division of Research, 2000 Broadway, Oakland, CA 94612.

Dr. Psaty: Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Metropolitan Park East Tower, 1730 Minor Avenue, Suite 1360, Seattle, WA 98101.

Dr. Von Korff: Group Health Research Institute, Group Health Cooperative, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101.

Author Contributions: Conception and design: K.M. Dunn, K.W. Saunders, C.M. Rutter, C.J. Banta-Green, J.O. Merrill, C.M. Weisner, C.I. Campbell, M. Von Korff.

Analysis and interpretation of the data: K.M. Dunn, K.W. Saunders, C.M. Rutter, C.J. Banta-Green, J.O. Merrill, M.D. Sullivan, M.J. Silverberg, C.I. Campbell, B.M. Psaty, M. Von Korff.

Drafting of the article: K.M. Dunn, M.D. Sullivan, M Von Korff.

Critical revision of the article for important intellectual content: K.M. Dunn, K.W. Saunders, C.M. Rutter, C.J. Banta-Green, J.O. Merrill, M.D. Sullivan, C.M. Weisner, M.J. Silverberg, C.I. Campbell, B.M. Psaty, M. Von Korff.

Final approval of the article: K.M. Dunn, K.W. Saunders, C.M. Rutter, C.J. Banta-Green, J.O. Merrill, M.D. Sullivan, C.M. Weisner, M.J. Silverberg, C.I. Campbell, B.M. Psaty, M. Von Korff.

Statistical expertise: C.M. Rutter, B.M. Psaty.

Obtaining of funding: C.M. Weisner, C.I. Campbell, M. Von Korff.

Administrative, technical, or logistic support: K.W. Saunders.

Collection and assembly of data: K.M. Dunn, K.W. Saunders, M. Von Korff.


Ann Intern Med. 2010;152(2):85-92. doi:10.7326/0003-4819-152-2-201001190-00006
Text Size: A A A

Background: Long-term opioid therapy for chronic noncancer pain is becoming increasingly common in community practice. Concomitant with this change in practice, rates of fatal opioid overdose have increased. The extent to which overdose risks are elevated among patients receiving medically prescribed long-term opioid therapy is unknown.

Objective: To estimate rates of opioid overdose and their association with an average prescribed daily opioid dose among patients receiving medically prescribed, long-term opioid therapy.

Design: Cox proportional hazards models were used to estimate overdose risk as a function of average daily opioid dose (morphine equivalents) received at the time of overdose.

Setting: HMO.

Patients: 9940 persons who received 3 or more opioid prescriptions within 90 days for chronic noncancer pain between 1997 and 2005.

Measurements: Average daily opioid dose over the previous 90 days from automated pharmacy data. Primary outcomes—nonfatal and fatal overdoses—were identified through diagnostic codes from inpatient and outpatient care and death certificates and were confirmed by medical record review.

Results: 51 opioid-related overdoses were identified, including 6 deaths. Compared with patients receiving 1 to 20 mg/d of opioids (0.2% annual overdose rate), patients receiving 50 to 99 mg/d had a 3.7-fold increase in overdose risk (95% CI, 1.5 to 9.5) and a 0.7% annual overdose rate. Patients receiving 100 mg/d or more had an 8.9-fold increase in overdose risk (CI, 4.0 to 19.7) and a 1.8% annual overdose rate.

Limitations: Increased overdose risk among patients receiving higher dose regimens may be due to confounding by patient differences and by use of opioids in ways not intended by prescribing physicians. The small number of overdoses in the study cohort is also a limitation.

Conclusion: Patients receiving higher doses of prescribed opioids are at increased risk for overdose, which underscores the need for close supervision of these patients.

Primary Funding Source: National Institute of Drug Abuse.

Figures

Grahic Jump Location
Figure.
Cohort entry, overdose events, and 90-day opioid exposure windows for patients who overdosed and comparators.

For each patient who overdosed, we compared the average opioid dose in the preceding 90 days with all patients who remained eligible as of the same number of elapsed days since the beginning of observation. We followed patients until their first opioid overdose or until they were censored because of health plan disenrollment, death, or the end of observation.

Grahic Jump Location

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Comments

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Overdose can occur at a patient's usual opioid dose
Posted on February 3, 2010
William C. Becker
Yale University School of Medicine
Conflict of Interest: None Declared

It seems the authors did not consider 2 relevant points: 1)The class of diuretics as a antihypertensive agent is not at all considered in the results, nor acknowledged in the discussion, though in the methods they are mentioned. Do the authors not consider them antihypertensive agents? I would like to know the OR for atrial fibrillations in those treated solely by diuretics in comparison to other drug families. 2) Calcium channel blockers are considered en-toto or dihydropyridine only? hard to see why verapamil and diltiazem should be included with dihydropyridines... I also wonder if centrally active agents such as clonidine guanafacine and the like were considered as an entity are they not used in Greta Britain?

Conflict of Interest:

None declared

OPIOID-RELATED MORTALITY AND RISK/BENEFIT RATIO
Posted on February 3, 2010
Stephen G. Gelfand
Appalachian Regional Rheumatology, Boone, NC
Conflict of Interest: None Declared

The observation that pain is 'untreated and undertreated' does not mean that opioids are 'underutilized'; in fact they are overutilized which has contributed to the rising volume of overdose and death as brought out in this Annals article by Dunn et al.(1) and the accompanying editorial (2). Given the large volume of the population suffering from chronic pain syndromes, especially those related to central pain sensitivity states such as occurs with unattenuated stress associated with varying degrees of anxiety and depressive disorders,it is clear that non-opioid medications along with self-management multidiscplinary therapies are the treatments of choice, while opioids in these settings can increase the risk of addiction, overdose and death. Furthermore, good evidence is lacking for the long-term [e.g. over 6 months] effectiveness and safety of opioid therapy for chronic noncancer pain (3).

Any decision to start opioid therapy for chronic noncancer pain must consider the type of pain being treated and the significant risk/benefit ratio, which, in addition to addiction, should include awareness of the mounting toll of ER visits, overdose and death related to prescription opioids (4,5). It should be noted that in the state of Florida alone, there were 890 oxycodone-related deaths in the 6 months from January to June 2009, which was a 14.4% increase compared to the previous 6 months, and which was almost double the number of oxycodone-related deaths of 923 for the entire year of 2006. The highest percentage of deaths occurred in the 35 and above age groups which comprised 64% of all oxycodone-related mortality (6), the age groups which receive the vast majority of prescriptions for opioid painkillers, including OxyContin.

References:

1. Dunn KM et al. Opioid prescriptions for chronic pain and overdose. A cohort study. Ann Intern Med. 2010; 152:85-92.

2. McLellan AT, Turner BJ. Chronic noncancer pain management and opioid overdose: Time to change prescribing practices. Ann Intern Med. 2010; 152:123-124.

3. Trescot AM et al. Opioid guidelines in the management of chronic noncancer pain. Pain Phys. 2006; 9:1-39.

4. Paulozzi LJ et al. Increasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Saf. 2006; 15:618-627.

5. Dhalla IA et al. Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone. CMAJ. 2009; 181[12]:891-896.

6. Florida Department of Law Enforcement. 2009 interim report of drugs identified in deceased persons by Florida Medical Examiners. Nov. 2009. [www.fdle.state.fl.us/publications/Examiners/2009DrugReport.pdf]

Conflict of Interest:

None declared

Opioid dose related to increased risk of overdose
Posted on February 5, 2010
Milap C. Nahata, PharmD, MS
The Ohio State University
Conflict of Interest: None Declared

We commend Dr. Dunn and colleagues on their findings of a dose- response relationship between opioid dose and overdose risk. Although some subjects partook in aberrant opioid use, most were not taking opioids for at least 6 months. The authors found that opioid doses of 20 mg daily were associated with lower potential for overdose than higher doses. The daily doses reported were reflective of the cumulative dose dispensed over 90 days, divided by 90 without indication of the prescribed duration of opioids. All subjects filled at least 3 opioid prescriptions, but the days supply was not reported. This may lead to misinterpretation of their finding. Consider the scenarios of Patients A and B, who have been opioid naive for at least 6 months and whose calculated average daily opioid dose was 20 mg over the 90-day period. Patient A took morphine 150 mg daily for a total of 12 days and Patient B took morphine 20 mg daily for 90 days. Both patients filled three morphine prescriptions and ingested a cumulative dose of 1800 mg over 90 days, with an average of 20 mg daily. It must be emphasized, however, that Patient A may be at a substantially higher risk of opioid-related overdoses than Patient B. Additional information, including the days supply of opioid prescriptions filled could have been useful, but clearly do not negate the value of the authors' findings, which offer guidance on safe initial doses of opioids for opioid-naive chronic nonmalignant pain.

Conflict of Interest:

None declared

Re:OPIOID-RELATED MORTALITY AND RISK/BENEFIT RATIO
Posted on February 7, 2010
Oscar A. Linares
University of Toledo College of Medicine
Conflict of Interest: None Declared

We disagree that "it is clear that non-opioid medications along with self-management multidiscplinary therapies are the treatments of choice." NSAIDs are deadlier than opioids, but there is no social stigma against these types of drugs nor towards patients that use them. In our experience, pain needs to be controlled first before patients can successfully complete a physical therapy program. We agree on a multidiscplinary approach, but opioids are often a necessary adjunt.

Conflict of Interest:

None declared

Re:RISK/BENEFIT RATIO OF OPIOIDS FOR CHRONIC NONCANCER PAIN
Posted on February 8, 2010
Stephen G. Gelfand, MD, FACP
Appalachian Regional Rheumatology, Boone, NC
Conflict of Interest: None Declared

Where is the evidence that opioid analgesics should be the first choice for drugs prescribed for chronic noncancer pain? Evidenced-based recommendations point to the opposite conclusion. These include: [1]a consensus panel recommendation for the management of neuropathic pain which considers opioids mainly as second-line agents,[2]a recent Cochrane systemic review on osteoarthritis of the knee or hip which concluded that the large increase in risks for adverse events of non-tramadol opioids outweigh any small to moderate benefits, and that they should not be used routinely,[3]a joint specialty clinical practice guideline for low back pain which placed opioids far down the list of treatment options, and [4] EULAR evidence-based recommendations which stated that strong opioids are not recommended for the pain of fibromyalgia syndrome.

It is apparent that even for tissue-derived chronic noncancer pain, opioids must be used very selectively, if at all, while for the large volume of people with central pain sensitivity states, the risks appear to far outweigh any perceived benefits. When the mounting toll of reported adverse events [including overdose and death] is factored in, it is clear that the nonselective long-term use of opioid therapy for chronic noncancer pain carries a significantly high risk/benefit ratio.

References:

[1]O'Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med. 2009;Oct;122[10 Suppl]:S22-32.

[2]Nuesch E et al. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2009; Oct 7;[4]:CD003115.

[3]Chou R et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007;147[7]:478-491.

[4]Carville SF et al. EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis. 2008;67:536-541.

Conflict of Interest:

None declared

Re: Author's response: Overdose can occur at a patient's usual opioid dose
Posted on March 10, 2010
Michael Von Korff
University of California, San Francisco
Conflict of Interest: None Declared

Becker and Nahata raise valuable points regarding our paper (1). Becker makes an important observation in noting that risks of adverse effects of opioids may differ depending on changes in intercurrent illness, particularly among older patients with multiple comorbidities. About 6-7 percent of all adults age 65 or older use opioids long-term for chronic non-cancer pain (2). There is remarkably little research evaluating risks of and risk factors for adverse medical and behavioral effects of long-term opioid use, particularly among elderly patients. Possible adverse effects of opioids include: serious fractures due to falls (3), acetaminophen toxicity (4); hyperalgesia; aspiration pneumonia; complications of chronic constipation; apathy, de-activation and depression; and cognitive impairment, among others. Careful evaluation of patient suitability for long-term opioid use, cautious prescribing, clear explanation of how to use opioids safely and potential risks, close medical monitoring of patients using opioids long-term, safety reminders, and other universal precautions could conceivably reduce risks of adverse effects. However, research evaluating harm reduction interventions among patients using opioids for chronic non-cancer pain is sparse, as is research weighing long-term benefits against the full range of medical and behavioral risks.

Nahata correctly identifies a limitation of our research. We assessed overdose risk relative to estimated average daily dose. Risks could potentially differ markedly depending on the actual pattern of opioid consumption. In fact, we know little about how physicians prescribe and patients use opioids for chronic pain in community practice. Since millions of U.S. adults use opioids long-term, research is needed concerning how opioids are actually used by chronic pain patients, risks and benefits of alternative opioid treatment regimens, and the effectiveness of universal precautions for preventing adverse effects. In the absence of an adequate evidence base for current prescribing practices, a cautious and vigilant stance toward long-term opioid prescribing for chronic non-cancer pain patients seems prudent.

References 1. Dunn KM, Saunders KW, Rutter CM, Banta-Green CJ, Merrill JO, Sullivan MD, Weisner CM, Silverberg MJ, Campbell CI, Psaty BM, Von Korff M. Opioid prescriptions for chronic pain and overdose: a cohort study. Annals of Internal Medicine 2010; 152:85-92.

2. Campbell CI, Weisner C, LeResche L, Ray T, Saunders K, Sullivan MD, Banta-Green C, Merrill JO, Silverberg MJ, Boudreau D, Satre DD, Von Korff M. Age and sex trends in long-term opioid analgesic use for non- cancer pain. Am J Public Health, In press.

3. Saunders KW, Dunn KM, Merrill JO, Sullivan MD, Weisner CM, Braden JB, Psaty BM, Von Korff M. Relationship of opioid use and dosage levels to fractures in older chronic pain patients. Journal of General Internal Medicine, Published online, January 5,2010.

4. Committee on the Safety of Medicines of the UK. Overdose risk prompts UK withdrawal of propoxyphene combination. J Pain Palliat Care Pharmacother. 2006;20:49-50.

Conflict of Interest:

None declared

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Summary for Patients

Overdose and Prescribed Opioids

The summary below is from the full report titled “Opioid Prescriptions for Chronic Pain and Overdose. A Cohort Study.” It is in the 19 January 2009 issue of Annals of Internal Medicine (volume 152, pages 85-92). The authors are K.M. Dunn, K.W. Saunders, C.M. Rutter, C.J. Banta-Green, J.O. Merrill, M.D. Sullivan, C.M. Weisner, M.J. Silverberg, C.I. Campbell, B.M. Psaty, and M. Von Korff.

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