Practice Guide for Continuous Opioid Therapy for Refractory Daily Headache
Practice Guide for Continuous Opioid Therapy for Refractory Daily Headache
Objectives.—To provide a guide to the use and limitations of continuous opioid therapy (COT, or daily scheduled opioids) for refractory daily headache, based on the best available evidence and expert clinical experience.
Background.—There has been a dramatic increase in opioid administration over the past 25 years, with limited evidence of efficacy for either pain reduction or increased function, and increasing evidence of adverse effects, including headache chronification. To date, there has been no consensus on headache-specific guidelines for selecting patients for COT, physician requirements, and treatment monitoring.
Methods.—A multidisciplinary committee of physicians and allied health professionals with extensive experience and expertise in the administration of opioids to headache patients, undertook a review of the available evidence from the research and clinical literature (using the PubMed database for articles through December 2009) to develop headache-specific treatment recommendations. This guide reflects the opinions of its authors and is not an official document of the American Headache Society.
Results.—The guide identifies factors that would qualify or disqualify the use of COT, including, determination of intractability prior to initiating COT, requisite experience of the prescriber, and requirements for a formal monitoring system to assess appropriate use, safety, efficacy, and functional impact. An appendix reviews the available evidence for efficacy of COT in chronic headache and noncancer pain, paradoxical effects (opioid-induced hyperalgesia, medication overuse headache, opioid-related reduction in triptan and nonsteroidal anti-inflammatory drug efficacy), other adverse effects (nausea and constipation, insomnia and sleep apnea, respiratory depression and sudden cardiac death, reductions in sex hormones, issues during pregnancy, neurocognitive functioning), and issues related to comorbid psychiatric disorders.
Conclusions.—Only a select and very limited group (estimate of 10–20%) of refractory headache patients who meet criteria for COT respond with convincing headache reduction and functional improvement over the long-term. Conservative and empirically based guidelines will help identify those patients for whom a COT trial may be appropriate, while protecting their welfare and safety.
The last 25 years have witnessed a reversal of the historic and traditional reluctance to administer opioids chronically for the treatment of chronic pain. The dynamics and machinations behind this reversal are numerous and largely beyond the scope of this document but include both growing eagerness to provide effective pain control to those who require it and heavily funded marketing and "educational" strategies by opioid manufacturers to alter the attitude toward opioid usage. These strategies included generous funding initiatives for physician advocates and professional society educational programming, and funding to liberalize the views of physicians, state medical board members, and government agencies.
The success of these efforts is evident. Of long-term opioid therapy, 90–95% is now prescribed for chronic noncancer pain (CNCP). Based on data from the National Ambulatory Care Survey, the prevalence of opioid prescriptions for chronic musculoskeletal pain doubled from 1980 to 2000 (from 8% to 16%), with no corresponding increase in the frequency of office visits for musculoskeletal pain. Prescriptions for more potent opioids (hydrocodone, oxycodone, morphine) increased from 2% to 9% of visits. The prevalence of visits on a national level where opioids were prescribed by primary care physicians increased by 44% in the decade between 1992 and 2001. In at least one state (Arkansas) the cumulative yearly dose of opioids increased by 37–38% between 2000 and 2005, for both commercial and Medicaid insurance patients, primarily due to the number of days opioids were prescribed. Between 1997 and 2003 the retail distribution of methadone in the USA rose by 824%; for oxycodone the increase was 660%. Recent review of a large medical insurance claims database found that 19% of the chronic opioid therapy prescriptions (greater than 180 days/year) were for headache, despite growing evidence that chronic use of opioids promotes the progression rather than control of the primary process related to headache (see later).
The Partnership for a Drug Free America in 2009 published its Partnership Attitude Tracking Study report, which evaluated 6518 teenagers in the USA, grades 7 through 12. Among the key findings were: 61% agree that prescription drugs are easier to get than illegal drugs; 41% believe that abuse of prescription and over-the-counter drugs is less dangerous than abuse of illegal drugs; 30% believe them to be nonaddictive; 20% have abused prescription drugs to get high; and 10% admit to abusing prescription pain killers. Reported abuse of narcotics other than heroin by 12th graders has remained relatively constant (above 9%) since it was first measured in 2002 through the most recently available data (2008): one in 10 report nonmedical use of Vicodin, and slightly more than one in 20 (5.3%) report recreational use of Oxycontin in the past year. Among persons age 12 and older who used prescription pain relievers for nonmedical purposes in the past year, 55.7% reported that the drug source for most recent use was a friend or relative, and received the drug at no expense – in those cases, 80.7% reported that the friend or relative had obtained the drugs as a prescription from only one doctor.
The Centers for Disease Control in 2009 reported poisoning deaths involving methadone increased from 790 to 5420 from 1999 to 2006. Fatal poisoning involving all opioid analgesics rose from 4000 to 13,800 fatalities during the same period, and involved nearly 40% of all poisoning deaths in 2006. Though cocaine and heroin remain responsible for many of the fatalities, the increase seems mostly to involve opioids, including methadone, Oxycontin, and Vicodin. Drug deaths now kill more people than auto accidents in 16 states, and counting. According to the National Drug Policy report released in May 2009, prescription opioid-related deaths increased 114% from 2001–2005.
The startling escalation in administration of opioids for CNCP has occurred in the face of little evidence of long-term efficacy. In fact, evidence that daily opioid administration (continuous opioid therapy or COT) is efficacious is lacking and does not appear to justify the aggressive advocacy and administration. Only a minority of those who participate in randomized, controlled trials of scheduled opioids appear to sustain benefit over the long term. For chronic daily headache (CDH), only 15–26% of patients showed significant benefit 3 years or longer after initiating treatment. Moreover, patient claims of global improvement were significantly elevated above that supported by the medical record, and a substantial number of patients who reported over 50% improvement in pain continued to report significant functional impairment. Meta-analytic reviews of evidence from long-term (6 months or longer) outcome studies of COT for chronic noncancer pain (CNCP) provide weak evidence of efficacy at best. In the case of chronic back pain, data failed to show efficacy over placebo or other control conditions, and in some cases, failed to show pain reduction from baseline.
Beyond opioid-related death as detailed above, other opioid-related adverse effects are highly prevalent, reported by as many as 77% of patients receiving COT for CNCP. The most commonly reported and easily identified include nausea and constipation. Less easily identified, but insidious and under-recognized, is the phenomenon of opioid-induced hypersensitivity to pain, often referred to as opioid-induced hyperalgesia (OIH). This apparent paradox, where even brief periods of opioid administration can activate pronociceptive mechanisms, including the release of proinflammatory cytokines, which may eventually override the analgesic effects. Endocrine changes, anxiety and depression, neurocognitive impairment in some patients, sleep disturbance (with associated daytime sleepiness), respiratory depression, and sudden cardiac death are among other significant adverse consequences that are often overlooked as associated with opioids. In November 2006, the United States Food and Drug Administration issued a Health Alert for health professionals on risk of death, cardiac arrhythmias (eg, QT interval prolongation), and narcotic overdose associated with methadone. It should be noted for balance that opioids spare the liver and kidneys – a significant advantage over some other simpler analgesics, such as the nonsteroidal anti-inflammatory drugs and acetaminophen.
Enhanced by advances in neuroimaging and neuroscience research, there exists an increasing understanding of the physiological pathways shared by various chronic pain conditions and the potential adverse influence that chronic opioid therapy has on pathophysiological mechanisms, ultimately leading to progression of the illness rather than its control, particularly in the domain of headache disorders. In the spectrum of chronic pain disorders, headache occupies a unique position, with a long-standing recognition of problems associated with frequent acute treatment usage, initially referred to as ergot or analgesic rebound. As far back as 1983, Saper proposed that the chronic use of medicine for acute headache exceeding 2–3 days of use per week, week after week, represented the threshold to establish the progressive dynamic. Clinical evidence implicating frequent use of opioids as a significant contributor to the chronification and treatment resistance of migraine is mounting and compelling. Recent epidemiological studies have identified the frequent use of opioids and opioid-combination drugs as a significant risk factor for the progression from episodic migraine to CDH, with an odds ratio of 2.3 (1.3–3.9). The critical level of exposure is around 8 days a month, with a more pronounced effect for men, a level of use somewhat below the current MOH criterion for opioids of 10 or more days per month in the International Classification of Headache Disorders, 2nd Edition (ICHD-II).
Recent guidelines for COT promulgated by the American Pain Society and American Academy of Pain Medicine identify headache as one of 4 common CNCP conditions (along with back pain, osteoarthritis, and fibromyalgia) where COT might be considered, but the guidelines do not address the unique aspects of headache, such as balancing the risk of MOH against the potential benefit of scheduled opioids.
In this context and with the growing concern and involvement of government and the health care professions in this matter, the American Headache Society (AHS) encouraged an expert panel to develop a guide for the identification of headache sufferers who might be appropriate candidates for COT, with recommendations for patient selection, physician preparation, and monitoring requirements. It should be noted, however, that this guide does not represent an official position paper of the AHS. This practice guide is based on empirical evidence where available (see Appendix) and on the consensus of clinical experience from a multidisciplinary panel of senior and scholarly clinicians with COT experience in the treatment of headache. We anticipate that these recommendations will be subject to further peer review and modification based on the accumulation of the clinical experience of headache specialists and additional outcome research.
Abstract and Introduction
Abstract
Objectives.—To provide a guide to the use and limitations of continuous opioid therapy (COT, or daily scheduled opioids) for refractory daily headache, based on the best available evidence and expert clinical experience.
Background.—There has been a dramatic increase in opioid administration over the past 25 years, with limited evidence of efficacy for either pain reduction or increased function, and increasing evidence of adverse effects, including headache chronification. To date, there has been no consensus on headache-specific guidelines for selecting patients for COT, physician requirements, and treatment monitoring.
Methods.—A multidisciplinary committee of physicians and allied health professionals with extensive experience and expertise in the administration of opioids to headache patients, undertook a review of the available evidence from the research and clinical literature (using the PubMed database for articles through December 2009) to develop headache-specific treatment recommendations. This guide reflects the opinions of its authors and is not an official document of the American Headache Society.
Results.—The guide identifies factors that would qualify or disqualify the use of COT, including, determination of intractability prior to initiating COT, requisite experience of the prescriber, and requirements for a formal monitoring system to assess appropriate use, safety, efficacy, and functional impact. An appendix reviews the available evidence for efficacy of COT in chronic headache and noncancer pain, paradoxical effects (opioid-induced hyperalgesia, medication overuse headache, opioid-related reduction in triptan and nonsteroidal anti-inflammatory drug efficacy), other adverse effects (nausea and constipation, insomnia and sleep apnea, respiratory depression and sudden cardiac death, reductions in sex hormones, issues during pregnancy, neurocognitive functioning), and issues related to comorbid psychiatric disorders.
Conclusions.—Only a select and very limited group (estimate of 10–20%) of refractory headache patients who meet criteria for COT respond with convincing headache reduction and functional improvement over the long-term. Conservative and empirically based guidelines will help identify those patients for whom a COT trial may be appropriate, while protecting their welfare and safety.
Introduction
The last 25 years have witnessed a reversal of the historic and traditional reluctance to administer opioids chronically for the treatment of chronic pain. The dynamics and machinations behind this reversal are numerous and largely beyond the scope of this document but include both growing eagerness to provide effective pain control to those who require it and heavily funded marketing and "educational" strategies by opioid manufacturers to alter the attitude toward opioid usage. These strategies included generous funding initiatives for physician advocates and professional society educational programming, and funding to liberalize the views of physicians, state medical board members, and government agencies.
Dramatic Increase in Opioid Administration
The success of these efforts is evident. Of long-term opioid therapy, 90–95% is now prescribed for chronic noncancer pain (CNCP). Based on data from the National Ambulatory Care Survey, the prevalence of opioid prescriptions for chronic musculoskeletal pain doubled from 1980 to 2000 (from 8% to 16%), with no corresponding increase in the frequency of office visits for musculoskeletal pain. Prescriptions for more potent opioids (hydrocodone, oxycodone, morphine) increased from 2% to 9% of visits. The prevalence of visits on a national level where opioids were prescribed by primary care physicians increased by 44% in the decade between 1992 and 2001. In at least one state (Arkansas) the cumulative yearly dose of opioids increased by 37–38% between 2000 and 2005, for both commercial and Medicaid insurance patients, primarily due to the number of days opioids were prescribed. Between 1997 and 2003 the retail distribution of methadone in the USA rose by 824%; for oxycodone the increase was 660%. Recent review of a large medical insurance claims database found that 19% of the chronic opioid therapy prescriptions (greater than 180 days/year) were for headache, despite growing evidence that chronic use of opioids promotes the progression rather than control of the primary process related to headache (see later).
Abuse and Diversion
The Partnership for a Drug Free America in 2009 published its Partnership Attitude Tracking Study report, which evaluated 6518 teenagers in the USA, grades 7 through 12. Among the key findings were: 61% agree that prescription drugs are easier to get than illegal drugs; 41% believe that abuse of prescription and over-the-counter drugs is less dangerous than abuse of illegal drugs; 30% believe them to be nonaddictive; 20% have abused prescription drugs to get high; and 10% admit to abusing prescription pain killers. Reported abuse of narcotics other than heroin by 12th graders has remained relatively constant (above 9%) since it was first measured in 2002 through the most recently available data (2008): one in 10 report nonmedical use of Vicodin, and slightly more than one in 20 (5.3%) report recreational use of Oxycontin in the past year. Among persons age 12 and older who used prescription pain relievers for nonmedical purposes in the past year, 55.7% reported that the drug source for most recent use was a friend or relative, and received the drug at no expense – in those cases, 80.7% reported that the friend or relative had obtained the drugs as a prescription from only one doctor.
Opioid-Related Deaths
The Centers for Disease Control in 2009 reported poisoning deaths involving methadone increased from 790 to 5420 from 1999 to 2006. Fatal poisoning involving all opioid analgesics rose from 4000 to 13,800 fatalities during the same period, and involved nearly 40% of all poisoning deaths in 2006. Though cocaine and heroin remain responsible for many of the fatalities, the increase seems mostly to involve opioids, including methadone, Oxycontin, and Vicodin. Drug deaths now kill more people than auto accidents in 16 states, and counting. According to the National Drug Policy report released in May 2009, prescription opioid-related deaths increased 114% from 2001–2005.
Limited Efficacy Data
The startling escalation in administration of opioids for CNCP has occurred in the face of little evidence of long-term efficacy. In fact, evidence that daily opioid administration (continuous opioid therapy or COT) is efficacious is lacking and does not appear to justify the aggressive advocacy and administration. Only a minority of those who participate in randomized, controlled trials of scheduled opioids appear to sustain benefit over the long term. For chronic daily headache (CDH), only 15–26% of patients showed significant benefit 3 years or longer after initiating treatment. Moreover, patient claims of global improvement were significantly elevated above that supported by the medical record, and a substantial number of patients who reported over 50% improvement in pain continued to report significant functional impairment. Meta-analytic reviews of evidence from long-term (6 months or longer) outcome studies of COT for chronic noncancer pain (CNCP) provide weak evidence of efficacy at best. In the case of chronic back pain, data failed to show efficacy over placebo or other control conditions, and in some cases, failed to show pain reduction from baseline.
Other Risks and Harms
Beyond opioid-related death as detailed above, other opioid-related adverse effects are highly prevalent, reported by as many as 77% of patients receiving COT for CNCP. The most commonly reported and easily identified include nausea and constipation. Less easily identified, but insidious and under-recognized, is the phenomenon of opioid-induced hypersensitivity to pain, often referred to as opioid-induced hyperalgesia (OIH). This apparent paradox, where even brief periods of opioid administration can activate pronociceptive mechanisms, including the release of proinflammatory cytokines, which may eventually override the analgesic effects. Endocrine changes, anxiety and depression, neurocognitive impairment in some patients, sleep disturbance (with associated daytime sleepiness), respiratory depression, and sudden cardiac death are among other significant adverse consequences that are often overlooked as associated with opioids. In November 2006, the United States Food and Drug Administration issued a Health Alert for health professionals on risk of death, cardiac arrhythmias (eg, QT interval prolongation), and narcotic overdose associated with methadone. It should be noted for balance that opioids spare the liver and kidneys – a significant advantage over some other simpler analgesics, such as the nonsteroidal anti-inflammatory drugs and acetaminophen.
Evidence for Opioid-Induced Illness Progression
Enhanced by advances in neuroimaging and neuroscience research, there exists an increasing understanding of the physiological pathways shared by various chronic pain conditions and the potential adverse influence that chronic opioid therapy has on pathophysiological mechanisms, ultimately leading to progression of the illness rather than its control, particularly in the domain of headache disorders. In the spectrum of chronic pain disorders, headache occupies a unique position, with a long-standing recognition of problems associated with frequent acute treatment usage, initially referred to as ergot or analgesic rebound. As far back as 1983, Saper proposed that the chronic use of medicine for acute headache exceeding 2–3 days of use per week, week after week, represented the threshold to establish the progressive dynamic. Clinical evidence implicating frequent use of opioids as a significant contributor to the chronification and treatment resistance of migraine is mounting and compelling. Recent epidemiological studies have identified the frequent use of opioids and opioid-combination drugs as a significant risk factor for the progression from episodic migraine to CDH, with an odds ratio of 2.3 (1.3–3.9). The critical level of exposure is around 8 days a month, with a more pronounced effect for men, a level of use somewhat below the current MOH criterion for opioids of 10 or more days per month in the International Classification of Headache Disorders, 2nd Edition (ICHD-II).
Lack of Headache-specific Guidelines
Recent guidelines for COT promulgated by the American Pain Society and American Academy of Pain Medicine identify headache as one of 4 common CNCP conditions (along with back pain, osteoarthritis, and fibromyalgia) where COT might be considered, but the guidelines do not address the unique aspects of headache, such as balancing the risk of MOH against the potential benefit of scheduled opioids.
In this context and with the growing concern and involvement of government and the health care professions in this matter, the American Headache Society (AHS) encouraged an expert panel to develop a guide for the identification of headache sufferers who might be appropriate candidates for COT, with recommendations for patient selection, physician preparation, and monitoring requirements. It should be noted, however, that this guide does not represent an official position paper of the AHS. This practice guide is based on empirical evidence where available (see Appendix) and on the consensus of clinical experience from a multidisciplinary panel of senior and scholarly clinicians with COT experience in the treatment of headache. We anticipate that these recommendations will be subject to further peer review and modification based on the accumulation of the clinical experience of headache specialists and additional outcome research.
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