Clustering of opioid prescribing and opioid-related mortality among family physicians in Ontario

Dear Editor,

I am fascinated by the wide range of sincere opinions when it comes to the question of treating chronic non-cancer pain with opioids. But in all the discussion one little fact is consistently overlooked, a fact that was stated most clearly by Eldon Tunks thirty years ago: you can't measure pain. It was true then, and it is equally true now. Which might have something to do with the absence of any solid, objective evidence that the effectiveness of opioid treatment outweighs the known and easily quantifiable risk.

Since pain itself cannot be measured, the temptation has been to set up surrogates, all of which suffer from the same logical flaw: to establish correlations with pain intensity and pain relief, you have to be able to measure pain. Of course if we could measure pain none of these surrogates would be necessary. Numerical and analog scales? We've all asked the "on a scale of one to ten" question, and received the answer "Twelve". Anyone who gives their chronic pain anything higher than a five has obviously never passed a kidney stone, or had a dentist hit a nerve.

Even so, the only person who can judge the effectiveness of pain relief is the person who feels the pain; and in comes 'personality', 'pain tolerance', primary and secondary gain, and the sheer impossibility of comparing present pain with past pain, or with hypothetical pain. If we can't measure pain, then we can't measure the effectiveness of pain treatment in terms of objective evidence; and basing opioid treatment on unquantifiable self-report, in the presence of significant risk of abuse, addiction, and even death, may not be the smartest strategy either.

But what would criticism be without a constructive suggestion or two? So here are a couple: 1) Let's stop referring to a pain management program with less than twenty places for a city of over half a million people as "state of the art"; 2) Since the evidence of risk points predominantly to oxycodone, rather than to opioids as a class, can we not find the will to outlaw what is quite possibly the most addictive substance it has been our collective misfortune to encounter?

Sincerely,

Dr. Timothy Mead

Conflict of Interest:

None declared

The study by Dhalla et al contributes to our understanding of the impact and causes of the opioid crisis in North America. Numerous studies have documented a dramatic increase in opioid-related harms, including rising rates of opioid addiction, overdose, emergency department visits and hospitalizations. These harms closely parallel the unprecedented increase in prescribing of controlled release opioids. These harms are dose-related. In one cohort study, pain patients on 100 mg/d morphine equivalent or more had a 9-fold increased risk of fatal or non-fatal overdose, compared to patients on 1-20 mg per day (Dunn 2010). The annual risk of overdose in the 100 mg/day group was 1.8%. Morphine 100 mg/d is equivalent to only 30 mg OxyContin bid. To my knowledge there is no medicine in primary care with such a high rate of life-threatening events.

Dhalla’s study demonstrates that a subgroup of physicians are high prescribers. This suggests that educational interventions can be tailored to specific communities and individual physicians. I’ve met many high prescribers over the years; the great majority impressed me as compassionate and caring. But they were influenced by an intense and sustained pharmaceutical marketing campaign which promoted a few simple but false messages: There is no ceiling dose for opioids; addiction is rare in pain patients; and opioids are very safe. The research by Dhalla and others have shown the terrible suffering and harm that these messages have caused.

Reference: Dunn KM, Saunders KW Rutter CM et al. Opioid prescriptions for chronic pain and overdose: A cohort study. Annals of Internal Medicine 2010; 152 (2): 85-92

Dear Editors,

The statement that “the findings in this study suggest that family physicians might be able to reduce opioid related harm by writing fewer prescriptions” is unfounded by the data within the study. Further, in the absence of information regarding the appropriateness of the prescriptions written, such action might harm patients.

The authors have failed to consider alternate explanations for the data. This study used data from the Ontario Public Drug Program and it is important to remember that this population has less access to determinants of health and will likely be a sicker population than the general Ontario population to start with. In addition, those requiring opioids may have more severe illness. It is possible that the variation in prescribing is related to the fact that many family doctors prefer to avoid seeing patients with chronic pain. There are a number of potential reasons that might contribute to this. The cases are complex and time consuming. People with chronic pain have been found to have the worst quality of life and high levels of depression as compared with other chronic diseases [1]. They have often suffered job loss and are on disability so there are forms that must be completed. Many have been injured in motor vehicle accidents so there may be lawsuits requiring the involvement of the health care professionals [2]. There is also inadequate training and education in medical school - in fact veterinarians get five times more education regarding pain management than physicians [3]. In many cases family physicians with an interest have had to seek specific training in pain management offered through CME programs, the Canadian Pain Society Education Special Interest Group refresher course or through mentorship networks such as that offered in the Nova Scotia Collaborative Care Network for Chronic Pain . It is possible that some of the physicians in this study have developed an interest in assisting people with pain and are prescribing appropriately according to the guidelines.

Opioids are a key treatment for moderate to severe pain. There is little argument that they are appropriate in acute and cancer pain. There is evidence that opioids exhibit efficacy in some people with chronic pain [4, 5]. This study did not collect data to allow an assessment of appropriateness of prescribing and therefore should not make suggestions to decrease opioid prescribing or to increase regulatory scrutiny as this may have an adverse effect on the quality of life of many people living with pain. There is a significant problem with access to appropriate treatment for people with pain in Canada [6], there is a need for a national strategy to address the problem of undertreatment, the lack of education and inadequate funding for research [7].

It is very important to assure a balanced perspective in this area so that we do not cause further harm to a group of people who are already suffering.

Sincerely,

Dr. Mary Lynch

President, Canadian Pain Society

1. Choiniere, M., et al., The Canadian STOP-PAIN Project-Part 1: Who are the patients on the waitlists of multidisciplinary pain treatment facilities? . Can J Anesth, 2010. 57: p. 539-548. ,P> 2. Lynch, M.E., Surviving your personal injuries litigation. 2003, Halifax: Queen Elizabeth Health Sciences Cantre.

3. Watt-Watson, J., et al., A survey of pre-licensure pain curricula in health science faculties in Canadian universities. Pain Res Manage, 2008. submitted: p. xx-xx.

4. Noble, M., et al., Long term opioid management of chronic noncancer pain. The Cochrane Collaboration, 2010(1): p. 1-70.

5. Furlan, A.D., et al., Opioids for chronic noncancer pain:meta-analysis of effectiveness and side effects. CMAJ, 2006. 174: p. 1589-1594.

6. Peng, P., et al., Challenges in accessing multidisciplinary pain treatment facilities in Canada. Can J Anesth, 2007. 54:12: p. 977-984.

7. Lynch, M.E., The need for a Canadian Pain Strategy. Pain Res Manage, 2011. 16: p. In Press.

The Editors thank Dr. Pakes for his letter and comments.

Electronic publication of an article in Canadian Family Physician does not reflect any lesser status of the published work. All Web Exclusive publications in CFP are fully indexed and searchable in PubMed and PubMed Central.

There is limited print space in medical journals due to declines in pharmaceutical adverstising which has been a major source of revenue for medical journals. CFP's response to this has been to publish more research in the online version of CFP as Web Exclusive articles. In so doing we have been able to publish more research per issue.

Nicholas Pimlott MD, CCFP On behalf of the Editors

As a group of Canadian physicians interested in the management of patients with chronic pain and addiction, we feel compelled to respond to the recent paper by Dhalla et al regarding opioid-related deaths in Ontario: Clustering of opioid prescribing and opioid-related mortality among family physicians in Ontario. Dhalla et al. Can Fam Phys 2011:57:e92 -96.

Similar to a previous paper by some of the same authors (CMAJ(2009)181:891-896), Dhalla and colleagues once again confuse association with causation. They over interpret statistics from administrative databases to make pronouncements on clinical pain management practice – an area which none of the authors profess to have any expertise.

They have failed to discuss relevant confounders. It is like saying that cardiac surgeons in major institutions have worse results than those in provincial hospitals, without taking into account the severity of the conditions treated. They have failed to consider alternative explanations for their results or discuss other important limitations of their study.

In 2006, there were approximately 12 million people in the Province of Ontario. This would mean approximately 2.3 million people with moderate to severe chronic pain (Nanos Survey 2008). If we assumed that somewhere 30-50% might be taking regular opioid therapy (likely higher than this), 406 deaths would result in a crude death rate of 50-60/100,000 people with pain on opioids (or about ~3 per 100,000 total population). With such small numbers, any flaws in the methodology of this study which change the numbers would have a very big impact on the reported percentages.

The reported Canadian population suicide rate is ~ 15/100,000 (Canadian Mental Health Association). In patients with persistent pain it is at least double ~ 30/100,000 (Tang 2006) Higher doses of opioids often are consistent with a longer time in treatment, poorer efficacy from other treatments and more opportunity for patients to realize that their pain will not go away. There is little organized support and a lack of other non-pharmacologic treatment options compared to patients with other chronic diseases. All of us can recount hearing patients with chronic severe pain say they feel like they have nothing to live for. If we subtract the numbers of people who may have committed suicide from Dhalla’s numbers, then the number of deaths “caused” by opioids shrinks significantly.

The authors used Coroner’s data for assigning deaths “related to opioids”. With all due respect to our hard-working coroners, assigning a cause of death in the case of a patient on therapeutic opioids can be an extremely difficult challenge. (Wallage 2006, Thompson 2008, Ferner 2008) There can be a very large overlap between blood levels of someone stable on long-term opioid therapy and someone found dead with opioids in their blood and therefore a known poor correlation between opioid blood levels and death (Tennant 2007). The definition of opioid-related death among coroners can be variable and can have a large impact (up to a two-fold difference) on reported death rates. ( Jauncey 2005)

How did the authors account for the impact of other substances also found in the blood of decedents? Which substance actually caused the patient’s death? Was the death most likely due to substance abuse/addiction/ (over 90% in Hall 2008) or was it therapeutic misadventure? The authors stated that they adjudicated questionable cases amongst themselves to come to a decision on cause of death, yet they did not report any expertise to allow them to do so.

The authors have suggested that there is an association between deaths and number of prescriptions written, particularly in the ante- mortem period. No information is provided regarding the drug or quantity prescribed. Therefore, the authors provide no evidence that the deaths amongst the patients of high prescribers are due to the drug they prescribed or the dose prescribed. What was the time between death and last prescription? If a physician writes a script for an opioid 12 months before the patient dies, is that doctor somehow responsible?

The vast majority of opioids prescribed for palliative care are prescribed by FP's often not "identified" as palliative care physicians as they have had no extra training that would justify that label even though it may be the focus of their work. How was this population of physicians identified or accounted for in the high prescribers? What about those who do both palliative care and chronic pain management.

The authors have provided no denominators. Whilst more deaths occurred amongst the patients of the high prescribers, the death rate per prescription written, drug used, or dose used is not calculated. If high prescribers were "responsible" for 63% of the deaths, but wrote more than 63% of the prescriptions, then it may be that they are actually safer prescribers compared with those that prescribe less frequently.

Dhalla et al conclude from their data that a small number of FPs are irresponsibly prescribing high dose opioids causing deaths among patients. They suggest targeting these doctors for “education” or regulatory attention. What we know from our communities is that a large proportion of family physicians are already reluctant to take on the care of patients with complex pain and will not prescribe any opioids even when appropriate. This leaves a small number of compassionate family doctors who have a special interest in pain to take on a disproportionate number of patients and therefore more likely accounts for the small number of high dose opioid prescribers.

The high prescribers were noted to be older and more experienced. Does this mean that, on average, they also have an older practice with a higher prevalence of chronic pain? The authors have provided no evidence to support any assertion that older, experienced practitioners are less likely to follow safe prescribing guidelines and hence are more in need of or amenable to "academic detailing" or regulatory scrutiny. On the contrary, those who write more opioid prescriptions may be more likely to seek further training, particularly given the regulatory environment for opioids that already exists in Canada. Family physicians are expected to manage complex patients with pain, having very little formal education and very few funded non- pharmacological treatment resources available. The database used in this study was from the Ontario Drug Benefit Program. This group is a vulnerable population that have less access to the determinants of health and are more at risk than the general population of Ontario. They would also have even less access to appropriate non-medication based care than most Ontarians. Dhalla et al offer a blanket criticism of and a call for a reduction in the use of opioids for chronic pain and yet do not suggest alternative solutions. Although the published scientific evidence for the use of opioids to treat chronic pain is still evolving, the balance of current evidence suggests that opioids can be an effective treatment in some people with a low overall risk of adverse effects, including addiction (Noble 2010). All physicians recognize that no treatment is risk-free and the potential benefits must always be balanced with potential harm. Even those clinicians with expertise in pain management know that there are no risk-free treatment options for severe pain. Acetaminophen, available for decades over the counter, has risks for organ toxicity when used chronically (FDA 2009). The recent Scottish Health Study found an increased risk of cardiovascular events and death in people taking tricyclics (Hamer 2011). The chronic use of NSAIDs is associated with an increased risk of stroke and cardiovascular deaths along with the known risks of death due to UGI bleeds and perforations. (Trelle 2011, Straube 2009) The best type of care for chronic pain is a biopsychosocialspiritual, interdisciplinary approach. Opioids can be an important pharmacologic component of such multi-modal care. Unfortunately, prescribing medication is often the only type of treatment funded by our health care system. When prescribed carefully and monitored appropriately, opioid therapy can result in reduced pain and suffering and improved quality of life. The key is to educate all physicians on appropriate assessment, efficacious treatments and careful prescribing rather than targeting a small number for “over-prescribing” opioids. Studies such as Dhalla et al that report on numbers without considering the clinical context do nothing to advance solutions for the epidemic of poorly-treated chronic pain in Canada. They only make family physicians even more reluctant to treat patients with pain. We would have appreciated a more thorough peer review of this paper prior to publication. We are doing our utmost to promote more dialogue and understanding to optimize patient care; and we hope for the same from all our colleagues.

Roman D. Jovey, M.D. Medical Director, CPM Centres for Pain Management & Physician Director, Addictions & Concurrent Disorders Centre Credit Valley Hospital, Mississauga, ON

Pam Squire MD CCFP CPE Clinical Assistant Professor University of British Columbia Vancouver, BC

Owen D Williamson, MBBS FRACS FFPMANZCA Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia

The following members of the Special Interest Group on Chronic Non- Cancer Pain of the College of Family Physicians of Canada, provided review, suggestions and endorsement of this letter: Ruth Dubin MD PhD FCFP Assistant Professor (Adjunct) Queen’s University Kingston, ON

Ian Forrester, MB.ChB.,MRCS General Practice, Pain and Addiction Medicine Edmonton, AB

John Fraser MD CCFP North End Community Health Centre Halifax, NS

Raju Hajela, MD MPH FASAM FCFP DABAM Consultant - Addiction Medicine, Occupational Health and Chronic Pain Calgary, AB

Lydia Hatcher MD CCFP, FCFP Mount Pearl, NFLD

Lori Montgomery MD CCFP Interim Medical Director Calgary Pain Program, Chronic Pain Centre Calgary, AB

Murray Opdahl MD CCFP Saskatoon, SK

Nadia Plach MD PhD FCFP Palliative Care Program, Hamilton Health Sciences Hamilton, ON

Mark Ware MD MRCP(UK) MSc Assistant Professor in Family Medicine McGill University Montreal, PQ

Erica L. Weinberg BSc MSc MPhil MD General Practitioner, practising in palliative care and pain management Toronto, ON

References:

Ferner RE. Post-mortem clinical pharmacology. Br J Clin Pharmacol. 2008; Oct;66(4):430-43.

Hamer M, David Batty G, Seldenrijk A, Kivimaki M. Antidepressant medication use and future risk of cardiovascular disease: the Scottish Health Survey. Eur Heart J. 2011 Feb;32(4):437-42.

Straube S, Tramèr MR, Moore RA, Derry S, McQuay HJ. Mortality with upper gastrointestinal bleeding and perforation: effects of time and NSAID use. BMC Gastroenterol. 2009 Jun 5;9:41.

Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, Egger M, Jüni P. Cardiovascular safety of non-steroidal anti- inflammatory drugs: network meta-analysis. BMJ. 2011 Jan 11;342:c7086.

Tang NK, Crane C. Suicidality in chronic pain: a review of the prevalence, risk factors and psychological links. Psychol Med. 2006 May;36(5):575-86.

Noble M, Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C, Schoelles KM. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD006605.

Nanos Canadian Pain Survey 2008.

Tennant F. Opioid serum concentrations in patients with chronic pain. J Palliat Med. 2007 Dec;10(6):1253-5.

Jauncey ME, Taylor LK, Degenhardt LJ.The definition of opioid-related deaths in Australia: implications for surveillance and policy. Drug Alcohol Rev. 2005 Sep;24(5):401-9.

Hall AJ, Logan JE, Toblin RL, et al. Patterns of Abuse Among Unintentional Pharmaceutical Overdose Fatalities JAMA. 2008;300(22):2613- 2620

Thompson JG, Vanderwerf S, Seningen J, Carr M, Kloss J, Apple FS. Free oxycodone concentrations in 67 postmortem cases from the Hennepin County medical examiner's office. J Anal Toxicol. 2008 Oct;32(8):673-9.

Wallage HR, Palmentier JP.Hydromorphone-related fatalities in Ontario. J Anal Toxicol. 2006 Apr;30(3):202-9.

I was deeply disappointed that the editors of CFP felt that the Dhalla et al paper on opiod prescribing should be relegated to e-pub only status. From an ethical perspective, this is one of the most important issues for family physicians in Ontario. In medicine we often fail in our duty to help our patients as much as we ideally should, sometimes we even make honest mistakes that result in adverse patient outcomes. Opoids are different. Through over-prescribing – in frequency, dosage and amount - physicians, often family or ER docs, actively harm thousands, if not millions of patients, causing dependence, addiction, and a myriad of other social and physical harms. It not only costs countless physician hours and wasted drug dollars, but it costs many patients and their families (and a substantial number of teens) their emotional and physical well-being, and increasingly their lives.

Barry N. Pakes MD MPH CCFP DTMH FRCP(C) PhD (c)

Program Director, Global Health Education Institute, Centre for International Health. Adjunct Professor, Dalla Lana School of Public Health, University of Toronto Clinician Investigator, Institute of Medical Sciences, University of Toronto Joint Centre for Bioethics, University of Toronto

Re” Clustering of opioid prescribing and opioid-related mortality among family physicians in Ontario” I.A. Dhalla et al. Can Fam Phys 2011:57:e92-96.

“MIND THE GAP”

“Do not put your faith in what statistics say until you have carefully considered what they do not say. ~William W. Watt”

The article by Dhalla et al. on opioid prescribing and opioid-related mortality reminds me of the phrase used by train and bus conductors as we step off their vehicles. They say it to ensure our safety and our safe progress as we embark on our journeys. We need to “mind the gap” between what this group’s population-based number-crunching actually tells us and what they conclude. In focusing solely on opiate prescriptions, these authors over- simplify the many “gaps” in care that may have led to so many tragic deaths.

First we must note the gap between the massive numbers of chronic pain sufferers (1 in 5 Canadians) and the pain education received by medical students (only 16 hours compared to 87 hours for veterinarians). Family physicians, who care for the majority of chronic pain patients, receive only 3.44 hours on chronic pain management during their residency training. And there are no licensure requirements for Canadian physicians in pain management.1,2,3,4

Our health ministry covers drugs, excluding less abuse-prone formulations (e.g. tramadol, transdermal buprenorphine). Ideal chronic pain management includes bio-psycho-social and rehabilitative treatment along with patient education and self-management, and exists in only a few publically-funded pain clinics that have 3-5 year wait times.5 The gulf between recommended and received pain care is especially great for the most financially threatened members of our society, those included in this study.

Then there is the gap between what we are told about the 408 people who died in 2006, and the “at least 1 publically funded opioid prescription in the year before death”. What other drugs and substances were in their bodies when they died? (Most opioid-related deaths are linked to multiple substances including recreational drugs, alcohol and benzodiazepines or other sedatives).6 Did these patients suffer from chronic pain, addiction, mood disorders or other medical conditions that predisposed to overdose?

An unbridgeable chasm exists between the data presented and the authors’ conclusion that “family physicians might be able to reduce the risk of opioid-related harm by writing fewer opioid prescriptions.” Biostatistics 101 teaches that correlation does not mean causation. Yet the implication is clear: if I wrote an opiate prescription 364 days before my patient died, I am responsible.

This leap of logic seems especially naïve considering that there is no mention of “Universal Precautions in Opiate Prescribing”, wherein patients are screened for addiction and risk of inappropriate medication use prior to opioid treatment. 7 This concept has been widely adopted as an educational requirement for practicing physicians in the United States, yet is mostly ignored in Canada. Ordering urine drug tests might be a surrogate marker for those physicians attempting to screen for opioid misuse. Such data would have provided useful information on how many family physicians in Ontario are aware of Universal Precautions.

Using a gratuitous comparison between falling HIV deaths and rising opiate-related deaths is ironic, considering that the great advances in HIV survival arose because of very vocal political action by the gay community. This led to massive R +D and markedly improved medical treatments which turned a death sentence into a manageable disease. One can only hope that chronic pain sufferers, along with those of us who dream of restoring them to functional and satisfying lives, will eventually achieve the same.

Ruth Dubin MD, PhD, FCFP Kingston Family Health Team, Assistant Professor (Adjunct) Queen’s University

1. Canadian Pain Society, Nanos Survey 2007. 2. Watt-Watson, et al. 2009 Pain Res. Manage 14: 439-444. 3. Watt-Watson, 2010. ABS.IASP Education Satellite symposium, Aug 2010. 4. Dubin et al 2011. ABS. Can Pain Society, Apr 2011. 5. Clark et al, 2005, Pain Res. Manage 10:155-157 6. Cone EJ et al.2004. J Anal Toxicol. 28(7):616-24. 7. Gourlay et al, 2005. Pain Medicine 6(2):107-112 and D. Gourlay pers. comm.

Re: Dhalla et al. Clustering of opioid prescribing and opioid-related mortality among family physicians in Ontario

The dramatic rise of opioid-related deaths, emergency visits and adverse events in the United States and Canada is of significant concern to health care regulators, family physicians and patients. Unfortunately this study provides little insight into causal relationships associated with the increase in opioid-related mortality and mistakenly concludes that the problem is somehow related to the very large variance between family physicians who prescribe opioids versus those that do not.

There is strong evidence that unintentional opioid-related mortality is primarily dose-related, and is more typically associated with alcohol or other substance use or abuse (http://www.nejm.org/doi/full/10.1056/NEJMp1011512).

Family physicians and chronic pain patients need to be aware of the real causes of the dramatic rise of opioid-related deaths, emergency visits and adverse events when considering the risks and benefits of the use of opioid treatments for chronic pain.