From: Boos, Terrence L. Sent: Wed, 1 Aug 2012 13:59:22 -0400 To: Rannazzisi, Joseph T.;Hill, Robert L.;Rannazzisi, Joseph T.;Hill, Robert L. Subject: data sources Attachments: Katz_0steoarthritis_2008.pdf, PROP Cautious Evidnce Based Prescribing.pdf, Policylmpact-PrescriptionPainkillerOD.pdf, Manchikanti_ASIPP Guidelines_2012.pdf, Dhalla_BMJ_2011.pdf, andrewkolodny-_RXDrugSummit.pdf

I have spoken with Bobby a few times today regarding trends in opioid overdose deaths and ED visits and attempted to pull some info.

Attached are some possible data sources to mirror CDC's methadone report. Please see Katz paper (2008), table 1 provides a great overview of data sources.

Also, Dr. Kolodny's presentation from the RX Drug Summit highlights TEDS data.

Anticipate you may have already visited these sources; therefore, if there are any specifics that can be provided in framing the issue, please let me know. Terry

Vol. II Page 198 Abuse-deterrent Opioid Formulations: Are They a Pipe Dream?

Nathaniel Katz, MD

Corresponding author minimizing abuse, because in principle, they support Nathaniel Katz, MD access to while minimizing certain types of abuse. Analgesic Research, 109 Highland Avenue, Suite B2, Needham, MA 02494, USA. This review focuses on whether this ADF principle can be E-mail: [email protected] translated into practice.

Current Rheumatology Reports 2008, 10:11—18 Current Medicine Group LLC ISSN 1523-3774 Copyright © 2008 by Current Medicine Group LLC Terminology Some progress has been made in achieving consensus on terms related to prescription opioid abuse [2*], but more The continued need for opioids to treat pain and work remains. The terms abuse and misuse are very widely their unavoidable link to abuse and addiction create used, but with different meanings by different authors. a need for risk mitigation approaches that optimize A recent working group adopted definitions used in this their risk-benefit ratio. Abuse-deterrent formulations review [3*»], and those follow upon other precedents. (ADFs) have emerged as a means for supporting opi Misuse refers to inappropriate use of a medication but for oid access while limiting abuse and its consequences. a medical purpose rather than for mind-altering effects. Several different types of ADFs have emerged includ Examples include unauthorized dose escalation for pain ing physical barriers to tampering, agonist-antagonist treatment, cutting extended-release (ER) formulations formulations, aversion, prodrugs, and alternative for faster analgesic onset or to save money, or sharing methods of administration. Each of these types has the medication with others in pain. Abuse is an umbrella the potential to reduce specific forms of prescription term referring to the use of a medication for its mind- opioid abuse. ADFs have the potential to reduce the altering effects, whether or not one also has pain or has public health burden of prescription opioid abuse, been prescribed the medication. Both abuse and misuse but they will require not only technically successful may also constitute noncompliance if one has received a formulations, but also appropriate scientific assess prescription with instructions not to engage in the forbid ment, widespread market penetration, and rational den behaviors. Several important phenomena do not fall expectations of their benefits. neatly into either abuse or misuse, such as suicide attempts and accidental pediatric ingestion. In this paper, ADF will be used to denote opioid Introduction formulations incorporating features that may deter one Few medical problems have persisted and have been or more common forms of prescription opioid abuse or characterized by as much confusion, rancor, inconsistent misuse or may minimize the harm resulting from such terminology, data misinterpretation, conflation with behaviors. This term is used rather than "abuse-resistant" sociologic myths, and lack of evidence as the issue of after a recent meeting on the subject concluded that prescription opioid abuse. Discussions about whether "resistance" may imply a degree of infallibility of these the therapeutic value of opioids is outweighed by their products that is unsupported by current data [3**]. abuse potential can be found as far back as 300 BC. The obvious solution— developing a strong nonaddictive analgesic—has met with no success despite millennia Public Health Consequences of Prescription of ethnobotanical efforts and decades of modern drug Opioid Abuse development. Opioid risk management refers to efforts Determining whether an ADF actually deters abuse designed to maximize the benefit-risk balance of opioids requires quantification of the public health consequences given their flaws [!••]. Abuse-deterrent formulations of abuse, misuse, and related phenomena (Table 1). The (ADFs) of strong opioids have the potential to provide links between these phenomena and the measurable public a modicum of balance in the effort to relieve pain while health events used to quantify them are presented here.

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Table 1. Inappropriate behaviors related lo prescription opioids to measurable public health events

Concept Measurable public health event Examples of data sources

Abuse Nonmedical use NSDUH

Abuse NSDUH

Addiction NSDUH

Abuse of specific products NAVIPPRO Entries into treatment for prescription opioid addiction NAVIPPRO, TEDS

New initiates to nonmedical prescription opioid use NSDUH

Nonmedical use among youth MTF, NSDUH

Altered route of ingestion of prescription opioids NAVIPPRO, TEDS (eg, intravenous, nasal)

Poisoning related to abuse TESS, RADARS, DAWN

Emergency department visits related to abuse DAWN

Abuse or misuse Opioid-related hospitalizations NCHS

Prescription opioid deaths DAWN, coroners' databases, NCHS

Misuse Misuse episodes Direct patient surveys*

Poisonings related to misuse TESS, RADARS

ED visits related to misuse DAWN

Suicide Prescription opioid suicide attempts DAWN

Accidental pediatric ingestion Pediatric exposures TESS, RADARS

Fatal pediatric exposures TESS, RADARS

"None published to the author's knowledge. DAWN — Drug Abuse Warning Network; MTF—Monitoring the Future; NAVIPPRO—National Addictions Vigilance Intervention and Prevention Program; NCHS — National Center for Health Statistics; NSDUH —National Survey on Drug Use and Health; RADARS— Researched Abuse, Diversion and Addiction-Related Surveillance; TEDS—Treatment Episode Data Set; TESS —Toxic Exposure Surveillance System.

Abuse commonly obtaining medications from dealers, doc Abuse encompasses a spectrum of behaviors that to some tor shopping, stealing, and other less socially acceptable extent fall along a continuum. Use for mind-altering methods [11]. effects may be called "nonmedical use" (further qualified Many of these features of abuse constitute measurable by frequency of use) [4**], and is often called "recreational public health events. Lifetime, past year, and past month use." This may lead to loss of control and compulsive use nonmedical use of prescription opioids are assessed annu despite negative consequences. The Diagnostic and Sta ally in the United States [4**]. In 2006, a projected 33.5 tistical Manual of Mental Disorders (DSM) divides these million Americans aged 12 years or older used a prescrip substance use disorders into "abuse" and "dependence," tion opioid nonmedically at least once; 12.6 million used in with the latter more severe than the former [5] and more the past year, and 5.2 million in the past month. More than appropriately called "addiction" [6]. Irrespective of the 1.6 million individuals were projected to meet DSM crite terminology, the key observation remains that some users ria for abuse or dependence. Although these data are useful progress, and preventing this progression is a central pub for prescription opioids as a class, at least initially, ADFs lic health target. are not likely to affect prescription opioid abuse overall, Almost all early users ingest their medications orally but are more likely to reduce abuse of specific products. A with or without chewing [7]. As abuse progresses, users different database called the National Addictions Vigilance increasingly modify the route of ingestion, frequently Intervention and Prevention Program (NAVIPPRO) has snorting then injecting [7]. Frequency of use and daily been set up to provide product-specific indices of prescrip dose may increase, and consequences may become more tion opioid abuse [12], NAVIPPRO indicates, for example, severe along a number of domains such as medical (eg, that approximately 70% of individuals in treatment for HIV, hepatitis), legal, and employment [81- Altering the prescription opioid abuse indicate past month nonmedi route of ingestion may also accelerate the progression of cal use of hydrocodone, by far the leading product overall; addiction by increasing the total exposure and the rate about 40% indicate past month use of oxycodone-ER, the of onset [9,10]. Sources of diverted medications also leading ER product among abusers [12]. shift, with early users obtaining medications primarily Of great importance for ADEs is monitoring altered from friends and family [4*»], and advanced users more routes of ingestion. For example, the NAVIPPRO database

Vol. II Page 200 Abuse-deterrent Opioid Formulations: Are They a Pipe Dream? Katz 13

indicates that among users of oxycodone-ER, 51% ingest report [18]. DAWN also provides data on the rate of it orally, 45% snort it, and 29% inject it; for emergency department visits associated with prescription ER the percentages are 30%, 25%, and 60%, respectively opioids, which numbered 132,207 in 2004. More specific- (Stephen Butler, PhD, Inflexxion, Newton, MA, personal categorizations of these events as misuse related are pos communication). By contrast, only 1% of hydrocodone sible but not presented here. users inject the drug. Such data can be used to validate an "injection-resistant" ADF, which would be expected Suicide to show a low number of individuals altering the oral for Suicide does not fit neatly under abuse or misuse as mulation for intravenous injection. Also, such data can be defined herein, because the individual attempting suicide used to determine what types of ADFs are needed. For is generally not using the medication for medical purposes example, it would seem pointless to develop an injection- at the time (misuse) or for mind-altering effects (abuse). proof formulation of hydrocodone, because few if any In the United States, over 9% of high school students users inject it. attempt suicide each year (approximately 1.3 million sui Other important and measurable indices of prescription cide attempts annually). The leading substance implicated opioid abuse include new initiates to prescription opioid in these events is prescription opioids, which are involved abuse (2.2 million in 2006, ahead of all other illicit drugs) in 36% of the events [19]. Although it is unclear how an [4**], nonmedical use among youth (9% of 12th graders ADF would decrease opioid-related suicide attempts, per used a prescription opioid nonmedically in 2006) [13*1, haps ADFs could be developed to be safer in overdose or poison control center calls (nearly 300,000 related to anal in coingestion with , a common accompaniment of gesics in 2004) [14*], emergency department visits (over intentional (or unintentional) overdose. 130,000 related to prescription opioids in 2004) [15**], and others. Such reports arise from both abuse and misuse, Accidental pediatric ingestion and although some systems attempt to disentangle these Accidental pediatric ingestion is among the most feared causes, the exact behavioral antecedent often is unclear or and mourned mishaps related to prescription opioids, difficult to classify. Nonetheless, such indices can be used and it is one of the chief risk management concerns of in a targeted manner to evaluate the potential impact of the US Food and Drug Administration (FDA). Analgesics ADFs on these manifestations of abuse and misuse. are the leading pharmaceutical class associated with acci dental pediatric ingestion in the United States; in 2004, Misuse they were responsible for 98,237 pediatric exposures, The consequences of misuse, if reported at all, may appear exceeded only by cosmetics, personal care products, and as a poison control center call, an emergency department cleaning substances [14*]. Again, it is unclear how ADFs visit, an opioid-related hospitalization, a spontaneous alone will deter accidental pediatric exposure, but it is adverse event report, or an opioid-related death. By the time conceivable that ADFs formulated to be safer in overdose those types of reports occur, it may be unclear whether could reduce the proportion of such events that are fatal. abuse, misuse, or something else led to the incident. To measure the impact of an ADF on misuse, one can use surveillance data (to the extent that the events are classi Types of Abuse-deterrent Formulations fied as misuse), or one can conduct direct patient surveys A number of opioids have been introduced over the past cen on misuse. To this author's knowledge, no direct surveys tury amid claims of being less subject to abuse only to create of opioid misuse have been published, although studies of epidemics of abuse, including heroin and Talwin (Flospira, aberrant behaviors are conceptually akin to misuse surveys Lake Forest, IL) [20,21*]. Indeed, other opioids such as and could be adapted for this purpose [16]. tramadol and buprenorphine appear to be abused less fre Several aspects of public health data likely reflect quently, but they do not seem as useful for severe pain as misuse. National mortality data indicate that the rate the full p-agonist opioids. Thus, most attempts to develop of unintentional poisoning deaths related to opioids ADFs have focused on formulating p-agonist opioids in has increased by 91% from 1999 to 2002, to a rate of such a manner as to prevent common types of abuse, or at approximately 100 per 10 million people per year [17*]. least to reduce the harmful consequences of such behav According to the Toxic Exposure Surveillance System iors. These strategies can be grouped into several different poison control center database, analgesics were the lead subtypes, although some efforts do not fit neatly into these ing cause of poisoning deaths in 2004, with 654 deaths categories, and other efforts comprise multiple strategies in reported to this specific system; analgesics were also the the same formulation. The major ADF types are discussed leading cause of poisonings overall, numbering nearly below without an attempt to be comprehensive. 300,000 in the same year [14*]. Deaths associated with prescription opioids in the Drug Abuse Warning Network Physical barriers (DAWN) database increased annually from 1997 to 2002, Common methods of tampering with prescription opioids with 1294 deaths reported in the most recent year of that consist of— in order of increasing effort required— simple

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Table 2. Abuse-deterrent formulations and their potential ability lo mitigate different types of abuse*

Alternative routes Type of abuse Physical barriers Agonisf-antagonist Aversion Prodrug of administration

Intravenous + + +

Snorting + + +

Chewing + + + +

Alcohol interaction +/- +/- +

Intact abuse +/-

Misuse +/- +/-

'The purpose of this table is not to present specific benefits of formulations, but rather to illustrate that different formulations will have specific effects on different abuse types, depending upon the exact nature of the formulation. (+)— potential benefit; (-)— no likely benefit; (+/-) —possible benefit, depending on the specifics of the formulation or the exact nature of the type of abuse/misuse. physical manipulations (eg, chewing, crushing), single- published data on the extent to which OROS hydromor- step chemical manipulations (eg, dissolving in water or phone may resist common forms of tampering, alcohol), multistep chemical manipulations (eg, dissolv- Tahle 2 provides a framework for considering the ing in alcohol then redissolving in water), and laboratory potential public health benefits of physical barrier-type extractions, which are rarely conducted "in the street" ADFs. The most direct benefit would be reduced inges these days [22*, 23]. tion by alternate routes of the parent product. If overall Several companies have announced programs to prescribing of ER products shifts to specific ADFs, there develop formulations that resist common methods of may he a reduction of altered ingestion of prescription tampering, although to this author's knowledge, none of opioids as a class. Secondary benefits could include reduc- these original research results have been published in the tion of injection-related diseases, reduction in the rate of peer-reviewed scientific literature. Several are in late-stage development of addiction, and potentially reduced rates clinical development. Remoxy (King Pharmaceuticals, of other health events. These ADFs may also diminish Bristol, TN, and Pain Therapeutics, San Mateo, CA) is consequences of misuse that involve tampering (such as an ER formulation of oxycodone that appears to resist a inadvertently chewing an ER formulation). These formula- number of common forms of physical and chemical tam- tions are not expected to reduce the rates or consequences pering, and has been tested in several pharmacokinetic of ingestion of intact oral formulations, perhaps the most studies and at least one clinical trial [24]. A formulation common type of abuse, with similar effects in resisting physical and chemical manipulation was presented by scientists from Grunen- Agonist—antagonist combinations thai (Germany) at a meeting of the College of Problems in Several formulations containing opioids in combination Drug Dependency in April 2005 [25]. A third company, with opioid antagonists for the purpose of deterring Collegium Pharmaceutical (Cumberland, RI), filed a pat- abuse are already on the market in the United States ent, announced the development of such an ADF, and and elsewhere [21*]. In response to widespread abuse recently announced a positive clinical proof-of-concept of pentazocine (Talwin) in the 1970s, the manufacturer study [26], although further information is not available, replaced Talwin with Talwin NX, a combination of 50 No doubt other such efforts are also underway. mg of pentazocine and 0.5 mg of naloxone. Because nal- Another formulation that appears to deter abuse is oxone has very poor oral bioavailability, the expectation already on the market, known as Osmotic Release Oral was that when taken orally, the naloxone would have System (OROS) [27], Methylphenidate is marketed in this no impact on analgesia but that when injected, the nal- formulation for attention deficit hyperactivity disorder oxone would he sufficient to eliminate the euphoria or under the brand name Concerta (ALZA, Mountain View, produce frank withdrawal. Indeed, Talwin's abuse rate CA, and McNeil Pediatrics, Fort Washington, PA). The appeared to drop precipitously after the introduction OROS formulation has been shown to resist common of Talwin NX, although several authors have suggested forms of physical and chemical tampering, and several that the decline in abuse of Talwin was more related to a lines of evidence suggest that Concerta has a lower abuse surge in availability of cheap heroin at the time, an argu- liability than immediate-release methylphenidate and pos- ment bolstered by case reports of addicts who habitually sibly other long-acting formulations of methylphenidate injected Talwin NX [29]. in both experimental [27] and real-world [28] settings. Valoron (tilidine, Pfizer, New York, NY) is an opioid An OROS formulation of hydromorphone is currently in analgesic that began to be abused in Germany and other late-stage clinical development. This author is unaware of countries in the late 1970s [21*]. The manufacturer then

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launched a combination product, Valoron N, containing 50 press releases and similar materials indicate that positive mg of tilidine and 4 mg of naloxone, to deter intravenous clinical proof-of-concept studies have been completed for abuse. Valoron N monitoring has generated little evidence these products, to the author's knowledge, no such trials of abuse, but it is unclear whether this is due to the addition have been published. of naloxone, because most abuse of tilidine was oral (not The aversion approach raises a number of issues. One intravenous), and presumably not affected by naloxone. issue is whether the aversive effects could occur occasion Buprenorphine is a partial p-opioid agonist used as an ally in patients who take the medication as directed, or analgesic and as maintenance treatment for opioid addic who unwittingly take the medication inappropriately, tion in many countries around the world. Buprenorphine such as by chewing or cutting the product. In such cases, was approved for the treatment of opioid addiction in the would physicians prescribe a product that adds only risk United States under the brand Subutex (Reckitt Benck- to the compliant patient, in order to deter inappropriate iser Pharmaceuticals, Berkshire, UK) in 2003. Because behavior by abusers? The second, more fundamental ques buprenorphine had been widely abused intravenously in tion is whether physical punishment will be considered by other countries, Suboxone (Reckitt Benckiser Pharma prescribers and by consumers to be an appropriate means ceuticals), a product consisting of buprenorphine and of deterring individuals from abusing medications. naloxone in a 4:1 ratio, was approved simultaneously with Subutex [21*]. Although pharmacologic studies Prodrugs show mixed results with regard to reduction in abuse A prodrug is a drug with little or no pharmacologic effect liability by the added naloxone, published reports sug until it is metabolized to an active form after ingestion. At gest that the combination may be less desirable to addicts a minimum, this feature may result in a delay in reaching than the single-entity product [301- Data on the relative maximum plasma concentrations of the active ingredient abuse rate of Subutex and Suboxone exist [311, but to this and therefore decrease reinforcing effects. If the specific author's knowledge, these data have not been published. metabolic systems are saturable, after a certain dose, Thus, Subuxone provides a third example of a successful further biotransformation to active form cannot occur, agonist-antagonist formulation marketed to deter abuse, thus reducing both maximal euphoria and possibly the without sufficient publicly available data to support firm risk of respiratory depression in overdose. In fact, codeine conclusions about effectiveness. appears to be a prodrug, because its analgesic effect and Several companies have announced development pro presumably euphoria result primarily from metabolism to grams of new opioid agonist-antagonist combinations. morphine. New River Pharmaceuticals, recently acquired Alpharma (Bridgewater, NJ) recently presented data from a by Shire (Hampshire, UK), announced such an approach phase 2 clinical trial on an ER morphine product containing [351. NRP-290 is a lysine-modified opioid prodrug that sequestered naltrexone demonstrating that the combina requires a biotransformation step to become active. The tion product relieved pain without significant "leakage" of activation of the prodrug by enzymatic cleavage is said to naltrexone, a major technical challenge in the development be limited to the gastrointestinal tract, and conversion is of sequestered antagonist formulations [32]. Elite Phar said not to occur with intravenous or intranasal admin maceuticals (Northvale, NJ) has also presented human istration. To date, to the author's knowledge, no clinical pharmacokinetic data on its ADF, oxycodone with seques trials demonstrating proof-of-concept for this product tered naltrexone, reporting that untampered product did not have been presented or published. release naltrexone, whereas the tampered product did [331- However, a predecessor product, also from Shire and based on this technology has been developed, approved, Aversion and launched in the United States. The product, Vyvanse A review of patent literature and corporate announce (lisdexamfetamine dimesylate), is a conjugate of dex ments indicates an alternative approach: opioid products troamphetamine and L-lysine, which is metabolized to containing an additional substance that produces some dextroamphetamine apparently by first-pass intestinal and/ type of unpleasant effect in patients who ingest tampered or hepatic metabolism, and is approved for the treatment of product [34,351. One approach involves incorporating attention deficit hyperactivity disorder [37]. Human stud capsaicin, a component of hot chili peppers. If swallowed ies demonstrated relatively less subjective effects compared whole, the capsaicin would not produce any effects; how to equivalent doses of dextroamphetamine, consistent with ever, if the product were crushed and snorted, dissolved a delayed time of maximum concentration but which could and injected, or inhaled, the capsaicin would produce an be overcome by increasing the Vyvanse dose. Unfortunately, intense burning discomfort that would leave one uninter no pharmacologic studies have been published demonstrat ested in a repeat experience. A second approach combines ing an asymptote of exposure at increasing doses. an opioid (oxycodone) with , which if taken in excessive doses, produces a classic niacin reaction con Alternative methods of administration sisting of warmth, flushing, and other uncomfortable Certain products, by virtue of the formulation's design to symptoms that resolve in 1 to 2 hours [36]. Although support the intended route of administration, seem rela-

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tively abuse deterrent. For example, transdermal fentanyl sources such as dealers, theft, cross-border smuggling, products, though certainly abused, are mentioned at only and the Internet. Abuse among this latter group would not a fraction of the rate of other ER opioids in abuse surveil be expected to change based on some clinicians shifting lance data [15", 381. The key feature of abuse deterrence to prescribing ADFs, and it would not be affected until of these products is that it is simply more difficult and shifts in prescribing had been so complete as to make the more dangerous to convert the drug in a transdermal more abusable opioids unavailable. The good news is that patch to the rapid-onset, supratherapeutic but nonlethal this is an achievable and perhaps inevitable goal. dose desired by abusers. Differences are likely to exist A third consideration is that all the foreseeable ADFs among products that further render one transdermal address only parts of the prescription opioid abuse prob product more attractive to abusers than another [39], lem. To a great extent, benefits will be product specific. Such features include the amount of drug left after the For example, an oxycodone-ER ADF would have more patch has been used, ease of dividing the medication in impact on the abuse of oxycodone-ER than on that of the product into precisely metered doses, ease of extract transdermal fentanyl or immediate-release oxycodone. ing the active ingredient into a usable rapid-onset form, Moreover, benefits will be specific to the type of abuse and "environmental" factors such as cost, availability, deterred by the formulation. Most ADFs are focused on and reputation. Several companies are developing other preventing tampering. Unfortunately, most prescription transdermal products such as transdermal buprenorphine, opioid abuse involves ingestion of intact formulations and if studied appropriately, these products may turn out and would not be mitigated by these ADFs. Table 2 pres to have abuse-deterrent properties. ents a conceptual schema for the types of prescription Other novel delivery approaches in development may opioid abuse that are likely to be deterred by specific for prove even more resistant to abuse. For example, Titan mulation approaches, which can be linked to the public- Pharmaceuticals (South San Francisco, CA) has announced health outcomes in Table 1. a program to develop a subcutaneous implant—insertable during an office procedure — that would release an opioid continuously for several months [40]. Other companies Conclusions have announced development programs focused on injec Intravenous injection and nasal ingestion of prescrip tions that would release opioid for over a month [21*,41], tion opioid formulations are likely to be the subtypes of Such implants, which would be essentially impossible to abuse most directly impacted by the first ADFs. Given abuse, could have a role in treating patients with comor- the ubiquity of street access to injectable ER formula bid substance abuse and chronic pain, a subgroup that tions, public health benefits of such ADFs likely will not probably accounts for 20% to 40% of the chronic pain be felt until the injectable formulations are no longer population on opioid therapy [42,43*]. readily available. ADFs of immediate-release opioids, such as prodrugs or aversive formulations, will be needed to address the larger problem of ingestion of intact Will Abuse-deterrent Formulations Achieve immediate-release formulations; to date, little data have Their Public Health Potential? been presented on such products. Several conditions seem necessary for ADFs to realize Nonetheless, we are entering a promising new era their public health benefits. First, they must be studied in which an iterative process of developing opioid for appropriately, so their abuse-deterrent properties can be mulations to deter aspects of prescription opioid abuse, verified [3**]. Otherwise, the FDA will not allow promo rationally and systematically evaluating their real-world tion of abuse-deterrent properties, payers will not pay effectiveness, and then improving upon their design, will for the medications, and clinicians will not prescribe bring us closer to realizing the twin goals of addressing them. The bench top testing, preclinical testing, human undertreated pain while simultaneously minimizing con clinical pharmacology studies, and even clinical trials, sequent harm. however promising, are all surrogate measures for the outcome measure of actual interest: real-world abuse. Although surrogate measures may be sufficient to sup Disclosure Dr. Katz is the President of Analgesic Research (Needham, MA), which port preliminary prescribing decisions, they can only has more than 100 clients. be validated in postmarketing epidemiologic studies or Related to the topic of this article, through his work with large clinical trials. Analgesic Research, he has received consulting fees or honoraria from Second, earlier generation, more abusable opioids Alpharma, King Pharmaceuticals, F.ndo Pharmaceuticals (Chadds Ford, PA), ALZA Pharmaceuticals (Mountain View, CA), Neuromed must become relatively unavailable. Most abusers obtain (Vancouver, BC), Grunenthal, New River Pharmaceuticals, Shire, their medications directly or indirectly from physicians' Purdue Pharma LP (Stamford, CT), and TheraQuest Biosciences (Blue prescriptions [4**], but many abusers, particularly those Bell, PA). Dr. Katz owns no stocks in any of the companies listed here. most severely addicted, obtain their medications through Dr. Katz also has a financial relationship with Inflexxion Inc.

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Addic preliminary experience with an case of cxtractability rating tion vs. dependence in DSM-V. Am J Psychiatry 2006, system for prescription opioids. Drug Dev Ind Pharm 2006, 163:764-765. 32:727-746. 7. Hays LR: A profile of OxyContin addiction. J Addict Dis A study summarizing how prescription opioid abusers extract 2004,23:1-9. opioids from marketed products. The paper also provides the only 8. White AG, Bimbaum I IG, Mareva MN, et al.: Direct costs public proposal for a standard battery to assess the extractability of of opioid abuse in an insured population in the United an opioid formulation. States. J Manag Care Pharm 2005, 11:469-479. 23. Cone EJ: Ephemeral profiles of prescription drug and 9. Compton WM, Volkow ND: Abuse of prescription drugs formulation tampering: evolving pscudoscicncc on the and the risk of addiction. Drug Alcohol Depend 2006, Internet. Drug Alcohol Depend 2006, 83(Suppl 1):S3 1—39. 83(Suppl 1):S4—7. 24. Webster LR: PTI-821: sustained-release oxycodone using 10. Marsch LA, Bickel WK, Badger GJ, et al.: Effects of gel-cap technology. Expert Opin lnvestig Drugs 2007, infusion rate of intravenously administered morphine on 16:359-3 66. physiological, psychomotor, and self-reported measures in 25. Bartholomaeus J, Arkcnau E, Ashworth JB: A new technol humans. ] Pharmacol Exp Ther 2001, 299:1056-1065. ogy to increase the mechanical stability of matrix tablets 11. Rosenblum A, Parrino M, Schnoll SH, et al.: Prescription to prevent abuse by crushing or chewing. Presented at the opioid abuse among enrollees into methadone maintenance College of Problems in Drug Dependency. Bethesda, MD; treatment. Drug Alcohol Depend 2007, 90:64-71. April 19-20, 2005. 12. Butler S, Budman S, Villapiano A, et al.: The NAVIPPRO 26. Collegium Pharmaceutical: Central nervous system. Avail System: new data on the feasibility of real-time, product able at http://www.collegiumpharma.com/products/cns. specific opioid surveillance. Presented at the American Pain html. Accessed November 28, 2007. Society Annual Meeting. Washington, DC; May 5-7, 2007. 27. Parasrampuria DA, Schoedel KA, Schuller R, et al.: Do 13.* Johnston I.D, O'Malley PM, Bachman JG, Schulenberg JE: formulation differences alter abuse liability of mcthylphc- Monitoring the future national results on adolescent drug nidate? A placebo-controlled, randomized, double-blind, use: overview of key findings, 2006. (NIH Publication crossover study in recreational drug users. / Clin Psycho- No. 07-6202). Bethesda, MD: National Institute on Drug pharmacol 2007, 27:459-467. Abuse; 2007. 28. Teter CJ, McCabe SE, LaGrange K, et al.: Illicit use of Provides the key data on drug abuse among US youth. specific prescription stimulants among college students: 14. • Watson WA, Litovitz TL, Rodgers GC Jr, et al.: 2004 prevalence, motives, and routes of administration. Pharma Annual report of the American Association of Poison cotherapy 2006, 26:1501-1510. Control Centers Toxic Exposure Surveillance System. Am J 29. Lahmeyer HW, Craig RJ: Pentazocine-naloxone: another Emerg Med 2005, 23:589-666. "addiction-proof" drug of abuse, bit ] Addict 1987, Most recent report available from the Toxic Exposure Surveillance 22:1163-1166. System, which highlights in detail the ways in which prescription opioid abuse and misuse may be illuminated by poison control data.

Vol. II Page 205 18 Osteoarthritis

30. Alho H, Sinclair D, Vuori E, Holopainen A: Abuse liability 38. Rosenblum A, Parrino M, Schnoll SH, et al.: Prescription of buprenorphine-naloxone tablets in untreated IV drug opioid abuse among enrollees into methadone maintenance users. Drug Alcohol Depend 20 07, 88:75-78. treatment. Drug Alcohol Depend 2007, 90:64-71. 31. US Food and Drug Administration, Center for Drug 39. Butler SF, Benoit CM, Budman SH, et al.: Development and Evaluation and Research: Subutex and Suboxone: questions validation of an opioid attractiveness scale: a novel measure and answers. Available at http://www.fda.gov/cder/drug/ of the attractiveness of opioid products to potential abusers. infopage/subutex_suboxone/subutex-qa.htm. Accessed Harm Redact J 2006, 3:5. November 28, 2007. 40. Bell J, White J, Saunders J, et al.: PROBUPHINE (buprenor- 32. Katz N, Sun S, Fox L, et al.: Treatment of osteoarthritis phine implant) provides sustained serum buprenorphine pain with extended-release morphine sulfate plus seques concentrations and long-term control of withdrawal tered naltrexone ASA 2007 Annual Meeting [abstract symptoms and cravings [poster|. Presented at the College #652984]. Presented at the American Society of Anesthesi on Problems of Drug Dependence 66th Annua! Scientific ologists. San Francisco, CA; October 15, 2007. Meeting. San Juan, Puerto Rico; June 12-17, 2004. 33. Elite Pharmaceuticals Inc.: Home page. Available at www. 41. Sobel BE, Sigmon SC, Walsh SL, et al.: Open-label trial of elitepharma.com. Accessed November 28, 2007. an injection depot formulation of buprenorphine in opioid 34. Woolf CJ, Hashmi M: Use and abuse of opioid analgesics: detoxification. Drug Alcohol Depend 2004, 73:11-22. potential methods to prevent and deter non-medical 42. Katz N, Fanciullo GJ: Role of urine toxicology testing in the consumption of prescription opioids. Curr Opin Investig management of chronic opioid therapy. Clin J Pain 2002, Drugs 2004, 5:61-66. 18(4 Suppl):S76-82. 35. Gershell L, Goater JJ: From the analyst's couch: making 43.• Ives TJ, Chelminski PR, Hammett-Stabler CA, et al.: gains in pain. Nat Rev Drug Discov 2006, 5:889-890. Predictors of opioid misuse in patients with chronic pain: a 36. Acura Pharmaceuticals Inc.: Home page. Available at http:// prospective cohort study. BMC Health Serv Res 2006, 6:46. www.acurapharm.com. Accessed November 28, 2007. One of the only prospective studies designed to determine the inci 37. Vyvanse [package insert]. Hampshire, UK: Shire Pharma dence of prescription opioid abuse (called "misuse" in the paper) ceuticals; 2007. among patients prescribed opioids for chronic pain.

Vol. II Page 206 PHYSICIANS FOR RESPONSIBLE OPIOID PRESCRIBING www.responsibleopioidprescribing.org

Cautious,

Evidence-Based Despite low-quality evidence supporting practice change, 1-6 Opioid Prescribing use of chronic opioid therapy (COT) for chronic non-cancer pain increased dramatically over the past two decades. 34-36 Concurrently, opioid analgesic overdose deaths, addiction, M & misuse and diversion have increased markedly.20-37

COT may provide modest, variable

short-term pain relief for some patients

with chronic pain. Long-term benefits

of COT for chronic pain have not been

established. Potential medical and

behavioral harms of opioids are an

important concern, particularly at

higher dosage levels and in higher risk

or medically complex patients. While

COT at lower doses may be a useful

The content printed in this guide has treatment for some patients, it should been distributed, uploaded to the web and/or endorsed by the following only be considered for carefully evalu agencies and organizations: ated, closely monitored patients when The American College of Medical Toxicology Group Health Research Institute a cautious, structured and selective ap Maimonides Medical Center

New York State Office of Alcoholism and proach is employed, and clear benefits Substance Abuse Services for pain and function are documented. SAMA Foundation The United States Centers for Disease Control COT always entails risks for patients, and Prevention Washington State Industrial Insurance their families and the community, so Medical Advisory Committee vigilance and caution are essential. Vol. II Page 207 PHYSICIANS FOR RESPONSIBLE OPIOID PRESCRIBING www.responsibleopioidprescribing.org Myths and Facts about Chronic Opioid Therapy (COT)

Myth: COT lor chronic pain is Fact: Evidence of long-term efficacy for chronic non-cancer pain (>16 weeks) is supported by strong evidence. limited,1 23 and of low quality.45 Opioids are effective for short-term pain manage ment. But, for many patients with chronic pain, analgesic efficacy is not maintained over long time periods.6

Myth: Physical dependence only happens Fact: With daily opioid use, physical dependence and tolerance can develop in with high doses over long periods of time. days or weeks.75 Myth: Patients who develop physical FACT: Successfully tapering chronic pain patients from opioids can be ditficult dependence on opioids can easily be tapered off. even for patients who are motivated to discontinue opioid use.33

Myth: Addiction is rare in patients Fact: Estimates vary. Between 4% and 26% of patients receiving COT have an opi receiving medically prescribed COT. oid use disorder.9"12 Among patients without an opioid use disorder, more than one in ten misuse opioids by: intentional over-sedation; concurrently using alcohol for pain relief; hoarding medications; increasing dose on their own; and borrowing opi oids from friends.9'15

Myth: Addiction is the main risk to be Fact: Opioids have significant risks besides addiction and misuse.1819 These risks concerned about when prescribing opioids. include respiratory depression and unintentional overdose death;20-21 serious frac tures from falls;22-23 hypogonadism and other endocrine effects that can cause a spectrum of adverse effects;2'1 increased pain sensitivity,25 sleep-disordered breath ing,26 chronic constipation and serious fecal impaction,27-28 and chronic dry mouth which can lead to tooth decay.29

Myth: Extended-release opioids are better than Fact: Extended-release opioids have not been proven short-acting opioids for managing chronic pain. to be safer or more effective than short-acting opioids for managing chronic pain.30

Myth: Prescribing high-dose opioid Fact: No randomized trials show long-term effectiveness of high opioid doses for therapy (>120 mg morphine equivalents/day) chronic non-cancer pain. Many patients on high doses continue to have substantial is supported by strong evidence that benefits pain and related dysfunction.32 Higher doses come with increased risks tor adverse outweigh risks. events and side effects including overdose, fractures, hormonal changes, and in creased pain sensitivity.18"26

Myth: Opioid overdoses only occur among Fact: Patients using prescription opioids are at risk of unintentional overdose and drug abusers and patients who attempt suicide. death.20 This risk increases with dose and when opioids are combined with other CNS like and alcohol.21

Myth: Dose escalation is the best response Fact: When treating chronic pain, dose escalation has not been proven to reduce when patients experience decreased pain control. pain or increase function, but it can increase risks.32

dependence develops within days or weeks. Due to risks of acci Do's & Don'ts for dental poisoning, it is important to store opioids in a medication Acute Pain Management lock box and flush unused opioids down a sink or toilet. DO explain that opioids are for time-limited use. With the DON'T start long-term use of opioids by accident. Long- first opioid prescription, set expectations that opioids should term opioid prescribing should only occur after careful patient be discontinued when the pain problem is no longer acute. evaluation, discussion ot risks and realistic expectations of bene fits, and clear explanation of rules for safe use. Routine authoriza DON'T stock your patients' medicine cabinets with un tion of refills may cause patients to expect the prescription to used opioids. Limit all initial and refill prescriptions for acute continue indefinitely. pain. A 30-day supply is often excessive - many patients only take a pill or two then leave the rest in their medicine cabinet. This in DON'T prescribe extended-release opioids for acute pain creases the risk of diversion, which in turn increases the risk of ad or to opioid-na'ive patients. Extended-release opioids are not diction and fatal overdose in families and communities. For those appropriate for managing acute pain and should never be prescribed patients who use the medicine daily for several weeks, physiologic to an opioid-naive patient. Vol. II Page 208 PHYSICIANS FOR RESPONSIBLE OPIOID PRESCRIBING www.responsibleopioidprescribing.org Do's & Don'ts for Chronic Pain Management

DON'T initiate chronic opioid therapy (COT) before con DO perform random urine drug screens on patients re sidering safer alternatives such as primary disease manage ceiving COT. Urine drug screening helps identify patients ment, cognitive-behavioral therapy (CBT), participating in using illicit drugs or not taking the medicine as prescribed. pleasant and rewarding life activities, physical therapy, non-opi-

oid analgesics and exercise. DON'T continue COT with patients who show no progress toward treatment goals defined by increased DO screen patients for depression and other psychiatric function and reduced pain. disorders before initiating COT. Patients with depression

and other mental health problems often present with pain prob DON'T assume patients know how to use opioids safely. lems. They may not know that mental health problems can con Opioids are powerful drugs that patients sometimes use in un tribute to chronic pain. These patients are at higher risk of safe ways. Risks of unsafe use increase with prescribed dose opioid addiction. They may be better served by mental health and are greater for extended-release medications with long half- treatment. life. Patients often do not understand that it can be unsafe to take extended-release opioids "as-needed for pain." Take time to DO talk with patients about therapeutic goals, opioid talk with patients about how they are using opioids. Ask patients risks, realistic benefits, and prescribing ground rules. about their problems and concerns.17 Therapeutic goals should include increased activity and im proved quality of life, not just pain relief. Patients should under DON'T assume patients use opioids as you intend. Many stand the full range of opioid risks and the limited benefits they patients vary their dose and use combinations of other CNS de can reasonably expect. The rules for safe and appropriate use of pressant drugs or alcohol in ways that you may not know about. opioids need to be explicit, preferably documented in a written Patients may also sell their medications or share them with oth treatment agreement. ers. Opioid misuse often occurs among patients who do not have an opioid use disorder.9'15 Vigilance for unsafe use is es DO realize that patients are reluctant to disclose a his sential. tory of substance abuse. A history of substance abuse indi

cates greater risk of opioid addiction, but getting an accurate DON'T start a treatment that you are not prepared to picture of past and current drug use can be difficult. If a patient stop. Don't initiate COT without benchmarks for stopping, a denies past or current substance abuse, recognize that they may procedure for tapering that you are willing and able to use, and be afraid to tell you the truth. Consult the medical record, a pre an approach to managing physical and psychological with scription drug monitoring database, and third parties as needed. drawal symptoms. If substance abuse is identified, taper opioids and make arrangements for substance abuse treatment. DO perform a thorough medical evaluation and a urine

drug screen before initiating COT. Starting chronic opioid DON'T assume patients are doing well with COT without therapy should be an affirmative decision based on adequate as careful evaluation. Careful and compassionate interviewing sessment of risk, urine drug screening, and use of a treatment about opioid use and misuse, questions about your patients' agreement. Because it can be difficult to know if a patient is problems and concerns,17 screening questionnaires, urine drug seeking opioids for addiction or diversion purposes, COT screening, and information from prescription drug monitoring should only be considered by a physician who has an ongoing databases often reveal problems with prescription opioids that relationship with the patient. The prescribing physician should would otherwise be missed. be willing to continue working with the patient if problems arise.

DON'T abandon patients with a prescription drug prob DO explain to patients that discontinuing opioids may lem. For patients who are misusing or addicted to prescription be difficult. Some patients find it difficult to taper off of opi opioids, offer help or referral to someone who can treat sub oids, particularly from higher dose regimens, even when they stance abuse. are eager to do so. Patients can experience increased pain, in somnia, or anxiety when tapering from opioids. These unpleas ant withdrawal symptoms can last for several weeks. Do not abandon chronic pain patients after discontinuing opioids. Vol. II Page 209 PHYSICIANS FOR RESPONSIBLE OPIOID PRESCRIBING www.responsibleopioidprescribing.org

Contributors

Physicians/Scientists: Patient/Family Advocates: External Reviewers: Andrew Kolodny, MD Peter Jackson Jane Ballantyne, MD Gary Franklin, MD, MPH Len Paulozzi, MD, MPH Betts Tully Roger Chou, MD Stephen Geltand, MD Jon Streltzer, MD Mark Edlund, MD. PhD Petros Levounis, MD. MA Art Van Zee, MD Richard A. Deyo, MD. MPH Mark Sullivan, MD, PhD Rosemary Orr, MD Michael Von Korff, ScD Thomas Kosten, MD Judith Turner, PhD

For additional information, please contact Physicians for Responsible Opioid Prescribing: Andrew Kolodny, MD, [email protected] or Michael Von Korff, ScD, [email protected]

References

1. Kalso E. Edwards JE, Moore RA, McQuayHJ. Opioids in chronic non-cancer pain: systematic review ot efficacy and safety. Pain 2004;112:372-80.

2. Papaleontiou M. Henderson CR, Turner BJ, Moore AA, Olkhovskaya V. Amanto L. Reid MC. Outcomes associated with opioid use in the treatment ot chronic non-cancer pain in older adults: A systemalic review and meta-analysis. JAGS 2010: 58:1353-1369.

3. Martell BA, O'Connor PG, Kerns RD, Becker WC, Morales KH, Kosten TR, et al. Systematic review: opioid treatment tor chronic back pain: prevalence, elticacy, and association wilh addiction. Ann Intern Med 2007; 146:116-27. 4. Chou R, Fanciullo GJ, Fine PG, Adler JA, Ballantyne JC, Davies P, Donovan Ml, Fishbain DA, Foley KM, Fudin J, Gilson AM, Keller A. Mauskop A. O'Connor PG, Passik SD, Pasternak GW, Portenoy RK. Rich BA. Roberts RG. Todd KH. Miaskowski C; American Pain Society - American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use ot chronic opioid therapy in chronic non-cancer pain. J Pain 2009; 10:1 13-130. 5. American Gerialrics Society Panel on the Pharmacological Management ot Persistent Pain in Older Persons. Pharmacological Management ot Persistent Pain in Older Persons. JAGS 2009; 57:1331-1346,2009. 6. Bal lantyne JC, Shin NS. Elticacy ot opioids tor chronic pain: a review ol the evidence. Clin J Pain 2008: 24:469-78. 7. McOuay H. Opioids in pain management. Lancet 1999, 353: 2229-2232. 8. Baily CP and Connor M. Opioids: Cellular mechanisms of tolerance and physical dependence. Current Opinion in Pharmacology 2005: 5:60-80. 9. Fleming MF, Balousek SL, Klessig CL, Mundt MP, Brown DO. Substance Use Disorders in a Primary Care Sample Receiving Daily Opioid Therapy. J Pain 2007; 8:573-582. 10. Banta-Green CJ, Merrill JO, Doyle SR, Boudreau DM, Calsyn DA. Measurement of opioid problems among chronic pain patients in a general medical population. Drug andAlcohol Dependence 2009; 104:43-49. 11. Becker WC, Fiellin DA, Gallagher RM, Barth KS, Ross JT, Oslin DW. The association between chronic pain and prescription drug abuse in Veterans. Pain Medicine 2009; 10:531-536. 12. Boscarino JA. Rutstalis M, Hoftman SN. Han JJ, Erlich PM, Gerhard GS, Stewart WF. Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system. Addiction 2010; 105:1776-1782. 13. Manchikanti L„ Fellows B„ Damron K.S., Pampati V., McManus C.D. Prevalence of illicit drug use among individuals wilh chronic pain in the Commonwealth ol Kentucky: an evaluation of patterns and trends. J KyMed Assoc 2005; 103: 55-62. 14. Ives TJ, Chelminski PR, Hammetl-Stabler CA, Malone RM, Perhac JS, Polisek NM, Shilliday BB, DeWalt DA, Pignone MP Predictors ol opioid misuse in palients wilh chronic pain: a prospective cohort sludy. BMC Health Services Research 2006; 6:46-55. 15. Banta-Green CJ, Merrill JO. Doyle SR, Boudreau DM, Calsyn DA. Opioid use behaviors, menial health and pain - Development ol a typology of chronic pain palients. Drug andAlcohol Dependence 2009; 104:34-42. 16. Goldsworthy RC, Schwartz NC, Mayhorn CB. Beyond Abuse and Exposure: Framing the Impact ol Prescription-Medicalion Sharing. Am J Public Health 2008; 98:1 1 15-1 121 . 17. Sullivan MD, Von Kortl M, Banla-Green C, Merrill JA, Saunders K. Problems and concerns of patients receiving chronic opioid therapy tor chronic non-cancer pain. Pain 201 0; 149:345-353. 18. Ballantyne JC, Mao J. Opioid therapy lor chronic pain. N Engl J Med 2003; 349:1943-53. 19. Von Kortf M. Commentary on Boscarino etal. (2010): Understanding the spectrum of opioid abuse, misuse and harms among chronic opioid therapy patients. Addiction 2010; 105:1783-1784. 20. Paulozzi LJ, Ryan GW. Opioid analgesics and rales of fatal drug poisoning in the United States. AmJPrevMed2006; 31:506-11. 21. Dunn KM, Saunders KW, Rutter CM, Banta-Green CJ, Merrill JO, Sullivan MD, Weisner CM.Silverberg MJ, Campbell CI, Psaty BM, Von Kortf M. Opioid prescriptions for chronic pain and overdose: a cohort study. Annals ol Internal Medicine 2010: 152:85-92.

22. Saunders KW, Dunn KM, Merrill JO, Sullivan MD, Weisner CM, Braden JB, Psaty BM, Von Korlt M. Relationship of opioid use and dosage levels to tractures in older chronic pain patients. Journal ol General Internal Medicine 201 0; 25:310-315. 23. Takkouche B, Montes-Martinez A, Gill S, Etminan M. Psychotropic medications and the risk of fracture. Drug Salely 2007; 30(2):1 71 -84. 24. Vuong C, Van Uum SH, O'Dell LE, Lutly K, Friedman TC. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr flei/2010; 31:98-132. 25. Zhou HY, Chen SR, Chen H, Pan HL. Opioid-induced long-term potentiation in the spinal cord is a presynaptic event. Neuroscience 2010; 30:4460-4466. 26. Walker JM. Famey RJ, Rhondeau SM, Boyle KM. Valentine K, Cloward TV. Shilling KC, Chronic Opioid Use is a Risk Factor lor Ihe Development ol Central Steep Apnea and Ataxic Breathing. J Clin Sleep Medicine 2007: 3:455-461 . 27. Tuteja AK, Biskupiak J, Stoddard GJ, Lipman AG. Opioid-induced bowel disorders and narcotic bowel syndrome in patients wilb chronic non-cancer pain. Neurogastroenlerot Mofr/2010; 22:424-30. 28. Bell TJ, Panchal SJ, Miaskowski C, Bolge SC, Milanova T, Williamson R. The prevalence, severity and impact ot opioid-induced bowel dyslunction: results ol a US and European Palienl Survey (PROBE 1). Pain Medicine 2009] 10:35-42. 29. Murray Thomson W. Poulton R, Mark Broadbent J, Al-Kubaisy S: Xerostomia and medications among 32-year olds. Ada Odonlol Scand 64:249-254, 2006 30. Chou R, Clark E. Helland M. Comparalive efficacy and safety ol long-acting oral opioids for chronic non-cancer pain: a systematic review. J Pain Symptom Manage 2003: 26:1026-1048. 31 . Lusher J. Elander J, Bevan D. Teller P. Burton B: Analgesic addiction and pseudoaddiction in painful chronic illness. Clin J Pain 2006: 22:316-324. 32. Franklin GM, Rahman EA. Turner JA. Daniell WA, Fulton-Kehoe D. Opioid use for chronic tow back pain. A prospective, populalion-based sludy among injured workers in Washington State, 2002-2005. Clin J Pain 2009] 25:743-751. 33. Blondell RD, Ashralioun L, Dambra CM, Foschio EM, Zielinski AL, Salcedo DM. A clinical trial comparing tapering doses ol buprenorphine wilh steady doses tor chronic pain and co-existent opioid addiction. J Addict Med 2010; 4:140-146. 34. Caudiil-Slosberg MA, Schwartz LM, Woloshin S. Office visits and analgesic prescriptions for musculoskeletal pain in US: 1980 vs 2000. Pain 2004; 109(3):514-519. 35. Boudreau D. Von Korff M, Rutter CM. etal. Trends in long-term opioid therapy lor chronic non-cancer pain. Pharmacoepidemiol Drug Sal 2009; 18(12):1 166-1 175. 36. Sullivan MD, Edlund MJ, Fan MY, et al. Trends in use of opioids for non-cancer pain conditions 2000-2005 in commercial and Medicaid insurance plans: the TROUP study. Pain 2008; 138(2):440-449. 37. Zacny J, Bigelow G, Compton P, Foley K, Iguchi M, Sannerud C. College on Problems ol Drug Dependence taskforce on prescription opioid non-medical use and abuse: posilion statement. Drug and alcohol dependence 2003; 69:215-232. Vol. II Page 210 a * J CT h i ?§ % ill

stKvices

National Center for Injury Prevention and Control M2 Division of Unintentional Injury Prevention s- Vol. II age ^ WHAT'S THE ISSUE?

In a period of nine months, a tiny Kentucky county of fewer than 1 2,000 people sees a 53-year-old mother, her 35-year-old son, and seven others die by overdosing on pain medications obtained from pain clinics in Florida.' In Utah, a 13-year-old fatally overdoses on oxycodone pills taken from a friend's grandmother.2 A 20-year-old Boston man dies from an overdose of methadone, only a year after his friend also died from a prescription drug overdose.3 One hundred people These are not isolated events. Drug overdose death die from drug rates in the United States have more than tripled since 1 990 and have never been higher. In 2008, more than overdoses every day 36,000 people died from drug overdoses, and most of in the United States.4 these deaths were caused by prescription drugs.4

Vol. II Page 212 12 Drug overdose death rates in the US have more than tripled since 1990.5

10

c I 8 3 a o a o o o o 6 o a5 a

2 f 4 (D a

2

1990 1992 1994 1996 1998 2000 2002 2004 2006 2008

"Deaths are those for which poisoning by drugs (illicit, prescription, and over-the-counter) was the underlying cause. Vol. II Page 213 WHAT DO WE KNOW?

The role of prescription painkillers Although many types of prescription drugs are abused, there is currently a growing, deadly epidemic of prescription painkiller abuse. Nearly three out of four prescription drug overdoses are caused by Commonly Abused Medications prescription painkillers—also called opioid pain relievers. The unprecedented rise in overdose deaths Opioids Derived from the opium poppy (or synthetic in the US parallels a 300% increase since 1999 in the versions of it) and used for pain relief. sale of these strong painkillers.4 These drugs were Examples include hydrocodone (Vicodin®), involved in 14,800 overdose deaths in 2008, more than oxycodone (OxyContin®, Percocef"), cocaine and heroin combined.4 fentanyl (Duragesic®, Fentora®), methadone, and codeine. The misuse and abuse of prescription painkillers Benzodiazepines was responsible for more than 475,000 emergency Central nervous system depressants used as department visits in 2009, a number that nearly , to induce sleep, prevent seizures, doubled in just five years.6 and relieve anxiety. Examples include (Xanax®), (Valium®), and (Ativan®). More than 1 2 million people reported using prescription

painkillers nonmedically in 201 0, that is, using them Amphetamine-like drugs without a prescription or for the feeling they cause.7 Central nervous system stimulants used to treat attention deficit hyperactivity disorder (ADHD). Examples include The role of alcohol and other drugs dextroamphetamine/amphetamine About one-half of prescription painkiller deaths involve (Adderall®, Adderall XR ), and at least one other drug, including benzodiazepines, methylphenidate (Ritalin®, Concerto®). cocaine, and heroin. Alcohol is also involved in many overdose deaths.8 Vol. II Page 214 In 2008, there were 1 4,800 prescription painkiller deaths.4 For every 1 death there are... I

treatment admissions for abuse9

emergency dept visits for misuse or abuse6

1 30 PeoP|e who abuse or are dependent7

825 nonmedical users7

Vol. II Page 215 How prescription painkiller deaths occur Prescription painkillers work by binding to receptors in the brain to decrease the perception of pain. These powerful drugs can create a feeling of euphoria, cause physical dependence, and, in some people, lead to addiction. Prescription painkillers also cause sedation and slow down a person's breathing. In 2010,2 million people reported using A person who is abusing prescription painkillers might prescription painkillers take larger doses to achieve a euphoric effect and reduce withdrawal symptoms. These larger doses nonmedically for the first can cause breathing to slow down so much that time within the last year— breathing stops, resulting in a fatal overdose. nearly 5,500 a day. 7

Vol. II Page 216 People who abuse prescription painkillers get drugs from a variety of sources7 Where the drugs come from Other _ ,, . Almost all prescription drugs involved in overdoses source 7.1% Got from drug come from prescriptions originally; very few come dealer or stranger 4.4% from pharmacy theft. However, once they are prescribed and dispensed, prescription drugs are Took from friend or relative without frequently diverted to people using them without asking 4.8% prescriptions. More than three out of four people who Bought from misuse prescription painkillers use drugs prescribed to friend or someone else.7 relative 1 1 .4%

Most prescription painkillers are prescribed by primary care and internal medicine doctors and dentists, not specialists.10 Roughly 20% of prescribers prescribe 80% Obtained free Prescribed by of all prescription painkillers.111213 from friend one doctor 1 7.3% or relative 55%

Vol. II Page 217 Who is most at risk Where overdose deaths are the highest Understanding the groups at highest risk for overdose The drug overdose epidemic is most severe in the can help states target interventions. Research shows Southwest and Appalachian region, and rates that some groups are particularly vulnerable to vary substantially between states. The highest drug prescription painkiller overdose: overdose death rates in 2008 were found in New Mexico and West Virginia, which had rates nearly five • People who obtain multiple controlled substance times that of the state with the lowest rate, Nebraska.4 prescriptions from multiple providers—a practice known as "doctor shopping." 14,15

• People who take high daily dosages of prescription painkillers and those who misuse multiple abuse-prone prescription drugs. 15.16,17.18,19

• Low-income people and those living in rural areas.

- People on Medicaid are prescribed painkillers at twice the rate of non-Medicaid patients and are at six times the risk of prescription painkillers overdose. 20-2' One Washington State study found that 45% of people who died from prescription painkiller overdoses were Medicaid enrollees.20

• People with mental illness and those with a history of substance abuse.19

Vol. II Page 218 Drug overdose death rates by state, 2008

wj 14.7

14.1 7.6 12.3

11.7 7.2 NH 9.3

9.7 VT 10.9 7.3 10.5 8.4 MA 11.8 14.4 12.2 > Rl 17.2 CT 10.8 7.1 5.5 NJ 8 DE 14.5 10.5 13.2 MD 11.9 10.4 14.6 m 9.1 DC 9.4 8 13.1

12.9 14.8 'a 13.1 a

13.1 12.6

10.6 13.1 9.5 Age-adjusted rate per 100,000 8.6 n 5.5-9.4

•v 9.5-12.3

12.4-14.8 9.4

14.9-27.0

Vol. II Page 219 WHAT CAN WE DO? CDC RECOMMENDATIONS

There are many different points of intervention to Prescription Drug Monitoring Programs prevent prescription drug overdoses. States play Prescription Drug Monitoring Programs (PDMPs) are a central role in protecting the public health and state-run electronic databases used to track the regulating health care and the practice of the health prescribing and dispensing of controlled prescription professions. As such, states are especially critical to drugs to patients. They are designed to monitor this reversing the prescription drug overdose epidemic. information for suspected abuse or diversion—that is, the channeling of the drug into an illegal use—and The following state policies show promise in reducing can give a prescriber or pharmacist critical prescription drug abuse while ensuring patients have information regarding a patient's controlled access to safe, effective pain treatment. substance prescription history. This information can help prescribers and pharmacists identify high-risk patients who would benefit from early interventions.

CDC recommends that PDMPs focus their resources on • patients at highest risk in terms of prescription painkiller dosage, numbers of controlled substance prescriptions, and numbers of prescribers; and • prescribers who clearly deviate from accepted medical practice in terms of prescription painkiller dosage, numbers of prescriptions for controlled substances, and proportion of doctor shoppers among their patients. Thirty-six states have CDC also recommends that PDMPs link to electronic 22 operational PDMPs. health records systems so that PDMP information is better integrated into health care providers' day-to day practices. Vol. II Page 220 Patient review and restriction programs Laws to prevent prescription drug State benefits programs (like Medicaid) and workers' abuse and diversion compensation programs should consider monitoring States can enact and enforce laws to prevent doctor prescription claims information and PDMP data shopping, the operation of rogue pain clinics or "pill (where applicable) for signs of inappropriate use of mills," and other laws to reduce prescription painkiller controlled prescription drugs. For patients whose use diversion and abuse while safeguarding legitimate of multiple providers cannot be justified on medical access to pain management services. These grounds, such programs should consider reimbursing laws should also be rigorously evaluated for their claims for controlled prescription drugs from a single effectiveness. designated physician and a single designated pharmacy. This can improve the coordination of Better access to substance abuse treatment care and use of medical services, as well as ensure Effective, accessible substance abuse treatment appropriate access, for patients who are at high risk programs could reduce overdose among people for overdose. struggling with dependence and addiction. States should increase access to these important programs Health care provider accountability States should ensure that providers follow evidence- based guidelines for the safe and effective use of prescription painkillers. Swift regulatory action taken against health care providers acting outside the limits of accepted medical practice can decrease provider behaviors that contribute to prescription painkiller These recommendations are based on promising abuse, diversion, and overdose. interventions and expert opinion. Additional research is needed to understand the impact of these interventions on reducing prescription drug overdose deaths.

Vol. II Page 221 The amount of prescription painkillers sold in states varies A

* The quantity of prescription painkillers sold to pharmacies, hospitals, and doctors' offices was 4 times larger in 2010 than in 1999. Enough prescription painkillers were prescribed in 201 0 to medicate every American adult around-the-clock for one month.

Kilograms of prescription painkillers sold. rates per 10,000 people

3.7-5.9 6.0-7.2 7.3-8.4 8.5-12.6

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POLICY. sE IW! [sjij IK 5. * IMPACT \ •I® Kl=A® '

For more information on Prescription Drug Overdose, contact the Centers for Disease Control and Prevention: www.cdc.gov/injury • [email protected] • 1-800-C DC-INFO (232-4636) | TTY 1-888-232-6348 November 201 1 For references, visit: www.cdc.gov/homeandrecreationalpyfet^/n^ji^ Vol. II Pain Physician 2012; 15:S67-S116 • ISSN 1533-3159

ASIPP - Opioid Guidelines 2012

American Society of Interventional Pain Physicians (ASIPP) Guidelines for Responsible Opioid Prescribing in Chronic Non-Cancer Pain: Part 2 - Guidance

Laxmaiah Manchikanti, MD1, Salahadin Abdi, MD, PhD2, Sairam Atluri, MD3, Carl C. Balog, MD4, Ramsin M. Benyamin, MD5, Mark V. Boswell, MD, PhD6, Keith R. Brown, PharmD7, Brian M. Bruel, MD8, David A. Bryce, MD9, Patricia A. Burks, LPT'0, Allen W. Burton, MD", Aaron K. Calodney, MD12, David L. Caraway, MD13, Kimberly A. Cash, RT'4, Paul J. Christo, MD15, Kim S. Damron, RN16, Sukdeb Datta, MD", Timothy R. Deer, MD18, Sudhir Diwan, MD", Ike Eriator, MD20, Frank J.E. Falco, MD2', Bert Fellows, MA22, Stephanie Geffert, MLIS23, Christopher G. Gharibo, MD24, Scott E. Glaser, MD25, Jay S. Grider, DO, PhD26, Haroon Flameed, MD27, Mariam Hameed, MD28, Flans Hansen, MD29, Michael E. Harned, MD30, Salim M. Hayek, MD, PhD31, Standiford Helm II, MD32, Joshua A. Hirsch, MD33, Jeffrey W. Janata, PhD34, Adam M. Kaye, PharmD35, Alan D. Kaye, MD, PhD36, David S. Kloth, MD37, Dhanalakshmi Koyyalagunta, MD38, Marion Lee, MD39, Yogesh Malla, MD40, Kavita N. Manchikanti, MD41, Carla D. McManus, RN, BSN42, Vidyasagar Pampati, MSc43, Allan T. Parr, MD44, Ramarao Pasupuleti, MD45, Vikram B. Patel, MD46, Nalini Sehgal, MD47, Sanford M. Silverman, MD48, Vijay Singh, MD49, Howard S. Smith, MD50, Lee T. Snook, MD51, Daneshvari R. Solanki, MD52, Deborah H. Tracy, MD53, Ricardo Vallejo, MD, PhD54, Bradley W. Wargo, DO55

Results:

From: American Society Part 2 of the guidelines on responsible opioid prescribing provides the following recommendations for of Interventional Pain initiating and maintaining chronic opioid therapy of 90 days or longer. Physicians 1. A) Comprehensive assessment and documentation is recommended before initiating opioid therapy, including documentation of comprehensive history, general medical condition, Complete author affiliations and disclosures psychosocial history, psychiatric status, and substance use history. (Evidence: good) listed on pages S98-S100. B) Despite limited evidence for reliability and accuracy, screening for opioid use is recommended, as it will identify opioid abusers and reduce opioid abuse. (Evidence: limited) Address Correspondence: C) Prescription monitoring programs must be implemented, as they provide data on patterns of ASIPP 81 Lakeview Drive prescription usage, reduce prescription drug abuse or doctor shopping. (Evidence: good to fair) Paducah, Kentucky 42003 D) Urine drug testing (UDT) must be implemented from initiation along with subsequent E-mail: [email protected] adherence monitoring to decrease prescription drug abuse or illicit drug use when patients are in chronic pain management therapy. (Evidence: good) Disclaimer: The authors are solely responsible for 2. A) Establish appropriate physical diagnosis and psychological diagnosis if available prior to the content of this article. initiating opioid therapy. (Evidence: good) No statement in this article B) Caution must be exercised in ordering various imaging and other evaluations, interpretation should be construed as an and communication with the patient; to avoid increased fear, activity restriction, requests for official position of ASIPP. increased opioids, and maladaptive behaviors. (Evidence: good) Manuscript received: C) Stratify patients into one of the 3 risk categories - low, medium, or high risk. 06/22/2012 D) A pain management consultation, may assist non-pain physicians, if high-dose opioid therapy Accepted for publication: is utilized. (Evidence: fair) 07/02/2012 3. Essential to establish medical necessity prior to initiation or maintenance of opioid therapy. Free full manuscript: (Evidence: good) www.painphysicianjournal. 4. Establish treatment goals of opioid therapy with regard to pain relief and improvement in function. com (Evidence: good) 5. A) Long-acting opioids in high doses are recommended only in specific circumstances with severe intractable pain that is not amenable to short-acting or moderate doses of long-acting opioids, as there is no significant difference between long-acting and short-acting opioids for their effectiveness or adverse effects. (Evidence: fair) B) The relative and absolute contraindications to opioid use in chronic non-cancer pain must be evaluated including respiratory instability, acute psychiatric instability, uncontrolled suicide risk, active or history of alcohol or substance abuse, confirmed allergy to opioid agents.

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coadministration of drugs capable of inducing life-limiting drug interaction, concomitant use of benzodiazepines, active diversion of controlled substances, and concomitant use of heavy doses of central nervous system depressants. (Evidence: fair to limited) 6. A robust agreement which is followed by all parties is essential in initiating and maintaining opioid therapy as such agreements reduce overuse, misuse, abuse, and diversion. (Evidence: fair) 7. A) Once medical necessity is established, opioid therapy may be initiated with low doses and short-acting drugs with appropriate monitoring to provide effective relief and avoid side effects. (Evidence: fair for short-term effectiveness, limited for long-term effectiveness) B) Up to 40 mg of morphine equivalent is considered as low dose, 41 to 90 mg of morphine equivalent as a moderate dose, and greater than 91 mg of morphine equivalence as high dose. (Evidence: fair) C) In reference to long-acting opioids, titration must be carried out with caution and overdose and misuse must be avoided. (Evidence: good) 8. A) Methadone is recommended for use in late stages after failure of other opioid therapy and only by clinicians with specific training in the risks and uses. (Evidence: limited) B) Monitoring recommendation for methadone prescription is that an electrocardiogram should be obtained prior to initiation, at 30 days and yearly thereafter. (Evidence: fair) 9. In order to reduce prescription drug abuse and doctor shopping, adherence monitoring by UDT and PMDPs provide evidence that is essential to the identification of those patients who are non-compliant or abusing prescription drugs or illicit drugs. (Evidence: fair) 10. Constipation must be closely monitored and a bowel regimen be initiated as soon as deemed necessary. (Evidence: good) 1 1 . Chronic opioid therapy may be continued, with continuous adherence monitoring, in well-selected populations, in conjunction with or after failure of other modalities of treatments with improvement in physical and functional status and minimal adverse effects. (Evidence: fair)

Disclaimer: The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care."

Key words: Chronic pain, persistent pain, non-cancer pain, controlled substances, substance abuse, prescription drug abuse, dependency, opioids, prescription monitoring, drug testing, adherence monitoring, diversion

Pain Physician 2012; 15:S67-S116

vidence-based clinical practice guidelines for is equivalent to 7.1 kg of opioid medication per 10,000 responsible opioid prescribing in non-cancer population or enough to supply every adult American i pain are statements developed to improve the with 5 mg of hydrocodone every 6 hours for 45 days. quality of care, patient access, treatment outcomes, Sales have increased 280% for hydrocodone, 1,293% appropriateness of care, deficiency and effectiveness, for methadone, and 866% for oxycodone from 1997 to and achieve cost containment by improving the cost- 2007 (31), with the estimated number of prescriptions benefit ratio. The objectives of these guidelines are filled for opioids exceeding 256 million in the United to provide clear and concise guidelines to physicians States in 2009 (42-44). From 2006 to 201 1, hydrocodone to improve patient access and to avoid diversion and was the number one prescription in the United States abuse. Part 1 of these guidelines describes evidence (45). In 2007, based on a study by the International Nar assessment (1), whereas Part 2 of these guidelines - the cotics Control Board (46), American's, constituting 4.6% present manuscript, describes guidance for responsible of the global population, accounted for over 99% of opioid prescribing. the global consumption of hydrocodone and 83% of The global epidemic of chronic pain with its related the global consumption of oxycodone,. disability and opioid use and its related fatalities, are The explosive use of therapeutic opioids, however, the predominant issues of concern in modern medicine, is accompanied by increasing fatalities and adverse con specifically in the United States (2-40). The escalating sequences, and a lack of evidence regarding long-term use of therapeutic opioids in the United States is cor effectiveness and safety in the treatment of chronic related to an increase in the supply of opioids, from 96 non-cancer pain (46-115). Even the Institute of Medi mg of morphine equivalence per person in the United cine (IOM) report, considered a blueprint for trans States in 1997 to 710 mg per person in 2010 (34,41). This forming prevention, care, education, and research on

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chronic pain recognizes the serious problem of diver Opioid use for non-therapeutic purposes and also sion and abuse of opioid drugs and has questions about for chronic pain has increased over the years (63,66 their long-term usefulness, all the while maintaining 68,70,76-79,85,106,127-176). It has been shown that that effective pain management is a moral imperative, 90% of patients present to pain management settings a professional responsibility, and the duty of the people with prior opioid therapy, with a similar number of pa in the healing professions (4,47). Coinciding with the tients on opioids in treatment (159-174). Further, Deyo liberalization of laws governing opioid prescribing for et al (30) illustrated that approximately 61 % of patients the treatment of chronic non-cancer pain by the state with low back pain in primary care settings were on a medical boards in the late 1990s, opioid prescriptions course of opioids and that of these, 19% were long- have seen dramatic increases for non-cancer pain over term users. Multiple surveys have illustrated that the the past 2 decades (116). In addition, the introduction majority of prescriptions are from primary specialties, of new pain management standards for inpatient and followed by surgical specialties rather than pain physi outpatient medical care implemented by the Joint Com cians (42-45). As shown in Figure 1, 42% of immediate mission on Accreditation of Healthcare Organizations release opioids and 44% of long-acting opioids were (JCAHO) in 2000 (1 1 7), multiple physicians and advocacy prescribed by primary care physicians, whereas special organizations promoting increased use of opioids in the ties identified as pain management, including anes treatment of chronic non-cancer pain, the introduction thesiology and PMR, contributed to 6% of immediate of long-acting opioids with aggressive marketing by the release opioids and 23% of long-acting opioids (42-45). pharmaceutical industry, and a growing awareness of Multiple guidelines have been published with ad right to pain relief, empowered by JCAHO standards, vice for long-term opioid therapy in chronic non-cancer have fueled the explosion in opioid use, at least in the pain. Stein et al (59) assessed recently published guide United Sates (118-121). It has been alleged, however, lines, which included the guidelines by the American that these positions are largely based on poor science Pain Society (APS)-American Academy of Pain Medicine and misinformation in relation to the safety and effec (AAPM) guidelines (50), British Pain Society's guidelines tiveness of opioids when prescribed by a physician and (52), Canadian National Opioid Use Guideline Group taken appropriately (51,60,62-65,1 18-132). (NOUGG) (54), German guidelines (49), and guidelines

Immediate Release Opioids Long Acting Opioids

36.9% 22.9% All Others All Others

"Vcy^ftN J\ 23.1% 7.4% - Orthopedic Anesthesiology/ 9q Surgery PM&R

s./p 42.1% 43.8% Primary Care Primary Care

Fig. 1. Tola! number of prescriptions dispensed in the U.S. by various specialties for IH and EK/LA opioids in 2009

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by the American Society of Interventional Pain Physi 5 clusters. Cluster 1 dealt with deciding to initiate opioid cians (55). It should be noted that this document serves, therapy with comprehensive assessment, addiction-risk in part, to update the American Society of Intervention screening, urine drug screening, opioid efficacy, risks, al Pain Physicians' guidelines. Sorgatz and Maier (57) adverse effects, complications, and ta summarized that the 5 guidelines impact assessment of pering. Cluster 2 dealt with conducting an opioid trial opioids in chronic non-cancer pain only in diction. They with titration and driving, stepped opioid selection, op stated the following: timal dose, watchful dose, and opioid misuse. Cluster 3 APS-AAPM: "Although evidence is limited, an described monitoring of long-term opioid therapy with expert panel (...) concludes that chronic opioid monitoring, switching or discontinuing opioids, impact therapy can be an effective therapy for carefully on driving, revisiting opioid trial steps, and collabora selected and monitored patients with chronic non- tive care. Cluster 4 described treating specific popu cancer pain. However, opioids are also associated lations with long-term opioid therapy including the with potentially serious harms (...) "(50). elderly, adolescents, pregnant patients, and patients The British Pain Society guidelines state "There is suffering with comorbid psychiatric conditions. Finally, evidence from clinical trials that opioids can be ef Cluster 5 described managing opioid misuse and ad fective in the short and medium term (...) However, diction with addiction treatment options, prescription the safety and efficacy of opioids in the long-term fraud, unacceptable patient behavior, and acute care is uncertain (...)" (52). opioid prescribing policies. The guidelines by American Society of Interven The British Pain Society's Opioids for Persistent Pain tional Pain Physicians state: "Opioids are commonly (52) described the pharmacology of opioids, necessity prescribed for chronic non-cancer pain and may be to prescribe opioids, adverse effects of opioid therapy, effective for short-term pain relief. However, long- practical aspects of prescribing, non-medical prescrip term effectiveness of 6 months or longer is variable tions of opioids, and opioids and problem drug use. ..." (55). Hughes et al (177) also performed a systematic re The Canadian guidelines National Opioid Use view of treatment guidelines, published in 2011. They Guideline Group (NOUGG) state that "opioids included 6 clinical guidelines meeting inclusion criteria showed only small to moderate benefits for no with one duplicate (50,54,55, 58, 178-180).Three of the ciceptive (...) neuropathic (...) improving function guidelines, including Canadian guidelines and APS- and relieving pain" (58). AAPM guidelines were included by Stein et al (59), whereas 3 other guidelines were not included by Stein In APS-AAPM guidelines for the use of chronic et al (178-180). Hughes et al (177) concluded that since opioid therapy in chronic non-cancer pain (50,51), de evidence supporting efficacy for the use of opioids as spite scant evidence, the expert panel concluded that treatment for chronic non-cancer pain was limited, opi chronic opioid therapy could be effective therapy for oids for chronic non-cancer pain should be reserved for carefully selected and monitored patients with chronic select patients with moderate or severe pain that sig non-cancer pain. They provided recommendations and nificantly affects function or quality of life. They also guidance on patient selection and risk stratification; concluded that continuation of opioid therapy is indi informed consent and opioid management plans, ini cated if documentation supports the opioid results in tiation and titration of chronic opioid therapy, use of improvement in those limitations. Furthermore, their methadone, monitoring of patients on chronic opioid recommendations included a comprehensive pre-treat- therapy, dose escalations, high-dose therapy, opioid ro ment assessment, identification of contraindications, tation, and indications for discontinuation of therapy, obtaining informed consent, establishing a written prevention and management of opioid-related adverse treatment plan with goals and objectives, using an opi effects, driving and work safety, identifying a medical oid treatment agreement, obtaining specialist referral home and when to obtain consultation, management when indicated, and establishing a follow-up plan that of breakthrough pain, chronic opioid therapy in preg includes monitoring for adverse effects, titration and nancy and opioid-related policies. rotation of medication, prescription use monitoring, use Canadian Guidelines (54) for Safe and Effective Use of drug screening, and thorough record keeping which of Opioids for Chronic Non-Cancer Pain have analyzed includes documentation of functional improvement. the evidence and have provided recommendations with However, the Interagency Guideline on Opioid

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Dosing for Chronic Non-Cancer Pain (53), also provided junction with interventional techniques (182). It has guidance sponsored by the Washington State Agency also been shown that interventional techniques may Medical Directors Group (AMDG). This guideline is pro reduce psychological distress and improve functional vided in 2 parts: Part 1 included guidance for initiation, status (183-201). More likely than not, the requirement transition, and maintenance of oral opioids for chronic for opioids and adjuvant drugs may be reduced or at non-cancer pain, and Part 2 describes guidance for op least become stable. Hence, interventional pain physi timizing treatment and when opioid doses are greater cians probably should not compare patients in their set than 120 mg morphine equivalence per day. tings undergoing interventional techniques with others Thus, in order to curtail opioid abuse but at the receiving drug therapy as mainstay treatment. Mono same time provide appropriate treatment for pain pa therapy, particularly with opioids, may be appropriate tients, the focus must be on misuse, abuse, and diver for only a small subgroup of those with chronic pain. sion, and should be addressed in 4 fronts: education, Additionally, in interventional pain management, the establishing medical necessity, supply, and drugs. These majority of the patients are presented on opioid ther guidelines have been prepared with these aspects as apy and it is well understood that once patients are on the primary focus and with consideration of up-to-date opioids, they will not be weaned off of them regardless literature, with special attention being given to the ef of reported improvements in pain relief and functional fectiveness of opioids in long-term therapy in conjunc status. tion with adverse consequences. Chronic opioid thera The concept of "universal precautions," first seen py has been defined as daily or near-daily use of opioids in medicine with the explosion of HIV and hepatitis for at least 90 days, often indefinitely (50). tainted blood, was introduced to counter the miscon In fact. Franklin et al (181) showed that this guid ception that a provider would be able to predict "by ance is effective in bending prescription opioid dosing looking" who might have a communicable blood-borne and reducing mortality. In this study, Franklin et al (181) disease. This led to the use of "precautions" (gloves, showed a substantial decline in both the morphine etc.) for all patients, regardless of their age or socio equivalent dose per day of long-acting Schedule II opi economic class. A rational approach to the treatment oids by 27% and the proportion of workers on doses of chronic pain with opioids has been described using a equal to or greater than 120 mg per day of morphine pain and addiction continuum and a substance use as equivalent dosage by 35%, compared prior to 2007. sessment in a pain patient leading to the implementa Further, there was also a 50% decrease from 2009 to tion of "universal precautions" in pain medicine (202). 2010 in the number of deaths. The current guidelines manuscript focuses on re Opioid prescribing may be different for different sponsible chronic opioid therapy, chronic opioid pre specialities and settings based on the speciality and scribing of 90 days or longer in chronic non-cancer training. Consequently, additional modalities may be pain, in order to improve quality of care, patient access, utilized instead of high dose opioid therapy, leading treatment outcomes, appropriateness of care, efficiency to low or moderate dose opioid therapy and avoid and effectiveness and achieve cost containment by im ing multiple complications (182). These include various proving the cost-benefit ratio. The objectives of these techniques of rehabilitation with therapeutic exer guidelines are to provide clear and concise guidelines cise programs, physical therapy, occupational therapy; to physicians, to improve patient access and to avoid cognitive behavioral therapy with psychological in diversion and abuse. Consequently, these guidelines terventions, surgical interventions, or interventional are developed to be used by physicians practicing in techniques. terventional pain management/pain medicine or other In interventional pain management, patients may specialists involved in chronic opioid therapy. Thus, the receive not only opioid analgesics, but also other con focus of these guidelines and also for physicians deal trolled or non-controlled drugs, to manage comorbid ing with chronic opioid therapy should be to curtail psychiatric and psychological disorders. Consequently, the abuse of opioids without jeopardizing non-cancer the effectiveness studies of opioids published thus far pain management. These guidelines only recommend may not apply in the majority of interventional pain proper use and do not recommend total elimination management patients. Indeed, in an interventional of opioids in managing chronic pain. Various principles pain practice, controlled substances may be prescribed of opioid use with appropriate evidence-based recom at lower doses, particularly opioid analgesics, in con mendations are illustrated in Figure 2 showing guid-

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ance to opioid therapy. Since evidence supporting the should be reserved for select patients with moderate or efficacy for use of opioids as treatment of chronic non- severe pain that significantly affects function or quality cancer pain is limited and based on short-term studies, of life. In addition, continuation of opioid therapy is in long-term opioid therapy for chronic non-cancer pain dicated if documentation supports the opioid results in

Patients with Chronic Non-Cancer Pain

INITIAL STEPS • Comprehensive assessment • Assessment of risk of misuse • Screening tests (optional) • Inquiry of prescription monitoring programs • Baseline urine drug testing

MEDICAL NECESSITY DIAGNOSIS • Physical diagnosis TREATMENT GOALS • X-rays, MRI, CT, neurophysiology studies • Non-controllcd substance therapy • Decrease pain by 30% and/or • Psychological evaluation (basic) • Physical modalities increase function by 30% • Precision diagnostic interventions • Behavioral interventions (optional) • Minimal adverse effects (optional) • Interventional pain management (optional) • Consultation(s) as needed • Other alternatives • Consultation(s) as needed I • Assess effectiveness of opioid therapy

INFORMED INITIAL TREATMENT ADHERENCE MONITORING SIDE EFFECTS DECISION-MAKING (8-12 WEEKS) • Prescription drug monitoring • Driving • Sedation • Controlled substance • Stratification of risk programs agreement • Understanding opioids • Urine drug testing (follow urine • Constipation • Random evaluations • Initiation with low dose short-acting drug testing algorithm) • Breathing including pill counts and opioid therapy • Pill counts urine drug testing • Titrate • Behavioral assessment during each visit

DISCONTINUE • Persistent or new pain CONTINUE • Abuse, misuse • Analgesia of 30% and/or activity increase by 30% • Lack of analgesia • No misuse, abuse, adverse effects, manageable • Lack of activity • Adverse effects • Aberrant behavior

• Taper and discontinue • Continue monitoring • Repeat comprehensive evaluation • Wean, discharge, or maintain • Consider consultation

Fig. 2. Guidance to opioid therapy.

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improvement in pain and function. If opioid therapy is tivities of daily living, work, play, and socialization. indicated, for initiation or continuation, recommenda Assessment may be performed utilizing the Oswes tions in this document may be followed. try Disability Index, Neck Disability Index, or another

measure. 1.0 Initial Steps of Opioid Therapy

Before the initiation of opioid therapy it is essential 1.1.5 Sleep Patterns that comprehensive assessment and documentation of Sleeping is an important function, specifically in the patient's physical condition, general medical condi patients with generalized pain problems such as fibro tion, psychological history, psychiatric status, substance myalgia and with the elderly. use and abuse history of the patient and family be ob tained (50,52,53,55,58,177-180). 1.1.6 Psychological Evaluation Psychological evaluation may be performed with 1.1 Comprehensive Assessment a simple evaluation for depression, anxiety, and so matization. Patients with major personality disorders 1.1.1 Pain Condition need further evaluation and appropriate consultations A thorough history and physical examination must (203-206). be documented to determine the type, cause, and nature Psychiatric status includes information regarding of the pain, including questions about past investigations the patient's current and past history of psychiatric dis and interventions for pain. This history also should include orders and treatments and family history of psychiatric medication trials and the pain intensity and the functional disorders. impairment that arises from it (i.e., impact of pain on ac tivities of daily living, work, and other aspects of life). In 1.1.7 Substance Use History addition, various circumstances which increase or exacer Substance use history includes multiple questions bate the pain and conditions which lead to diminution of in reference to current, past, and family history of sub pain must be documented (203-206). A physical diagno stance use, abuse, and addiction to alcohol, tobacco, sis must be established prior to initiating opioid therapy. prescription drugs, street drugs, illicit drugs, over-the- The diagnosis should not be non-specific such as low back counter medications, solvents, etc. Furthermore, history pain, knee pain etc., but should be objective and some in reference to attendance at a treatment program for what specific based on the type of pain and abnormali addiction or treatment in an outpatient office detoxifi ties identified. This will assist in future treatments based cation etc., must be documented (203-206). on whether the pain is nociceptive, neuropathic, somatic, radicular, widespread, or localized. 1. 1.8 Addiction Risk Screening Before initiating opioid therapy, a physician may 1.1.2 General Medical History consider using a screening tool to determine the pa General medical history includes questions about tient's risk for opioid addiction. This evaluation is part general physical health, emotional health, and medi of the comprehensive assessment. Comprehensive his cation usage (203-206). Chronic pain patients tend to tory also includes a thorough review of the patient's al have multiple medical comorbid conditions which may cohol and other substance use. The history is important increase the pain levels or may interact with multiple in assessing the patients risk for opioid misuse or addic other drugs. tion. Various screening tools may help with the deter mination. Most of the screening tools have not been 1. 1.3 Psychosocial History studied in depth, validated, or been compared to each Psychosocial history includes information regard other. Thus, the evidence is poor as to their reliability ing their upbringing, family and social support, family (1,40,77-79,207-214). obligations, work status, use of alcohol, smoking, and living arrangements. 1.1.9 Prescription Monitoring Programs Before initiating therapy, a physician must obtain 1.1.4 Functional Status data from the prescription monitoring program. If a A history of the functional status of a patient in prescription monitoring program is not available, the cludes information about their ability to perform ac- physician must request information from all previous

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physicians as well as pharmacies a patient uses or has 1.1.10 Urine Drug Screening used. While the evidence shows a general lack of re In initiating and maintaining chronic opioid thera liability and accuracy for the multiple screening tools py, urine drug testing (UDT) must be used to establish for opioid abuse, there is good evidence that prescrip a baseline measure of risk or to monitor compliance tion monitoring programs provide data on patterns of (40,51,54,149,172,173,207-213,225-234). However, it is prescription usage, and fair evidence that prescription essential to understand pharmacology, pharmacody drug monitoring programs (PDMPs) can reduce pre namics, drug interactions, and to have knowledge of scription drug abuse or doctor shopping (1). However, interpretation and a plan in place to use the results, the evidence that PDMPs reduce emergency room visits, without financial considerations as the driving force drug overdoses, or deaths is poor. PDMPs collect state (235-239). wide data about prescription drugs and track their flow UDT has been described in Part I and other manu (213,215-224). There are 3 components of these pro scripts (40,53,54,225-231,237-240). Various details of in grams. The first component involves collecting data for terpretation of UDT are shown in Tables 1-3. prescriptions, documenting the physicians who wrote Physicians face multiple issues when utilizing UDT. them and the pharmacies that dispensed them. With In particular, the implication that the physician does the enactment of the National All Schedules Electronic not trust his or her patient. Information gained from Reporting (NASPER) Act, physicians will have access to UDT is limited regarding whether a patient is taking a database that has the capacity to monitor all transac the dosages prescribed, or if they are a high metab- tions. In fact, some states are already mandating such olizer. UDT can reveal whether they are taking illicit use of prescription monitoring programs (221). To date, substances. in the United States 38 states have functioning PDMPs, Drug screening should not imply that a physician with 48 states with legislation passed (224), but there does not trust the patients or that patients are not is a significant difference in the manner and frequency trustworthy. The literature, however, shows that with which the data is collected. self-reporting of drug use and behavioral monitor-

Table 1. Urine drug testing: Typical screening and confirmation cut-off concentrations and detection times for drugs oj abuse.

Screening cut-off Confirmation cut Immunoassay (I) Drug concentrations ng/mL off concentrations Urine detection time Chromatography (C) urine ng/mL

Hydrocodone 300 50 1-2 days I&C

Oxycodone 100 50 1-3 days I&C

Morphine 300 50 3-4 days I&C

Methadone 300 100 5-10 days I&C

Hydromorphone 300 100 1-2 days l&C

Meperidine 300 100 1-2 days I&C

Codeine 300 50 1-3 days I&C

Benzodiazepines 200 20-50 Up to 30 days 1

Barbiturates 200 100 2- 10 days I&C

1-3 days for casual use; up to Marijuana 50 15 I&C 1 1 weeks for chronic use

Cocaine 300 50 1-3 days I&C

Amphetamine 1,000 100 2-4 days I&C

Methamphetamine 1,000 100 2-4 days I&C

Heroin* 10 25 1 -3 days I&C

Phencydidine 25 10 2-8 days I&C

"6-MAM, the specific metabolite is detected only for 6 hours.

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Table 2. Drug cross-reactants.

Drug Group Cross Reactivity Based on Product Insert Cross Reactivity Based on Potential Cross-Reaction

Cannabinoids Dronabinol (Marinol) NSAIDs (Sustiva) Hemp Seed Oil ( seed) Pantoprazole (Protonix) Nexium Prilosec

Opioids 6-Acctylmorphine Fluoroquinolones Ethyl morphine Ofloxacin (Floxin) Oxymorphone Papaverine Oxycodone Poppy Seeds Methadone Rifampicin & Rifampin (Rimactane, Rifadin, Rofact) Dextromethorphan Levofloxacin (Levaquin)

Amphetamines Dextroamphetamine + amphetamine (Adderall) Ephedrine Methylphenidate Bupropion Dcsipramine Amantadine Ranitidine Phenylpropanolam ine Vicks Vapor Spray Phentcrmine (Adipex/Obcnix/Oby-Trim) Pseudoephcdrinc

Methamphetamine d-Methamphetamine Bupropion (Wellbutrin & Zyban) d- Amphetamine Chloroquine (Aralen) Chloroquine (Aralen) (Thorazine, I.argactil) Desoxyephedrine Desipramine (Norpramin) MDMA (Ecstasy) Dextroamphetamine (Dexedrine) Methamphetamine (Desoxyn) Ephedrine (Ephedra and Ma Huang) Fenfluramine (Fen Phen) I.abetalol (I.abetalol) Mexiletine (Mexitil) n-acetyl procainamide (Procainamide) Phenylephrine (Neo-synephrine) Propranolol (Inderal) Pseudoephedrine (Claritin-D) Quinacrine (Atabrine, Mepacrine) Ranitidine (Zantac) Selegiline (Selegiline) Trazodone (Desyrel, Desyrel Dividose) Tyramine (Tyramine)

PCP None Chlorpromazine Meperidine Dextromethorphan (Benadryl) (Mellaril) Venlafaxine (Effexor)

Benzodiazepine (Tenix) Oxaprozin (Daypro) (Mystan) Sertraline (Zoloft) (ProSom) Some herbal agents

Cocaine Benzoylecgonine TAC Solution (TAC Solution) Ecgonine Ecgonine Methyl Ester

ETOFI None Asthma inhalers (sometimes)

Methadone None Propoxyphene Seroquel

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Table 2 (cont.). Drug cross-reactants.

Drug Group Cross Reactivity Based on Product Insert Cross Reactivity Based oil Potential Cross- Reaction

Barbiturates (Dilantin) (Mysoline)

Oxycodone Hydrocodone Hydromorphone (Dilaudid) Oxymorphone (Numorphan) Codeine (Codeine)

Source: DrugCheck* Cross Reactivity Chart (wivw.drugcheck.com/_images/DC145_Cross-Reactivity_chart.pdf)

Table 3. Interpreting unexpected results of urine drug screens.

Unexpected Result Possible Explanations Actions lor the Physician

1 UDS negative for • False negative. • Repeat test using chromatography; specify the drug of interest prescribed opioid. • Non-compliance. (e.g. oxycodone often missed by immunoassay). • Diversion. • Take a detailed history of the patients medication use for the preceding 7 days (e.g., could learn that patient ran out several days prior to test). • Ask patient if they've given the drug to others. • Monitor compliance with pill counts.

2 UDS positive for non- • False positive. • Repeat UDS regularly. prescribed opioid or • Patient acquired opioids from other • Ask the patient if they accessed opioids from other sources. benzodiazepines. sources (double doctoring, "street"). • Assess for opioid misuse/addiction. • Review/revise treatment agreement.

3 UDS positive for illicit • False positive. • Repeat UDS regularly. drugs (e.g., cocaine, • Patient is occasional user or addicted to the • Assess for abuse/addiction and refer for addiction treatment cannabis). illicit drug. as appropriate. • Cannabis is positive for patients taking • Ask about medical prescription of dronabinol, THC:CBD or dronabinol (Marinol"), THOCBD (Sativex") medical marijuana access program. or using medical marijuana.

4 Urine creatinine is • Patient added water to sample. • Repeat UDS. lower than 2-3 mmol/ • Consider supervised collection or temperature testing. liter. • Take a detailed history of the patient's medication use for the preceding 7 days. • Review/revise treatment agreement.

5 Urine sample is cold. • Delay in handling sample (urine cools • Repeat UDS, consider supervised collection or temperature within minutes). testing. • Patient added water to sample. • Take a detailed history of the patient's medication use for the preceding 7 days. • Review/revise treatment agreement.

UDS=urine drug screen; TFIC=Tetrahydrocannabinol; CBD=

Source: Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain© 2010 National Opioid Use Guideline Group (NOUGG) (54).

ing fail to detect problems with drug misuse and opioid therapy. The UDT not only provides adher abuse (53). Creating a UDT policy that is applicable ence monitoring, but it is also a monitoring tool for universally and consistently with all patients as safety. sists to "de-stigmatize" UDT and can potentially As it is very difficult to correlate urine drug concen convince patients that it has nothing to do with an tration with a patient's dose, it is not feasible for individual patient or their trustworthiness (53,54). the physician to ascertain whether or not a patient Consequently, the practice can explain to patients has taken the dose of opioid appropriately using that drug testing is a routine procedure for all pa UDT. UDT can, however, detect the parent drug tients starting or maintained on opioid therapy and and/or its metabolites and demonstrate recent use it is an important tool for monitoring the safety of of prescribed drugs and illegal substances. UDT will

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not detect the amount of medication taken, when sue, the Drug Enforcement Administration (DEA) it was taken or identify the source of the drug. currently classifies it as a Schedule I drug. For that Some patients state that the expected drug is not reason, many providers do not prescribe opioids to found in the urine because they are high metab- patients using marijuana or give them one opportu olizers. They may state that they are on diuretics nity to stop using them. Other providers reference and are drinking fluids to lose weight or on diet state "medical marijuana" laws (http://apps.leg. pills, and since they have so much fat, it cannot wa.gov/RCW/default.aspx?cite=69.51A&full=true) be detected. Most of the explanations are untrue, (53) and feel comfortable prescribing opioids to however, as only a small percentage of persons are marijuana users. Some providers adopt a "don't considered ultra rapid metabolizers and may me ask, don't tell" policy, whereas others request the tabolize specific drugs more rapidly than typical lab to remove marijuana from the UDT so that patients (53). It would be rare for someone to take positive results are not seen. While this may be a an opioid as prescribed and have a negative UDT. risky practice, physicians should create their office Moreover, diuretics, water intake, and excessive fat policies and disclose them to patients. These poli do not influence urine drug concentrations to an cies, should, of course, follow all state and federal extent that one cannot influence urine drug con regulations apart from policies addressing personal centrations. It is also crucial that the testing meth ethics and beliefs. odology used to identify the specific medication of interest have a low cut-off threshold. When pos 1.2 Recommendations sible, "no threshold" should be requested. 1. Comprehensive assessment and documentation is recommended before initiating opioid therapy, in There is a misconception that short-acting opioids are cluding documentation of comprehensive history, not detected in the urine. In fact, most opioids are general medical condition, psychosocial history, detectable in the body from one to 2 days. Short- psychiatric status, and substance use history. (Evi acting opioids can be detected with no threshold dence: good) testing. 2. Despite limited evidence for reliability and accu Confirmation of the results is a major issue. Propo racy, screening for opioid use is recommended, as nents argue that each and every specimen must be it will identify opioid abusers and reduce opioid sent to the lab and confirmed for a myriad of drugs; abuse. (Evidence: limited) while others state that immunoassay testing is reli 3. Prescription monitoring programs must be imple able and that confirmation should only be request mented due to regulations, as they provide data on ed if there are questions with reference to results patterns of prescription usage, reduce prescription and patient history. If a patient admits that they drug abuse or doctor shopping, and PDMPs may have used a licit or illicit drug other than the pre reduce emergency room visits, drug overdoses, or scriptions and if that drug is testing positive, there deaths. (Evidence: good to fair) is no need to confirm this with laboratory testing. 4. UDT must be implemented from initiation along If, however, the patient denies any such use, it is with subsequent adherence monitoring, in an in- essential that the result is confirmed through labo office setting with immunoassay and confirmation ratory testing with LC/MS/MS. There is a significant for accuracy with chromatography in select cases, correlation between immunoassay and chromatog to identify patients who are non-compliant or raphy for a majority of drugs (172,173). However, abusing prescription drugs or illicit drugs, and UDT on occasion, it should be noted that even confir may decrease prescription drug abuse or illicit drug matory testing requires expert assistance for inter use when patients are in chronic pain management pretation (53). Most importantly with confirmation therapy. (Evidence: good) testing, while noting that financial incentives are 2.Q Establishing Diagnosis put aside, understanding the pharmacology and metabolism of the drugs is essential. Diagnosis may be established by various means Some of the most common questions arise when including physical examination, x-rays, magnetic reso dealing with marijuana. While for many people nance imaging (MRI), computed tomography (CT), and marijuana is a highly controversial and complex is- neurophysiologic studies. Furthermore, psychological

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evaluations and precision diagnostic interventions may cations and those whose living arrangements create a also be applied. Diagnostic interventional techniques risk for medication misuse or diversion. The manage will assist in making the proper diagnosis by follow ment of patients with a history of substance abuse or ing an algorithmic approach. Research shows that in with a coexisting psychiatric disorder may require ex approximately 70% to 85% of patients with spinal tra care, monitoring, documentation, and consultation pain, an accurate diagnosis may not be provided even with, or referral to, an addictionologist. The lack of with the available history, physical examination, elec well-trained psychologists and psychiatrists in chronic tromyographic (EMG)/nerve conduction studies, and pain management in many regions of the country may radiologic evaluation (179,240-269). With precise di make this referral difficult to obtain. Likewise, in many agnostic interventional techniques, the chances of an locations there are no clinically trained addiction spe accurate diagnosis may be improved substantially, and cialists with whom to collaborate. proper treatment may be offered (270-273). Once the Interagency guidelines on opioid dosing for diagnosis is established, various modalities of therapy chronic non-cancer pain (53) have proven to be effec may be offered with interventional techniques or other tive in reducing opioid usage and deaths, and include techniques. Whatever opioids are required will be pre thresholds for pain consultation. The hallmark of this scribed in low doses or eliminated. guideline (53) is a recommendation not to prescribe Given the degree to which routine imaging has more than an average daily morphine equivalent dose been criticized, it may be appropriate that physicians of 120 mg without either the patient demonstrating follow the recommendations provided by professional improvement in function and pain or first obtaining a organizations and governmental organizations. In or consultation from a pain management expert. This con dering various investigations, being conservative may cept was based on the results of a study by Dunn et al be prudent, along with their interpretation, due to (135), which showed that patients receiving 100 mg or findings in asymptomatic patients and also the psycho more per day morphine equivalent doses had a 9-fold logical factors and nocebo effect introduced in these increase in overdose risk with 12% fatal overdoses and patients with graphic description of asymptomatic ab most overdoses being medically serious. Furthermore, normalities (252-292). Guidelines provided by specialty high-dose opioid therapy can be ineffective and/or un societies are appropriate if they were peer-reviewed safe (53). Higher strength opioids may be associated and developed utilizing guidance from IOM criteria. with poorer functional outcomes and adverse conse Early imaging is discouraged in all circles. It is also cru quences (26,32,33,90, 1 35,293-296). cial to realize that numerous abnormalities are gener ally found on imaging in asymptomatic subjects (262 2.2 Recommendations 292). In the era of information disclosure and electronic 1. Establish appropriate physical diagnosis and psy media, findings which do not correlate with symptoms chological diagnosis if available prior to initiating and do not provide certainty as a pathological entity opioid therapy. (Evidence: good) should be addressed by qualified physicians, not by 2. Caution must be exercised in ordering various im technologists and radiologists, without any clinical cor aging and other evaluations, and only appropriate relation. Irrelevant and non-corroborative findings cre information in the realm of clinical relevance shall ate fear and activity avoidance, resulting in negative be provided by the treating physician to the pa consequences including requests for increased opioid tients when there is correlation of the symptoms dosages. with findings; to avoid increased fear, activity re The role of neurophysiologic testing is limited in striction, requests for increased opioids, and mal chronic pain management, even though some insurers adaptive behaviors. (Evidence: good) mistakenly focus on the neurophysiologic evaluation 3. A pain management consultation, for non-pain and findings (252-256,275). physicians, if high-dose opioid therapy is being uti lized. (Evidence: fair) 2.1 Consultation(s) 3.0 Establishing Medical Necessity Physicians should be willing to refer a patient as clinically indicated for additional evaluation to achieve To establish medical necessity for opioid therapy, it treatment objectives. Special attention should be given is essential to have a physical diagnosis and information to those patients who are at risk of misusing their medi- of multiple modalities of treatments available including

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conservative, various other alternatives, and consulta clinically significant and/or functional status improve tions if necessary. These include non-controlled sub ment of 30% or more. For interventional techniques, stance therapy, physical modalities, behavioral inter significant improvement has been defined as 50% re ventions, interventional pain management techniques, duction in pain scores and disability scores for evalua and any other alternatives. tion purposes. Medical necessity is established only when the fol Before starting opioids, physicians should insure lowing criteria are met: pain of moderate to severe that the patient's expectations are realistic. The goal degree; suspected organic problem; documented fail of opioid therapy for chronic non-cancer pain is rarely ure to respond to non-controlled substance, adjuvant the elimination of pain, but rather an improvement agents, physician ordered physical therapy, structured in function or a reduction of pain intensity by at least exercise program; and interventional techniques, spe 30%. Before starting opioids, a discussion with the pa cifically for long-term high-dose therapy. tient about specific goals related to pain reduction and Opioids may be used as a second-line treatment. functional improvement should address any unrealistic For non-opioid controlled substance, appropriate docu expectations. These goals, once established should be mentation of psychological status must be documented. documented in the patient's record; they are critical in Continued medical necessity depends on the fol determining that opioids are effective and should be lowing 4 "A's": monitored over time (54). • Analgesia • Activity 4.1 Recommendations • Aberrant behavior It is essential to establish treatment goals of opioid • Adverse effects therapy with regard to pain relief and improvement in function. (Evidence: good) Behavioral interventions, interventional pain man 5.0 Assessment Of Effectiveness Of agement, various other alternatives, and consultations Opioid Therapy as needed must be obtained. The effectiveness of various types of opioids must 3.1 Recommendations be clearly defined. The evidence for various types of It is essential to establish medical necessity prior to opioids is described as follows. initiation or maintenance of opioid therapy. (Evidence: 1. Nociceptive pain — Opioids showed only small to good) moderate benefits for nociceptive pain for improv ing function and relieving pain on a short-term basis 4.Q Establishing Treatment Goals of 3 months or less. If opioids are required, patients It is essential to establish treatment goals. Treat generally respond to moderate doses after failure ment goals should combine pain relief with improve of alternative techniques and non-opioid manage ment in activity and minimal or no adverse effects. To ment (1 ,49-58,62,68,73,76,90,9 1 , 1 32,302-3 1 6). achieve the treatment goals, outcomes assessment is 2. Neuropathic pain — Opioids showed only small essential. Outcomes may be assessed by numeric rating to moderate benefits for neuropathic pain (1,49 scale pain (0-10 scale), functional assessment using the 58,73,90,132,303,317-319). However, it is the gen Oswestry Disability Index (0-50 scale). Neck Disability eral belief that opioids are resistant in neuropathic Index (0-50 scale), employment status, and/or improve pain and these patients may require higher opioid ment in activity status. The minimum amount of change doses in combination with tricyclic in pain score in order to be clinically meaningful has or . been described as a 2-point change on a scale of 0 to 3. Widespread soft tissue pain — The benefit of the 10 (or 20 percentage points), based on findings in trials weak opioid tramadol for fibromyalgia was small. which have been commonly utilized studying general Other pain-relief options should be considered (54). chronic pain (297), chronic musculoskeletal pain (298), 4. Headache and other problems — Opioids are not and chronic low back pain (297-302). Consequently, usually indicated for migraine or tension head for guideline purposes, it would be appropriate to use aches, or for patients with functional gastrointes clinically meaningful pain relief of at least 30% and/or tinal problems (316). a 3-point change on an 11-point scale of 0-10, or as Multiple manuscripts, systematic and compre-

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hensive reviews, and guidelines have been published concomitant use of benzodiazepines, active diver evaluating the effectiveness and safety of opioids sion of controlled substances, and concomitant use (1,49-58,62,68,73,76,90,91,132,302-319). With extensive of heavy doses of central nervous system depres review as shown in Part 1 (1), it was concluded that the sants, such as benzodiazepines. (Evidence: fair to short-term effectiveness of opioids is fair, whereas long- limited) term effectiveness of opioids is limited or poor. There is 6.Q Informed Decision-Making also fair evidence for lack of significant difference in ef fectiveness or adverse effects between long-acting and Informed decision-making with appropriate con short-acting opioids. The evidence for improvement in sent is not only essential but mandatory. A discussion quality of life parameters is fair for short-term and poor about potential benefits, adverse effects, complica for long-term. There is no published evidence for opi tions, and risks helps the physician and patient make oid rotation. a joint decision on whether to proceed with the opioid An evaluation of individual drugs also showed vari therapy (54). There have been substantial descriptions able evidence with lack of available evidence for hy- in reference to informed consent and treatment agree drocodone, fair for short-term, and poor for long-term ments and their effectiveness (1,320-327). for oxycodone, morphine, and fentanyl. The evidence The following must be explained to patients and for tramadol is fair in osteoarthritis. The evidence for understood by patients before starting on opioids: methadone, oxymorphone, hydromorphone, tapent- 1) Opioids are used to improve the ability to be active adol, codeine, and buprenorphine is limited for either and reduce pain, if appropriate criteria are met, in short-term or long-term improvement. conjunction with or without various other modali An evaluation of the effectiveness, adverse effects, ties of treatments including cognitive behavioral and indications in special populations showed the evi therapy, behavior modification, therapeutic exer dence is fair for short-term and poor for long-term in cise program, increased activity, positive attitudes, the elderly, poor in children, adolescents, and in pa physical therapy, psychotherapy, other drug thera tients with generalized anxiety disorder, depression, py, or interventional techniques. and high risk psychological disorders such as personal 2) Opioids may help on a short-term basis, but they ity disorders. have substantial risks. 3) Common side effects include nausea (28%), consti 5.1 Recommendations pation (26%), drowsiness (24%), dizziness (18%), 1. Clinicians must understand the effectiveness and dry-skin/itching (15%), and vomiting (15%) (54). adverse consequences of long-term opioid therapy However, these side effects can be minimized by in chronic non-cancer pain and its limitations. (Evi slowly increasing the dose of the drug and starting dence: fair for short-term, limited for long-term) a bowel regimen to manage constipation which 2. The long-acting opioids in high doses are recom may be the most long-lasting side effect of all. mended only in specific circumstances with severe More serious complications include the effect on intractable pain that is not amenable to short-act driving, respiratory depression, drug dependen ing or moderate doses of long-acting opioids, as cy, drug addiction, hormonal deficiency, fatigue, there is no significant difference between long-act weakness, impotency, sexual dysfunction, etc., ing and short-acting opioids for their effectiveness overdose, and death. Patients and physicians must or adverse effects. (Evidence: fair) take these complications and adverse consequenc 3. A trial of opioid rotation may be considered for es very seriously. Managing side effects through patients requiring escalating doses. (Evidence: polypharmacy and the combination of various sed limited) ative may not be useful. 4. It is recommended that contraindications to opioid 4) The development of tolerance, dependency, ad use in chronic non-cancer pain must be evaluated diction, and hyperalgesia are a major concern. Al including respiratory instability, acute psychiatric though the majority of patients believe that they instability, uncontrolled suicide risk, active or his can not develop addiction, many patients believe tory of alcohol or substance abuse, confirmed al they develop tolerance and request higher doses lergy to opioid agents, coadministration of drugs believing that they are entitled for increase in capable of inducing life-limiting drug interaction. doses and frequency with continued pain manage-

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ment. However, physicians must educate patients often includes clear descriptions of medication use and on common aspects of addiction, hyperalgesia, abuse, as well as the consequences for violating the and medication adjustment with emphasis on low contract, which are as follows: dose or no opioid therapy and multidisciplinary 1) One prescribing doctor and one designated

management. pharmacy 5) Abrupt stoppage of medication results in with 2) Urine/serum drug screening when requested drawal states. Opioids overdoses are common, 3) No early refills and no medications called in often resulting in various morbidities including 4) If medications are lost or stolen, then a police re death. Mixing opioids with alcohol or port could be required before considering addi drugs, such as antianxiety drugs and sleeping medi tional prescriptions. cations increase the risk of overdose significantly. Patients must understand the signs of overdosage. Additional items to be included in an agreement 6) Drugs prescribed to one patient may be disastrous are listed in Table 4. to another person. Thus, medication should be Overall, there is fair evidence to support the use safely secured by patients and never shared. of treatment agreements. Though in non-randomized The informed consent and treatment agreement studies (325), one found that treatment agreements

Table 4. Sample controlled substance agreement.

We are committed to doing all we can to treat your chronic pain condition. In some cases, controlled substances are used as a therapeutic option in the management of chronic pain and related anxiety and depression, which is strictly regulated by both state and federal agencies. This agreement is a tool to protect both you and your physician by establishing guidelines, within the laws, for proper controlled substance use. The words "we" and "our" refer to the facility, and the words "I", "you", "your", "me", or "my" refer to you, the patient.

1. i. I understand that chronic opioid therapy has been associated with not only addiction and abuse, but also multiple medical problems including the suppression of endocrine function resulting in low hormonal levels in men and women which may affect mood, stamina, sexual desire, and physical and sexual performance.

ii. For female patients: If I plan to become pregnant or believe that I have become pregnant while taking this medication, I am aware that, should I carry the baby to delivery while taking these medications; the baby will be physically dependent upon opioids. I will immediately call my obstetrician and this office to inform them of my pregnancy. I am also aware that opioids may cause a birth defect, even though it is extremely rare.

iii. I have been informed that long-term and/or high doses of pain medications may also cause increased levels of pain known as opioid induced hyperalgesia (pain medicine causing more pain) where simple touch will be predicted as pain and pain gradually increases in intensity and also the location with hurting all over the body. I understand that opioid-induced hyperalgesia is a normal, expected result of using these medicines for a long period of time. This is only treated with addition of non-steroidal anti-inflammatory drugs such as Advil, Ibuprofen, etc., or by reducing or stopping opioids.

iv. I understand that physical dependence is not the same as addiction. I am aware physical dependence means that if my pain medicine use is markedly decreased, stopped, or reversed by some of the agents mentioned above, I will experience a withdrawal syndrome. This means I may have any or all of the following: runny nose, yawning, large pupils, goose bumps, abdominal pain and cramping, diarrhea, irritability, aches throughout my body, and a flu-like feeling. I am aware that opioid withdrawal is uncomfortable, and could even result in heart attack, stroke, or death.

v. I am aware that tolerance to analgesia means that I may require more medicine to get the same amount of pain relief. I am aware that tolerance to analgesia does not seem to be a big problem for most patients with chronic pain; however, it has been seen and may occur to me. If it occurs, increasing doses may not always help and may cause unacceptable side effects. Tolerance or failure to respond well to opioids may cause my doctor to choose another form of treatment, reduce the dose, or stop it.

2. i. All controlled substances must come from the physician whose signature appears below or during his/her absence, by the covering physician, unless specific authorization is obtained for an exception.

ii. I understand that I must tell the physician whose signature appears below or during his/her absence, the covering physician, all drugs that I am taking, have purchased, or have obtained, even over-the-counter medications. Failure to do so may result in drug interactions or overdoses that could result in harm to me, including death.

iii. I will not seek prescriptions for controlled substances from any other physician, health care provider, or dentist. I understand it is unlawful to be prescribed the same controlled medication by more than one physician at a time without each physician's knowledge.

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Table 4 (cont.). Sample controlled substance agreement.

iv. I also understand that it is unlawful to obtain or to attempt to obtain a prescription for a controlled substance by knowingly misrepresenting facts to a physician or his/her staff or knowingly withholding facts from a physician or his/her staff (including failure to inform the physician or his/her staff of all controlled substances that I have been prescribed).

3. All controlled substances must be obtained at the same pharmacy where possible. Should the need arise to change pharmacies, our office must be informed. The pharmacy that you have selected is: Phone:

4. i. You may not share, sell, or otherwise permit others, including your spouse or family members, to have access to any controlled substances that you have been prescribed.

ii. Early refills will not be given. I will not consume excessive amount (I will follow prescribed instructions) and remain compliant to all aspects of treatment. Renewals are based upon keeping scheduled appointments. Please do not make phone calls for change in prescriptions unless you develop side effects or early refills and do not phone for refills after hours or on weekends.

iii. Medication changes will not be made between appointments unless medically necessary, which will be determined by the physician.

5. Unannounced pill counts, random urine or serum, or planned drug screening may be requested from you and your cooperation is required. Presence of unauthorized substances in urine or serum toxicology screens may result in your discharge from treatment by the facility and its physicians and staff.

6. I will not consume excessive amounts of alcohol in conjunction with controlled substances. I will not use, purchase, or otherwise obtain any other legal drugs except as specifically authorized by the physician whose signature appears below or during his/her absence, by the covering physician, as set forth in Section 1 above. I will not use, purchase, or otherwise obtain any illegal drugs, including marijuana, cocaine, etc. I understand that driving while under the influence of any substance, including a prescribed controlled substance or any combination of substances (e.g., alcohol and prescription drugs), which impairs my driving ability, may result in DUI charges.

7. Medications or written prescriptions may not be replaced if they are lost, stolen, get wet, are destroyed, left on an airplane, etc. If your medication has been stolen, it will not be replaced unless explicit proof is provided with direct evidence from authorities. A report narrating what you told the authorities is not enough.

8. In the event you are arrested or incarcerated related to legal or illegal drugs (including alcohol), refills on controlled substances will not be given.

9. I understand that failure to adhere to these policies may result in cessation of therapy with controlled substances prescribed by this physician and other physicians at the facility and that law enforcement officials may be contacted.

10. I also understand that the prescribing physician has permission to discuss all diagnostic and treatment details, including medications, with dispensing pharmacists, other professionals who provide your health care, or appropriate drug and law enforcement agencies for the purpose of maintaining accountability.

11. I affirm that I have full right and power to sign and to be bound by this agreement, that I have read it, and understand and accept all of its terms. A copy of this document has been given to me.

Patient's full name

Patient's signature Date

Physician's signature Date

improve compliance (326), while another found that Informed consent or agreements also mandate primary-care physicians were more willing to pre that multiple random evaluations, including pill counts scribe opioids to patients if the pain medicine physi and UDT, must be performed. Furthermore, based on cian also signed an agreement ("tri-lateral contract") the state regulation, evaluation of prescription drug (327). patterns are monitored by state controlled substance monitoring programs.

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6.1 Recommendations and low-risk groups; monitoring patients by using urine A robust agreement which is followed by all parties drug screening, prescription monitoring programs, and is essential in initiating and maintaining opioid therapy, pill counts; and lastly, establishing dose limits. as such agreements reduce overuse, misuse, abuse, and Atluri et al (40) described that stratification of pa diversion. (Evidence: fair) tients into different risk categories requires the use of existing screening tools designed specifically to screen 7.Q Initial Treatment for opioid misuse (subjective tools like Screener and Initiation of treatment is based on evaluation of Opioid Assessment for Patients with Pain (SOAPP) (332), stratification of risk, knowledge and understanding of Pain Medication Questionnaire (PMQ) (333), Prescrip opioids, initiation with low-dose, short-acting, opioid tion Drug Use Questionnaire-Patient Version (PDUQp) therapy, and titration during an 8 to 12 week period. (334), or objective tools like Addiction Behaviors Check list (ABC) (214), Diagnosis, Intractability, Risk Efficacy 7.1 Stratification of Risk (DIRE) Score (335), and the tool by Atluri and Sudarshan Stratification of risk for patients initiated or main (21 1) to classify patients as high-risk, medium-risk, and tained on chronic opioid therapy is crucial to prevent low-risk. They described that objective tools may be misuse and abuse. These principles may also be applied better than subjective tools. Solanki et al (77) and Seh- for patients who are treated for acute pain manage gal et al (79) concluded that there was no single screen ment, but also have other risk factors and for whom ing tool that can be applied universally. Similarly, Chou pain may become chronic. Chronic opioid therapy has and Huffman also (51) concluded that most of the stud been defined as therapy lasting for at least 90 days, on ies evaluating the screening tools had methodological a daily, or on a near daily basis (50,328). Consequently, flaws. However, some believe that screening tools may all guidelines recommend that before initiating chronic play an important role in curbing abuse. opioid therapy for any patient and in high-risk patients In risk stratification, it is important to utilize multi for acute pain therapy, a clinician should conduct a his ple models incorporating psychological and behavioral tory, physical examination, and appropriate testing, in factors to explain the pain experience (336). Positive cluding an assessment of risk of substance abuse, misuse, psychology has highlighted the importance of personal or addiction. Chou et al (50) provided strong recom resources in adapting to stressful situations. Thus, resil mendation with low-quality evidence. In addition, they ience has been defined as the ability to adapt to stress also recommended that a benefit to harm evaluation ful circumstances and has been strongly associated including a history, physical examination, and appropri with decreased perceptions of stress (337). Some also ate diagnostic testing, which should be performed and have defined resilience as a multidimensional construct documented before initiation and on an on-going basis composed of a constitutional variable such as tempera during chronic opioid therapy. Atluri et al (40) describe ment and personality accompanied by specific skills risk stratification of patients into different categories as (338). Others (339) have observed that resilience can be the first step. The risk stratification is justified in all pa seen as synonymous with reduced vulnerability (340), tients due to the significant proportion of misuse and with the ability to adapt to adversity (341), or coping abuse, which may range as high as 50% (50,150,207 (342,343). In general, resilience is associated with less 214,329). Chou et al (50) described that risk stratification depression and greater wellbeing and mental health pertaining to outcomes associated with abuse liability (338,339,344). Thus, Ramirez-Maestre et al (336) showed of opioids—misuse, abuse, addiction, and diversion — is that adjustment to chronic pain is mainly explained by a vital but relatively undeveloped skill for many clini psychological variables such as resilience, pain accep cians (50, 330). All clinicians prescribing opioids, however, tance, and coping, not the length of time in pain. Re should be knowledgeable about the risk factors for opi silience prevents patients with chronic spinal pain from oid abuse. Moreover, it is also essential to perform an suffering emotional distress, because higher levels of assessment of risks for opioid-associated adverse effects, resilience are associated with lower levels of depression given their high prevalence (50,331), even though it is and anxiety. The study showed that resilience is an im difficult to perform, often time consuming, and without portant resource for recovery from distress for individu any reliable evidence of tools. Atluri et al (40) described als with chronic spinal pain. Furthermore, the study also the 3 cornerstones for responsible prescribing or stratify concluded positive personality characteristics could play ing patients by using screening tools into high, medium. a crucial role in patient adjustment and that clinicians

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should take into account the positive path to improved with or without various tools, but with proper history, capacity in order to better understand the chronic pain examination, and monitoring by PDMPs, UDT, and sim experience. ple psychological evaluation. Based on the present evidence, regardless of use of screening tools, patients may be classified into 3 cat 7.2 Understanding Opioids egories as follows: Table 5 shows commonly used opioids, and Table 6 Low risk — Low risk patients include those with a shows commonly used benzodiazepines available in the definable physical pathology; objective signs and United States with various generic and brand names. As reliable symptoms; clinical correlation with diag illustrated in these tables, these drugs are available with nostic testing including MR I, physical examination, multiple names. Consequently they may have multiple and interventional diagnostic techniques; with or interactions with drugs (53,345-364). The literature is without mild psychological comorbidities; with or highly variable on combinations of acetaminophen and without mild coexisting medical disorders; no or the total dose of acetaminophen. However on January well defined and controlled personal or family his 13, 2011, the Food and Drug Administration (FDA) an tory of alcoholism or substance abuse; age of 45 nounced that there is no data that indicates that tak or greater; high levels of pain acceptance and ac ing more than 325 mg of acetaminophen per dosage tive coping strategies; and well-motivated patients unit provides more pain relief (345). Further, the FDA with willingness to participate in multimodal ther has stated that the maximum daily dose of acetamino apy and attempting to function at normal levels. phen be less than 4,000 mg for acute pain and 2,000 Medium risk — Medium risk patients include those mg per day for chronic pain. The present consensus ap with significant pain problems with objective signs pears to be taking around 2,000 mg of acetaminophen and symptoms confirmed by radiological evalu per day (346-350,360). With recommended low-dose ation, physical examination, or diagnostic inter therapy, this should not be an issue unless patients take ventions; with moderate psychological problems, acetaminophen over the counter. Thus, they should be well-controlled by medical therapy; moderate co instructed not to use products with acetaminophen or existing medical disorders well controlled by medi take additional acetaminophen. Lower doses have been cal therapy and which are not affected by chronic recommended specifically for tramadol and acetamino opioid therapy such as central sleep apnea; those phen combinations as well as in patients with hepatic who develop mild tolerance but not hyperalgesia abnormalities and alcoholics. without physical dependence or addiction; past Acetaminophen toxicity causes the majority of cas history of personal or family history of alcoholism es of acute renal failure in the United States (346,347). or substance abuse; involvement of more than 3 Sub-clinical liver toxicity has been shown to occur with regions of the body; with defined pathology with doses below 4 grams per day (347,348). Alcohol also moderate levels of pain acceptance and coping competes for the same metabolic pathway as acetamin strategies; and willing to participate in multimodal ophen placing heavy drinkers at higher risk for toxicity. therapy and attempting to function in their normal Chronic alcohol use is an independent risk factor for daily lives. mortality in acetaminophen poisoning (349). High-risk — High-risk patients include those with widespread pain without objective signs and symp 7.3 Dose Limits toms (involvement of more than 3 regions of the With overwhelming evidence for the misuse, body); aberrant drug-related behavior; history of abuse, and limited efficacy of chronic opioid thera misuse, abuse, addiction, diversion, dependency, py, the rationale for high-dose opioids is being re tolerance and hyperalgesia and alcoholism; with examined (40,49-55,57,98,181,363). Generally, it is major psychological disorders; age of less than 45; believed that patients who do not respond to a low HIV related pain; high levels of pain exacerbation or medium-dose of opioids will not respond to larger and low levels of coping strategies; unwilling to doses although individual circumstances also exist participate in multimodal therapy; and not func (40). In 2007, the state of Washington issued inter tioning close to a near normal lifestyle. agency guidelines that include the daily dose should not exceed 120 mg of morphine equivalent dose. The The patients may be stratified into these categories guidelines by APS and AAPM in 2009 defined the

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Table 5. Opioids with various generic and brand names available in the United States.

DRUG (GENERIC NAME) BRAND NAME(S)

Hydrocodone

Hydrocodone with acetaminophen Anexsia", Co-Gesic", Hycet*, Liquicet", Lorcet", Lorcet Plus", Lortab", Maxidone", Norco", Polygesic", Stagesic", Vicodin*, Vicodin ES", Xodol*, Zamicet*, Zolvit", Zydone*

Hydrocodone with ibuprofen Vicoprofen", Ibudone'

Hydrocodone with aspirin Lortab ASA

Oxycodone

Oxycodone HCL OxyContin", Oxy-IR*, Roxicodone"

Oxycodone HCL with acetaminophen Endocet", Percocet", Pcrcocct-Demi", Tylox", Roxicet*

Oxycodone HCL/ ASA Endodan", Percodan", Pcrcodan-Demi", Roxiprin"

Oxycodone HCL with ibuprofen Combunox*

Morphine

Morphine sulfate Avinza*, Radian', MS Contin*, MSIR*, Oraniorph", Rescudose", Roxanol*

Morphine and Naltrexone Embeda*

Fcntanyl (transdermal) Duragesic', Actiq*, Fentora TM, Lazanda, Onsolis

Methadone HCL Dolophine', Methadose*

Hydroinorphone HCL Dilaudid", Exalgo", Hydrostat*, Palladone"

Oxyniorphone Opana", Numorphan*

Codeine

Codeine monohydrate/sulphate trihydrate Codeine

Codeine phosphate/acetaminophen/ caffeine Tylenol' (No. 1, 2, 3)

Codeine phosphate/acetaminophen without caffeine Empracet"

Pentazocine HCL Talwin", Talxin NX", Talacen"

Meperidine Demerol*

Tramadol

Tramadol Rybix*, Ryzolt", UltranT, Ultram ER'

Tramadol/ Acetaminophen Ultracet'

Dronabinol Marinol'

Buprcnorphine Buprenex", Subutex", Suboxone*, Norspan'

Tapentadol Nucynta", Nucynta ER*

"high doses" to 100 mg morphine equivalent dose Bohnert et al (87) in a national sample of Veterans (51). The Canadian Guidelines in 2010 identified 200 Health Administration patients revealed that there mg morphine equivalent dose as a watchful dose (54). was a dose-response relationship between the maxi However, there has been only limited data verifying mum daily prescribed dose of opioids and the risk of the safety of these recommended doses, especially in opioid overdose deaths. The overdose death rate for high-risk patients. Franklin et al (181) showed the ef patients receiving a dose of less than 20 mg morphine fectiveness of dose limitation with reduction in dos equivalent dose was 0.1 1 per 1,000 compared to those age, frequency, and death rate. In addition, 5 studies getting more than 100 mg morphine equivalent dose, showed that the rate of overdose was directly propor for whom the death rate was 1.24. This difference tional to the prescribed opioid dose (87,135,364-366). was even higher in those with a history of substance

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Table 6. Benzodiazepines with various generic and brand names available in the United States.

DRUG (GENERIC NAME) BRAND NAME (S)

Alprazolam Xanax*, Niravam*

Chlordiazepoxide Librium"

Clonazepam Klonopin*

Clorazepate Tranxene"

Diazepam Valium", Valrelease"

Estazolam ProSom"

Flurazepam Dalmane*,

Lorazepam Ativan*

Midazolam Versed"

Oxazepam Serax*

Quazepam Doral*

Temazepam Resloril"

Triazolam Halcion*

abuse with 0.54% versus 2.9%. Based on these results, population for very high and 7.92 for high. However, the the authors concluded that the risk of opioid overdose opioid-related mortality rate was 1.63 per 1,000 in those increased when the opioid dose was equivalent to 50 with moderate doses. In addition, the overall death rate mg morphine equivalent dose or higher. Dunn et al from any cause was much higher in patients receiving (135) in a population from a health maintenance or opioids (20.05) when compared to those who were not ganization (HMO) in Washington State, reported a receiving any opioids (4.0) per 1,000 population. Frank 9-fold increase in opioid overdoses in patients receiv lin et al (181) showed that appropriate guidelines with ing high dose opioids (> 100 mg morphine equivalent dose limitation considering 120 mg morphine equiva dose) when compared to those getting low dose (< 20 lent doses as high dose reduced overall opioids per day mg morphine equivalent dose). There was a 3.7-fold by 27% and long-acting Schedule II opioids by 37% in increase in overdose events in patients receiving doses the proportion of the workers on doses of greater than between 50 to 99 mg morphine equivalent doses ver 120 mg per day morphine equivalent dosage. Moreover, sus those getting less than 20 mg morphine equiva the number of deaths was reduced by 50% from 2009 lent dose. Paulozzi et al (364) found that compared to 2010. Rome et al (363) in a report of outcomes of a to patients receiving lower opioid doses or no opioid chronic non-cancer pain rehabilitation program accord prescriptions, the risk of overdose was greater if daily ing to opioid use and status at admission stratified the opioid doses were above 40 mg morphine equivalent participants into non-opioid grouping in 221 patients, dose. Braden et al (366) found that patients in Arkan low-dose (< 41 mg per day) in opioid users in 71 patients, sas receiving morphine equivalent doses of more than and high-dose (> 41 mg per day, an average of 137.48 120 mg per day were more likely to have drug-related mg per day) in opioid users in 64 patients. The outcomes encounters than those getting lower doses. Gomes at discharge showed that patients taking higher doses et al (365) found that patients from Ontario's Public reported significantly greater catastrophizing and great Drug Plan receiving very high doses (> 400 mg mor er pain severity than the non-opioid group. Two other phine equivalent dose) and high doses (200 to 400 studies conducted in the worker's compensation popula morphine equivalent dose) had a much higher over tion also showed similar results (367,368). Adverse events dose death rate than those getting moderate doses were also reported more commonly at higher daily doses (< 200 mg morphine equivalent dose). Moreover, they (369,370). Pascual et al (369) showed the increasing fre also showed that in very high and high dose patients quency of adverse effects of high dose tramadol (over the opioid-related mortality rates were 9.94 per 1,000 400 mg) compared with lower doses, with 2 patients ex-

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periencing seizures. Huse et al (370) in a randomized trial available literature correlates increasing mortality with showed that attention deficit was more common dur increasing doses. In addition, several studies have dem ing morphine treatment compared to placebo, which onstrated that for patients with severe pain on high was more pronounced when a higher dose was taken. opioid doses, tapering resulted in reduced pain and im Other studies (98,296,370-372) have shown that there proved mood (54,363,373-375). was a dose-dependent relationship between chronic opi In 2008, opioid pain relievers were involved in oid use, specifically with high doses and sleep disorders. 14,800 drug overdose deaths in the United States com Ballantyne and Mao (296) in 2003 indicated that doses pared to 1 1,500 of 27,500 fatal unintended drug over higher than 100 mg of morphine equivalent dose per dose deaths in 2007 — an increase of 3,300 in just one day have not been validated in clinical trials and should year (34). Consequently, based on statistics, it has been be considered excessive. concluded that opioid analgesics contributed to fatali The above studies illustrate the dose-related ef ties based on opioid abuse and increases, doctor shop fects at 40 mg morphine equivalent dose (364), 50 mg ping, and other aspects of drug abuse as illustrated in morphine equivalent dose (87,135), 120 mg morphine Figure 3. The Centers for Disease Control and Preven equivalent dose (177,366), and 200 mg morphine tion (CDC) (34) also reported the percentage of prescrip equivalent dose (365). Thus far, it appears that all the tion drug overdoses by risk group in the United States.

8

0PR deaths/100,000 7- — — Treatment admissions/10,000

0PR sales kg/10,000

6-

5-

o> / to 4- J / cc / / 3- s * * * 2-

* 1 -

0 -1—i1111111111r 1999 2001 2003 2005 2007 2009

Year

* Age-adjusted rates per 100,000 population for OI'R deaths, crude rates per 10,000 population for OPR abuse treatment admissions, and crude rates per 10,000 population for kilograms of OPR sold.

Fig. 3. Rates of opioid pain reliever overdose death, opioid pain relief treatment admissions, and kilograms of opioid pain reliev ers sold - United States. 1999-2010.

Source: Centers for Disease Control and Prevention. Vital signs: Overdoses of prescription opioid pain relievers - United States, 1999-2008. MMWR Morb Mortal Wkly Rep 201 1; 60:1487-1492 (83).

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This concluded that approximately 80% of prescribed in opioid-treated patients compared to matched cohort low doses (less than 100 mg morphine equivalent dose of chronic pain patients not using opioids. Sjogren et al per day) were by a single practitioner, accounting for (33) in a population based cohort study on chronic pain an estimated 20% of all prescription overdoses (Fig. and the role of opioids, showed that the odds of recov 4). In contrast, among the remaining 20% of patients, ery from chronic pain were almost 4 times higher among 10% were prescribed high doses greater than 100 mg individuals not using opioids compared with individuals of morphine equivalent dose per day (85-87) of opioids using opioids. In addition, they also showed that use of by single prescribers accounting for an estimated 40% strong opioids was associated with poor health-related of the prescription opioid overdoses (87,135). The re quality of life and higher risk of death. maining 10% of patients seeing multiple doctors and Therefore, we have reached a consensus on the fol typically involved in drug diversion contributed to 40% lowing: low-dose is up to 40 mg of morphine equiva of overdoses (375). lent dose, moderate dose is 41 to 90 mg morphine Multiple studies in the literature have report equivalent dose, and high dose is any dose after 91 or ed an association between opioid prescribing and higher mg of morphine equivalent dosages. These dos overall health status, with increased disability, medi es are lower than described by the CDC, which shows cal costs, subsequent surgery, and continued or late >100 mg as high dose and Washington State guidelines, opioid use (23,31,33,36,167,293-295,367,368,377- which show 120 mg as the high dose, but considered 387). Overall, epidemiologic studies are less posi reasonable, based on current evidence, and a cautious tive with regards to improvement in function and approach, specifically when a patient is receiving mul quality of life with opioids in chronic pain patients timodal therapy. (23,31,33,36,49,55,56,57,133,167,293-295,367,368,377- 389). In fact, in an epidemiologic study from Denmark by 7.4 Initiation with Low-Dose Opioid Therapy Breivik et al (23) where opioids were prescribed liberally A physician should follow the principles of pre for chronic pain, it was demonstrated that in patients scribing a low opiate dose as reasonably achievable or receiving opioids, pain was worse, health care utiliza ALARA (as low as reasonably achievable) similar to ra tion was higher, and activity levels were lower compared diation exposure guidelines to provide therapeutic ef to a matched cohort of chronic pain patients not us fect without major side effects (390-402). ing opioids. Eriksen et al (32) also reported worse pain, Low dose therapy may be effective with a reduc higher health care utilization, and lower activity levels tion in the rate of complications, side effects, and ad-

100% -|

B Patients seeing multiple 10% 80% - 3= 40% doctors and typically involved in drug diversion

60% - Patients seeing one doctor, high dose

40% - 80% 40% a Patients seeing one doctor,

20% - low dose 20% 0% Patients Overdoses

Fig. 4. Percentage of patients and prescription drug overdoses, by risk group - United Stales.

Source: Centers for Disease Control and Prevention. CDC grand rounds: Prescription drug overdoses - a U.S. epidemic. MMWR Morb Mortal Wkly Rep 2012; 61:10-13 (34).

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Table 7. Recommended low-dose opioid therapyfor select opioids showing starting doses and maintenance doses.

Opioid Recommended Starting Recommended Starting Dose For Recommended Dose For Opioid-Naive Opioid Exposed Patient's High Maintenance Dose Patients Doses Leading To High Risks.

Hydrocodone 5 to 10 mg, 2 to 3 times daily 5 to 10 mg, 3 to 4 times daily 30 to 40 mg for 24 hours

Morphine

Morphine Immediate Release Not recommended 10 mg, 2 to 3 times 30 to 60 mg per day

Morphine Sustained Release Not recommended 15 to 30 mg twice daily 60 to 90 mg daily

Oxycodone

Oxycodone 5 to 10 mg, 2 to 3 times daily 5 to 10 mg, 3 to 4 times daily 30 to 40 mg per day

Oxycodone Sustained Release Not recommended 10 mg for 12 hours 30 to 60 mg for 24 hours

Methadone Not recommended 2 to 5 mg, 2 to 3 times daily 1 0 to 30 mg per day

Transdermal Fentanyl Not recommended 12.5 to 25 meg q72h 25 to 50 meg per 72 hours

Hydromorphone

Hydromorphone Immediate Release 2 mg bid or tid 2 to 4 mg, 2 to 3 times daily 8 to 16 mg per day

Hydromorphone Sustained Release Not recommended 5 mg to 10 mg, 2 times daily 20 to 40 mg daily

Codeine 15 mg bid or tid 30 mg bid to qid 120 to 160 mg daily

Oxymorphone

Oxymorphone Immediate Release 5 mg bid or tid 5 to 10 mg 2 to 3 times daily 30 to 40 mg per day

Oxymorphone Sustained Release Not recommended 10 mg ql2h 40 to 60 mg per day

Tramadol

Tramadol 50 mg bid or tid 50 mg 3 to 4 times daily 1 50 to 300 mg per day

Tramadol Sustained Release Not recommended 200 mg daily 200 to 350 mg per day

verse effects, specifically when opioid therapy is com other low-potency opioids have low ratios of abuse bined with other modalities including interventional to prescription use, related to oxycodone, hydromor techniques. Consideration of higher dosage requires phone, and hydrocodone. Tramadol also has a low risk careful reassessment of the pain and risk of misuse, and of addiction, and experimental studies suggest that frequent monitoring with evidence of improved pa it has fewer psychoactive effects than other opioids tient outcomes if at all necessary. (403,404). Flowever, neither tramadol nor codeine are Based on the available literature recommended readily tolerated by the majority of patients long-term. low-dose therapy is shown in Table 7 for chronic non- In chronic pain management settings, the majority of cancer pain along with a description of dosing thresh patients have allegedly used these drugs (Tramadol and olds for selected opioids (1,49-55,58). codeine) and refuse to try them. Oxycodone, hydroco Thus, for mild to moderate pain, first line therapy done, and hydromorphone have been shown to have should start with tramadol, codeine, or hydrocodone. higher abuse liability than other opioids (54,405-411). For second line mild to moderate pain therapy, clini Butler et al (407) in a study of the 14 most desirable opi cians should start with hydrocodone or oxycodone. For oid formulations, found that prescription opioid misus severe pain, first line therapy may start with hydroco ers ranked controlled release oxycodone, immediate done, oxycodone, hydromorphone, or morphine, with release hydromorphone, and oxycodone as the most second line therapy leading to fentanyl and if abso desirable. Cicero et al (408) in a national surveillance lutely necessary, the third line therapy for severe pain study of addiction experts, law enforcement agencies, with methadone or buprenorphine (54). The literature and poison control centers, identified hydrocodone illustrates that codeine and tramadol may have a lower and oxycodone (immediate release and controlled) as abuse risk than more potent opioids (54,403-405). by far the most commonly abused opioids in the United Abuse rates measured from Drug Abuse Warning States. Network Data (DAWN) (405) showed that codeine and Morphine can cause toxicity in patients with re-

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nal dysfunction (54,406). It has been shown that M-6 increased with long-term use, renal insufficiency, and glucuronide, an active metabolite of morphine, accu concurrent benzodiazepine use (428). mulates in the serum of patients and causes central Long-acting opioids are generally provided in high nervous system and respiratory depression. The degree dose formulations, increasing the risk of abuse and of accumulation was related to the morphine dose and overdose. Furthermore, long-acting opioids can easily the extent of renal impairment (412). be converted to immediate release by crushing or bit Fentanyl, 80-100 times as potent as morphine can ing the tablet. Thus, OxyContin 80 mg tablet is equiva cause significant central nervous system and respiratory lent to 16 Percocet tablets (54). depression and also has been shown to contribute to numerous overdose deaths (54,349,413-416). Fentanyl 7.5 Titrate was a contributing cause in 100 overdose deaths in On Opioid medications must be started at low doses tario between 2002 and 2004 with fentanyl intoxication and titrated gradually to higher amounts if necessary. being the sole cause of death in 54 of the patients with All attempts must be made to maintain patients on low therapeutic and illicit use of fentanyl including chew er doses, including use of other drugs. Combinations of ing and ingesting fentanyl patches (414). In addition, short- and long-acting, and high doses of long-acting fentanyl-laced heroin appeared simultaneously in vari opioids must be prescribed with extreme caution. ous parts of the United States, beginning in 2005, with 55 drug overdose cases resulting in 12 deaths in the first 7.6 Recommendations half of 2006 (415). Fentanyl toxicity was related to 92% 1. Once medical necessity is established, opioid ther of the fentanyl-related deaths and is attributed par apy may be initiated with low doses and short-act tially due to cytochrome P450 3A4*1B and 3A5*3 vari ing drugs with appropriate monitoring to provide ant alleles, resulting in variable fentanyl metabolism. effective relief and avoid side effects. (Evidence: Furthermore, the FDA (417), in July of 2005, issued a fair for short-term effectiveness, limited for long- public health advisory calling attention to an increase term effectiveness) in the number of fentanyl-patch-related overdoses and 2. We are recommending up to 40 mg of morphine deaths, particularly among patients ignoring the prod equivalent doses as low dose, 41 to 90 mg of mor uct's boxed warnings and instructions for use. Another phine equivalent dose as a moderate dose, and issue has been that up to 10% of Caucasians lack the greater than 91 mg of morphine equivalence as enzyme CYP450 2D6 that converts codeine to mor high doses. (Evidence: fair) phine. Consequently, when switching from codeine to 3. In reference to long-acting opioids, titration must fentanyl, regardless of the codeine dose, caution must be carried out with caution and overdose and mis be exercised as patients may have little or no opioid use must be avoided. (Evidence: good) tolerance (418-421). 4. Methadone is recommended for use in late stages In reference to methadone, even though it after failure of other opioid therapy and only by has not been shown to be more effective than clinicians with specific training in the risks and uses. other opioids, it has been used extensively in the (Evidence: limited) United States and associated with multiple ad 8.Q Aphereiuce Monitoring verse consequences including prolonged QT interval (50,51,54,60,99,101,102,153,308,313,361,422-427). The role of adherence monitoring with various Methadone has been associated with numerous over tools has been described as part of the initial evalua dose deaths in pain patients with analgesic use increas tion. This must be continued through the treatment ing sharply in the United States, with a 1,293% increase phase with PDMPs, UDT, pill counts, and behavioral as from 1997 to 2007 (31). Methadone is also, however, sessment during each visit. Adherence monitoring is de dispensed in methadone clinics with very little regula pendent on risk stratification. Monitoring based on risk tion and supervision. stratification is illustrated in Figure 5 (40). An algorith Meperidine is not recommended in chronic pain mic approach to UDT is illustrated in Figure 6. Flowever, settings due to adverse neurological events resulting regulations with stricter criteria take priority over these in confusion and seizures with long-term treatment algorithmic approaches. secondary to accumulation of toxic metabolite Norme- Aberrant drug-related behaviors, include alteration peridine. The adverse events with meperidine are also of prescriptions or the route of delivery, doctor shop-

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Chronic Pain

> r Screening Tool

May Use Objective screening tools: DIREScore, ABC Checklist, screening tool by Atluri & Sudarshan.

-or- Subjective screening tools: SOAPP, PDUQp, PMQ. I Medium Low Risk High Risk Risk +UDS: every 1 -2 +UDS: every 3-6 +UDS: every 6-12 months years months +PMP: 3 times a year +PMP: twice per +PMP: 4 times per +Use > 50 mo MED year year occasionally* +Use > 50 mq MED +Avoid Opioids or use +lf aberrant behaviors are if needed* very low doses (10 mq demonstrated, counseling +lf aberrant MED) must be done to address behaviors are them and if the behavior is +Avoid dose demonstrated, unchanged, opioid use escalations counseling must be must be seriously +Use > 50 mq MED done to address reconsidered. RARELY* them and if the +Patients displaying behavior is aberrant behaviors unchanged, opioid should be weaned off use must be opioids seriously reconsidered.

*MED - Morphine Equivalent Dose

Fig. 5. Risk stratification and adherence monitoring.

Reproduced with permission from: Atluri SL, Akbik H, Sudarshan G. Prevention of opioid abuse in chronic non-cancer pain: An algorithmic. evidence-based approach. Pain Physician 2012; 15:ES177-ES189.

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Patient with Chronic Pain

1

Comprehensive Assessment Physical, functional, psychosocial, opioid dependency or abuse, illicit drug use Baseline Assessment

Point of Care Testing (Immunoassay)

Appropriate Inappropriate or or Explained Result Unexplained Result I Confirmatory Testing I

Appropriate Inappropriate

or or Explained Result Unexplained Result I

• Continued monitoring* • Education with continued opioid therapy

or • Discontinue opioid therapy I

Repeat UDT one month or next appointment

Appropriate Inappropriate Initiation of Opioid Therapy & Compliance Monitoring < or or Explained Result Unexplained Result

Random Point of Care testing

in 1 to 3 months • Confirmatory Testing i • Initiation or continued non-opioid therapy i i • Education Appropriale Inappropriate

or or Explained Result Unexplained Result Appropriate

or Abnormal Results Explained Result

Follow-up random testing in 6-12 months Start Opioid Therapy • Non-opioid therapy • Follow-up testing in 3months • Follow abnormal result algorithm I • Monitoring • Education Complaints, questions, behavioral issues r Complaints, Questions, Behavioral issues

Follow inappropriate or unexplained result algorithm "Based on zero-tolerance

Fig. 6. Algorithmic steps in urine drug testing in chronic pain. Reproduced with permission from: Christo PJ, Manchikanti L, Ruan X, Bottros M, Hansen H, Solanki DR, Jordan AE, Colson J. Urine drug testing in chronic pain. Pain Physician 201 1; 14:123-143 (226).

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ping or accessing opioids from other sources, multiple plications do resolve except for sexual dysfunction and unauthorized dose escalations, drug seeking behavior fatigue, which increase with long-term treatment with with focus on certain types of opioids and benzodiaz hormonal imbalances. However, the complications are epines, loss of prescriptions, requests for early refills, more frequent, longer lasting, and severe in long-term aggressive complaining, staff harassment, complaining high-dose opioid therapy. Peripheral edema, though about other patients, questioning rights and responsi observed in a small proportion of patients, could be bilities, repeated withdrawal symptoms, exacerbation a major issue. Neuroendocrine abnormalities with of underlying mood or anxiety disorders, alcohol use, erectile dysfunction must be taken into consideration poor social functioning, loss of job and loss of activities and explained to the patient, with appropriate refer of daily living, emphatic views on opioid medication ral when indicated. Similarly sleep apnea and opioid- and illicit drugs as well as legalization of illicit drugs. induced hyperalgesia (OIH) must be handled appropri ately (1). 8.1 Recommendations Neuroendocrine abnormalities and erectile dys 1. Monitoring recommendation for methadone pre function can be experienced with long-term opioid scription is that an electrocardiogram should be therapy in as many as 11% of the patients (296,430 obtained prior to initiation, at 30 days and yearly 435). Some outdated reports essentially state that pa thereafter. (Evidence: fair) tients taking opioid medications reported better sexual 2. In order to reduce prescription drug abuse and function, which was likely an improvement of well-be doctor shopping, adherence monitoring by UDT ing (429). Thus, in the short-term, a patient may notice and PMDPs provide evidence that is essential to the improvement in many aspects including sexual func identification of those patients who are non-com tion, but in the long-term, opioids may cause neuroen pliant or abusing prescription drugs or illicit drugs. docrine dysfunction. (Evidence: fair) Smith and Elliott (478) described that opioid-in- duced androgen deficiency (OPIAD) is characterized by 9.0 Monitoring and Managing Side the presence of inappropriate low levels of gonado Effects tropin (follicle-stimulating hormone and leuteiniz- Multiple side effects, including effect on driving, ing hormone) leading to the inadequate production sedation, constipation, and breathing specifically in of sex hormones, particularly . Symptoms patients with respiratory disorders, must be monitored. that may manifest in patients with OPIAD include re Adverse effects have been commonly reported duced libido, erectile dysfunction, fatigue, hot flashes, with nausea in 28%, constipation in 26%, somnolence/ and depression. Physical findings may include reduced drowsiness in 24%, dizziness/vertigo in 18%, dry-skin/ facial and body hair, anemia, decreased muscle mass, itching/pleuritis in 15%, and vomiting in 15% of pa weight gain, and osteopenia or osteoporosis. While the tients on relatively high-dose opioids. Low-dose opi literature regarding OPIAD remains limited, OPIAD can oids, however, have been accompanied by lesser com have a significant negative impact on the quality of life plications (1,54,346-354,403-477). The majority of these of opioid users. Thus, clinicians should anticipate the adverse effects are resolved with continued treatment potential for its occurrence whenever long-term opi and dose adjustments. However, constipation may not oid prescribing is undertaken and develop appropriate be resolved and requires a bowel regimen. Further management strategies. Once diagnosed, treatment more, with long-term therapy and high doses, other for OPIAD may be offered utilizing a number of andro complications may be noted including hypogonad gen replacement therapy options including a variety of ism, neuroendocrine dysfunction, sleep disorders, and testosterone preparations and, for female patients, de- hyperalgesia (1,54,403-477). Other effects which are hydroepiandrosterone (DHEA) supplementation. seen in less than 10% of the population include dry OIH and the treatment of breakthrough pain in mouth, headache, sexual dysfunction, hot flashes, loss chronic non-cancer pain are controversial issues. OIH of appetite, abdominal pain, fatigue, sleeplessness/ is more commonly accepted even though the concept , sweating, blurred vision/confusion, muscle of breakthrough pain continues to be mired in beliefs contractions, diarrhea, ataxia, edema, difficulty urinat of pseudoaddiction and undertreatment of pain. The ing, restless legs, application site reaction, heartburn, evidence is in contrast to the fact that pain may be es anxiety, and weakness (54). The majority of these com- sentially overtreated in many countries, specifically

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with opioids, even though overall there may also be an simple and effective. Multiple publications have evalu undertreatment of pain in some regions and segments ated opioid antagonists in the prevention or treatment of the population (75,95). of opioid-induced bowel dysfunction (479,480), but the Opioids can aggravate not just central sleep apnea, evidence is insufficient to recommend such antagonists but frequently may also significantly aggravate obstruc to prevent bowel dysfunction. tive sleep apnea. High opioid doses may contribute to During dosage titration in a trial of opioid therapy, sleep movement disorders including myoclonus and advise the patient to avoid driving a motor vehicle or sometimes choreiform movement, and in combination dangerous activities such as use of heavy machinery, un with benzodiazepines and other drugs may significantly til a stable dosage is established, it is certain the opioid contribute to oxygen desaturation (326,437-449). The does not cause sedation; and when taking opioids with most serious complications include respiratory depres alcohol, benzodiazepines, or other sedating drugs (54). sion and death, which may occur when initial doses are When assessing safety to drive in patients on long-term too high, opioids are titrated too rapidly, or opioids are opioid therapy, consider factors that could impair cog combined with other drugs that are associated with re nition and psychomotor ability, such as a consistently spiratory depression or that may potentiate opioid-in- severe pain rating, disordered sleep, and concomitant duced respiratory depression such as benzodiazepines or medications that increase sedation (54). abuse of opioids with or without other drugs (472-477). Wilhelmi and Cohen (481) in a focused review de Many herbals and over-the-counters, including diphen scribed a framework for "driving under the influence of hydramine preparations can contribute to a dose-depen drugs" policy for the opioid-using driver. Driving under the dant respiratory depression. Patients with sleep apnea influence of drugs is a term used to designate the action of or with other pulmonary conditions may be at a higher driving an automobile after the consumption of drugs or risk for respiratory depression and opioids should be ini medications other than alcohol that interfere with the ca tiated, titrated, and monitored closely with as low a dose pacity to operate a vehicle safely. Unlike recreational drugs, as possible. Furthermore, high opioid doses may contrib prescription medications, specifically opioids and benzodi ute to sleep movement disorders including sleep apnea. azepines, pose a unique challenge to those attempting to Part 1 with evidence assessment showed that the harness their benefits, yet protect the driving public. Wil evidence is fair for existence of opioid hyperalgesia helmi and Cohen (481) concluded that a sizable percentage with chronic opioid therapy (1,75,95). However, debate of the driving public has detectable levels of opioids within continues on this aspect. Tompkins and Campbell (454) their bodies. The best available evidence demonstrates psy questioned whether OIH is clinically relevant or an ex chomotor impairment following acute administration of traneous research phenomenon, nothing that not all opioids or an increase in opioid dosage, but impairment evidence supports the clinical importance of OIH, and diminishes with chronic, stable opioid dosage. Thus, it is es that there is some doubt as to whether the phenom sential to take into account the evidence in chronic pain enon exists at all. Overall, there is growing evidence to patients when balancing the benefit of pain relief against support the presence and consequences of opioid hy the need for public roadway protection. Similarly, policy peralgesia, along with the benefits of reducing opioid makers also should take into account these issues during doses or weaning patients off of opioids. drafting driving under the influence of drugs legislation. Among the multiple side effects, constipation is one of the most common opioid-related adverse effects 9.1 Recommendations (331). Constipation may become a major issue with con 1. It is essential to monitor for side effects and man tinued exposure to opioids in a significant proportion age them appropriately including discontinuation of patients. In addition, in older adults or other patients of opioids if indicated. (Evidence: fair) with additional reasons to develop constipation, con 2. Constipation must be closely monitored and a stipation may be more frequent and also problematic. bowel regimen be initiated as soon as deemed nec Consequently, a physician should consider the initiation essary. (Evidence: good) of a bowel regimen even before the development of 3. It is recommended that a policy of driving under constipation and definitely after the development of the influence of drugs be developed and moni constipation. Even though the evidence for bowel regi tored during initiation of therapy, changes in the men is anecdotal, regimens, including increased fluid dosages, and addition of other centrally acting and fiber intake, stool softeners, and laxatives, are often agents. (Evidence: good)

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10.0 The Final Phase equivalent reported the smallest reduction in pain After initiation of opioid therapy and stable main scores, on average a 1.1 point decrease. tenance for 8 to 12 weeks with appropriate outcomes, In patients with dependency, office-based opioid it is essential to arrive at a conclusion to either continue dependence treatment may be provided. In a narrative or to discontinue the opioids. review, Colson et al (483) described that office-based If the patient continues with persistent pain or opioid dependence treatment is a viable alternative there is new pain, a comprehensive evaluation must be to methadone treatment or rehabilitation programs. repeated or a referral may be made. Similarly, if there is However, office-based treatment of opioid dependen any indication of abuse, misuse, lack of analgesia, lack cy requires a special licensure from the DEA. Thus, for of activity, adverse effects, or aberrant behavior, the physicians providing opioid management of pain, the physician must taper the drug therapy and discontinue. use of buprenorphine/naloxone is an important tool to Alternate modalities must be pursued at this stage. consider for opioid dependence issues, which arise in Opioid therapy is continued if appropriate analgesia treating chronic pain. and functional status is achieved either with opioid thera If it is required, tapering or discontinuation of opioid py alone or in conjunction with other modalities. Minimal therapy may be considered; however, for a patient who requirements for continued opioid therapy are analge has not been taking medication on a long-term basis, ta sia of at least 30%, and/or activity improvement of 30% pering or weaning is not necessary and discontinuation without misuse/abuse, or major adverse effects. However, may be carried out. Tapering may be carried out slowly if treatment is successful, one may attempt to wean from with a decrease by 10% of the original dose per week. opioids if necessary. If necessary to continue, monitoring This is generally well tolerated with minimal adverse phys must be continued and the patient be discharged either iological effects. However, some patients can be tapered with improvement or with any deficiencies. or weaned more rapidly without any major problems Patients on high doses, obtaining inadequate an over a 6 to 8 week period. During this period, if opioid algesia, and with other issues may be converted to abstinence syndrome is encountered, it is rarely medically sublingual buprenorphine. Daitch et al (482) described serious, even though symptoms may be quite unpleasant. conversion of chronic pain patients from full opioid ag The symptoms of abstinence syndrome, including nausea, onists to sublingual buprenorphine. They described the diarrhea, muscle pain, and myoclonus, can be managed results from clinical records of 100 chronic pain patients with 0.1 to 0.2 mg orally every 6 hours or cloni- with 60 men and 44 women aged 21 to 78 and who dine transdermal patch 0.1 mg - 24 hours weekly during had previously been treated with opioid agonist drugs. the taper. Patients should be monitored often for signifi They were converted to buprenorphine sublingual tab cant hypotension and anticholinergic side effects. While let form during the study. After initiation of buprenor rare, in some patients it may be necessary to slow the phine sublingual therapy for more than 2 months, the tapering and weaning timeline from weekly to monthly mean pain scores on a scale from 0 to 10 decreased dosage adjustments. If the patient is not following the by 3 points. However, patient quality of life was not tapering dosages and abusing them, then tapering is go significantly affected by buprenorphine sublingual ing to be unsuccessful and patients must be referred to therapy. The success rate was highest for patients using detoxification facilities or advised to do so. morphine, oxycodone, and fentanyl before buprenor Symptoms of mild opioid withdrawal occasionally phine sublingual induction. These patient groups had may persist for 6 months after opioids have been discon a 3.7-point decrease in pain for those taking morphine, tinued. The physician may also consider using adjuvant a 2.5-point decrease in pain for those taking oxycodo agents such as antidepressants to manage irritability and ne, and a 2.2-point decrease for those taking fentanyl. sleep disturbance, or antiepileptics for neuropathic pain. The smallest pain reduction was seen in the patient However, physicians should be cautious and preferably groups using oxymorphone. In addition, patients tak not treat withdrawal symptoms with opioids or benzo ing between 100 to 199 mg morphine equivalent per diazepines once the weaning process or discontinuation day experienced the greatest reduction (2.7 points) in of opioids is started. The patient may be referred for pain scores. Patients taking between 200 to 299 mg of counseling or other support during the weaning period if morphine equivalent before buprenorphine sublingual there are significant behavioral issues. If such issues arise, induction exhibited a decrease of over 2 points on av the physician should refer the patient to a chemical de erage. Patients taking greater than 400 mg morphine pendency center for complicated withdrawal symptoms.

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Physicians not trained in pain management may refer published regulations and recommendations for prescrib their patients with these issues to pain management spe ing controlled substances. Physicians are advised to refer cialists or addictionologists. to those regulations for their respective state. Physicians should not prescribe scheduled drugs for themselves or 10.1 Recommendations immediate family except in emergency situations. 1. Chronic opioid therapy may be continued, with The following criteria should be considered care continuous adherence monitoring, modified at any fully in providing controlled substances: time during this phase, with fair evidence showing 1. Complete initial evaluation, including history and effectiveness of opioids in well-selected popula physical examination tions, in conjunction with or after failure of oth 2. Psychological evaluation er modalities of treatments with improvement in 3. Physiological and functional assessment, as neces physical and functional status and minimal adverse sary and feasible effects. (Evidence: fair) 4. Indications and medical necessity 2. Methadone is recommended for use in late stages 5. The use of the lowest possible dose to provide ad after failure of other opioid therapy and only by equate analgesia with minimum side effects should clinicians with specific training in the risks and uses. be the goal of opioid therapy (Evidence: limited) 6. In general, do not combine opioids with sedative- 3. A trial of opioid rotation may be considered for pa hypnotics, benzodiazepines, or barbiturates for tients requiring escalating doses. (Evidence: limited) chronic, non-cancer pain unless there is a specific 4. Chronic opioid therapy should be monitored for medical indication for the combination adverse effects and to manage them appropriately. 7. Adherence to the controlled substance agreement (Evidence: good) with patients understanding the risks and benefits of controlled substances and the policy and regula 11. 0 Documentation tions of the practitioner, including controlled sub The physician should keep accurate and complete stances being prescribed by only one practitioner medical records, which include all aspects of interven and being obtained from only one pharmacy tional pain management and medical care. These com 8. Monitoring for drug abuse or diversion should be prise, but are not limited to: routine, and if confirmed, referral to rehabilitation • Medical history and physical examination centers may be made, with termination of prescrip • Diagnostic, therapeutic, and laboratory results tions of controlled substances. • Evaluations and consultations 12. 0 Summary • Treatment objectives • Discussion of risks, benefits, and limitations of The evidence synthesis and guidance preparation treatments provides the following recommendations with 10 steps • Details of different treatments and medications, in to opioid therapy: cluding date, type, dosage, and quantity prescribed • Instructions to the patient 12.1 Initial Steps of Opioid Therapy • Periodic reviews of outcomes, including documen • Comprehensive assessment and documentation is tation of functional status, preferably using vali recommended before initiating opioid therapy, dated tools. documentation of comprehensive history, general medical condition, psychosocial history, psychiat Records should remain current and be maintained ric status, and substance use history. (Evidence: in an accessible manner and readily available for re good) view, not only for the physician and other members of • Despite limited evidence for reliability and accu the practice, but also for authorities. racy, screening for opioid use is recommended, as To be in compliance with controlled substance laws it will identify opioid abusers and reduce opioid and regulations required to prescribe, dispense, or admin abuse. (Evidence: limited) ister controlled substances, the physician must have an • Prescription monitoring programs must be imple active license in the state and comply with applicable fed mented due to regulations, AS they provide data eral and state regulations. Various licensure boards have on patterns of prescription usage, reduce prescrip-

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tion drug abuse or doctor shopping, and PDMPs ing and short-acting opioids for their effectiveness may reduce emergency room visits, drug overdos or adverse effects. (Evidence: fair) es, or deaths. (Evidence: good to fair) • A trial of opioid rotation may be considered for • UDT must be implemented from initiation along patients requiring escalating doses. (Evidence: with subsequent adherence monitoring, in an in- limited) office setting with immunoassay and confirmation • It is recommended that contraindications to opioid for accuracy with chromatography in select cases, use in chronic non-cancer pain must be evaluated to identify patients who are non-compliant or including respiratory instability, acute psychiatric in abusing prescription drugs or illicit drugs, and UDT stability, uncontrolled suicide risk, active or history may decrease prescription drug abuse or illicit drug of alcohol or substance abuse, confirmed allergy to use when patients are in chronic pain management opioid agents, coadministration of drugs capable of therapy. (Evidence: good) inducing life-limiting drug interaction, concomitant use of benzodiazepines, active diversion of con 12.2 Establish Diagnosis trolled substances, and concomitant use of heavy • Establish appropriate physical diagnosis and psy doses of central nervous system depressants, such as chological diagnosis if available prior to initiating benzodiazepines. (Evidence: fair to limited) opioid therapy. (Evidence: good) • Caution must be exercised in ordering various im 12.6 Informed Decision-Making aging and other evaluations, and only appropriate A robust agreement which is followed by all parties information in the realm of clinical relevance shall is essential in initiating and maintaining opioid therapy be provided by the treating physician to the pa as such agreements reduce overuse, misuse, abuse, and tients when there is correlation of the symptoms diversion. (Evidence: fair) with findings, to avoid increased fear, activity re striction, requests for increased opioids, and mal 12.7 Initial Treatment adaptive behaviors. (Evidence: good) • Once medical necessity is established, opioid ther • A pain management consultation, for non-pain apy may be initiated with low doses and short-act physicians, if high-dose opioid therapy is being uti ing drugs with appropriate monitoring to provide lized. (Evidence: fair) effective relief and avoid side effects. (Evidence: fair for short-term effectiveness, limited for long- 12.3 Establishing Medical Necessity term effectiveness) It is essential to establish medical necessity prior to • We are recommending up to 40 mg of morphine initiation or maintenance of opioid therapy. (Evidence: equivalent doses as low dose, 41 to 90 mg of mor good) phine equivalent dose as a moderate dose, and greater than 91 mg of morphine equivalence as 12.4 Establishing Treatment Goals high doses. (Evidence: fair) It is essential to establish treatment goals of opioid • In reference to long-acting opioids, titration must therapy with regard to pain relief and improvement in be carried out with caution and overdose and mis function. (Evidence: good) use must be avoided. (Evidence: good) • Methadone is recommended for use in late stages 12.5 Assessment of Effectiveness of Opioid after failure of other opioid therapy and only by Therapy clinicians with specific training in the risks and uses. • Clinicians must understand the effectiveness and (Evidence: limited) adverse consequences of long-term opioid therapy in chronic non-cancer pain and its limitations. (Evi 12.8 Adherence Monitoring dence: fair for short-term, limited for long-term) • Monitoring recommendation for methadone pre • The long-acting opioids in high doses are recom scription is that an electrocardiogram should be mended only in specific circumstances with severe obtained prior to initiation, at 30 days and yearly intractable pain that is not amenable to short-act thereafter. (Evidence: fair) ing or moderate doses of long-acting opioids, as • In order to reduce prescription drug abuse and there is no significant difference between long-act- doctor shopping, adherence monitoring by UDT

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and PMDPs provide evidence that is essential to the management are summarized. The majority of treat identification of those patients who are non-com ment recommendations are based on evidence consen pliant or abusing prescription drugs or illicit drugs. sus and practice patterns, rather than high quality evi (Evidence: fair) dence alone. Thus, opioids for chronic non-cancer pain should be reserved for select patients with moderate or 12.9 Monitoring and Managing Side Effects severe pain that significantly affects function or quality • It is essential to monitor for side effects and man of life. Appropriate evaluation, documentation, screen age them appropriately including discontinuation ing, and risk stratification is indicated from initiation of opioids if indicated. (Evidence: fair) through the continuation of opioid therapy. • Constipation must be closely monitored and a In conclusion, the focus of these guidelines has been bowel regimen be initiated as soon as deemed nec to objectively evaluate the evidence with the application essary. (Evidence: good) of consensus and practice patterns to curb opioid abuse, • It is recommended that a policy of driving under misuse, and overuse, and at the same time maintain ac the influence of drugs be developed and moni cess to opioids for patients who are in need of them. tored during initiation of therapy, changes in the Acknowledgments dosages, and addition of other centrally acting agents. (Evidence: good) The authors wish to thank Sekar Edem for assistance in the search of the literature; Alvaro F. Gomez, MA, and 12.10 The Final Phase Tom Prigge, MA, for manuscript review; and Tonie M. • Chronic opioid therapy may be continued, with Hatton and Diane E. Neihoff, transcriptionists, for their continuous adherence monitoring, modified at any assistance in preparation of this manuscript. We would time during this phase, with fair evidence showing like to thank the editorial board of Pain Physician for effectiveness of opioids in well-selected popula review and criticism in improving the manuscript. tions, in conjunction with or after failure of oth Disclosures er modalities of treatments with improvement in physical and functional status and minimal adverse Funding: There was no external funding in the prep effects. (Evidence: fair) aration of this manuscript. Internal funding provided by • Methadone and buprenorphine are recommended the American Society of Interventional Pain Physicians for use in late stages after failure of other opioid was limited to travel and lodging expenses of the authors. therapy and only by clinicians with specific training Editorially, appropriate measures were taken to avoid in the risks and uses. (Evidence: limited) any conflicting opinions from authors receiving funding • A trial of opioid rotation may be considered for pa from the industry. The panel was multidisciplinary with tients requiring escalating doses. (Evidence: limited) academicians, practitioners, and geographically diverse. • Chronic opioid therapy should be monitored for Of the 55 members involved in preparing the guidelines, adverse effects and to manage them appropriately. there were 2 pharmacists, 2 psychologists, 2 registered (Evidence: good) nurses, one statistician, one physical therapist, 2 research coordinators, one librarian, one academic radiologist, 3 13. 0 CONCLUSION residents or fellows, and the remaining (40) were practic These guidelines were developed based on an ex ing interventional pain physicians, either in an academic tensive review of the literature, consensus among the setting or in private practice. Many of the practitioners panelists, and practice patterns. There are numerous fa are also involved in drug detoxification. talities with increasing therapeutic use and abuse, this Author withdrawals: The first author of the 2008 may be related to a lack of understanding and educa opioid guidelines, Andrea Trescot, MD, who has not par tion in the proper application of opioid therapy. Fur ticipated initially, has withdrawn her name due to time thermore, the evidence supporting efficacy for use of constraints. A second author, Xiulu Ruan, MD, who par opioids as a treatment for chronic non-cancer pain is fair ticipated sporadically, withdrew his name due to time for short-term to improve pain and function, whereas it constraints and lack of appropriate involvement. is limited due to lack of literature in reference to long- term efficacy or effectiveness. For practitioners consid Conflicts of Interest: ering opioid use, multiple recommendations for opioid Ten of the 55 authors provided information that they

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received funding from the industry; however, of these, harvard.edu only 2 (less than 4%) were receiving funding from drug 3. Sairam Atluri, MD is Medical Director, Tri-State Spine makers and with multidisciplinary authorships (18%) re Care Institute, Cincinnati, OH [email protected] ceiving funding for research or engaged in speaking from 4. Carl C. Balog, MD is an interventional pain physician at the industry. Oregon Pain Associates, Portland, OR drcsaba@com-

Dr. Benyamin is a clinical investigator with Epimed and cast.net receives research support from Cephalon/Teva, Bio- 5. Ramsin M. Benyamin, MD is the Medical Director, Mil Delivery Sciences International, Inc., Mundipharma lennium Pain Center, Bloomington, IL, and Clinical Research GmbH & Co., AstraZeneca, Purdue Pharma, Assistant Professor of Surgery, College of Medicine, LP, and Theravance. University of Illinois, Urbana-Champaign, IL ramsin- Dr. Burton is a consultant for Medtronic and Boston Scien [email protected] tific. He serves on the Speaker's Bureau for Johnson & 6. Mark V. Boswell, MD, PhD is Chairman, Department of Johnson, Archimedes, Cephalon, and Jazz. Anesthesiology and Perioperative Medicine, Univer Dr. Caraway is a consultant for Medtronic, Inc., Spinal sity of Louisville, Louisville, KY mark.boswell@louis- Modulation, Inc., and Vertos, Inc. ville.edu Dr. Datta receives research support from Sucampo Phar 7. Keith R. Brown, PharmD is a pharmacist at Murray Cal maceuticals and an honorarium from Smith and loway County Hospital, Murray, KY krbrownrph@aol.

Nephew. com Dr. Deer is a consultant and research advisor for Bioness, 8. Brian M. Bruel, MD is Assistant Professor, Departments Medtronic, St. Jude, Spinal Modulation, and Vertos. of Physical Medicine & Rehabilitation and Anesthe Dr. Falco is a Consultant for St. Jude Medical Inc. and siology & Pain Management, McDermott Center for Joimax Inc. Pain Management, UTSW Spine Center, University of Dr. Grider is an educational trainer for Vertos Medical Texas Southwestern Medical Center , Dallas, TX bbru- Dr. Hayek is a consultant for Boston Scientific. [email protected] Dr. Helm is a clinical investigator with Epimed and receives 9. David A. Bryce, MD is from Advanced Pain Manage research support from Cephalon/Teva, AstraZeneca, ment, Madison, [email protected] and Purdue Pharma, LP. 10. Patricia A. Burks, LPT is a licensed physical therapist at Dr. Hirsch is a consultant for CareFusion and receives roy the Pain Management Center of Paducah, Paducah, alties for products related to vertebral augmenta KY [email protected] tion. He also participated in an Aetrium focus group 11. Allen W. Burton, MD is a Professor and Chairman, De and received compensation. partment of Pain Medicine, University of Texas MD Dr. A. Kaye is a speaker for Depomed, Inc. Anderson Cancer Center, Houston, TX awburton@ Dr. Silverman is a Speaker for Purdue Pharma and Reckit houstonpainassociates.com Benckiser 12. Aaron K. Calodney, MD is a Staff Physician and Direc Dr. Vallejo receives research support from Cephalon/Teva, tor and Research Coordinator Implantable Therapies BioDelivery Sciences International, Inc., Mundip at NeuroCare Network, Tyler, TX aaroncalodney@

harma Research GmbH & Co., AstraZeneca, Purdue me.com Pharma, LP, and Theravance. 13. David L. Caraway, MD is with St. Mary's Pain Relief Center, Huntington, WV [email protected] Author Affiliations 14. Kimberly A. Cash, RT is a Research Coordinator at the Note: All authors after the first author are listed in alpha Pain Management Center of Paducah, Paducah, KY betical order. [email protected] 1. Laxmaiah Manchikanti, MD is Medical Director of the 15. Paul J. Christo, MD is Associate Professor, Johns Hop Pain Management Center of Paducah, Paducah, KY kins University School of Medicine, Director, Multidisci and Clinical Professor, Anesthesiology and Periopera plinary Pain Fellowship (2003-201 1), Director, Blaustein tive Medicine, University of Louisville, Louisville, KY Pain Treatment Center (2003-2008), Division of Pain [email protected] Medicine, Department of Anesthesiology and Critical 2. Salahadin Abdi, MD, PhD is Chief, Division of Pain Medi Care Medicine, Baltimore, MD. [email protected] cine at Beth Israel Deaconess Medical Center, Brook- 16. Kim S. Damron, RN is a Nursing Administrator at the line, MA, and Associate Professor of Anesthesiology, Pain Management Center of Paducah, Paducah, KY Harvard Medical School, Boston, MA. sabdi@bidmc. [email protected] wvwv.painphysicianjournal.com S99

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17. Sukdeb Datta, MD is Medical Director, Laser Spine & ment of Anesthesiology, Division of Pain Medicine, Pain Institute, New York, NY [email protected] University of Kentucky, Lexington, KY. mharned@

18. Timothy R. Deer, MD is Medical Director, The Center me.com for Pain Relief and Clinical Professor, Anesthesiology, 31. Salim M. Hayek, MD, PhD is Associate Professor, De West Virginia University School of Medicine, Charles partment of Anesthesiology, Chief of the Division ton, WV [email protected] of Pain Medicine, University Hospitals of Cleveland, 19. Sudhir Diwan, MD is Executive Director of The Spine Cleveland, OH; and a member of the Outcomes Re and Pain Institute of New York. sudhir.diwan63@ search Consortium, Cleveland, OH. Salim. hayek@uh- gmail.com hospitals.org 20. Ike Eriator, MD is Associate Professor of Public Health, 32. Standiford Helm II, MD is Medical Director, The Helm Jackson State University, Jackson, MS, Director of the Center for Pain Management, Laguna Hills, CA. Pain Program, University of Mississippi Medical Cen [email protected] ter, Jackson, MS [email protected] 33. Joshua A. Hirsch, MD is Chief of Minimally Invasive 21 . Frank J.E. Falco, MD is Medical Director of the Mid At Spine Surgery, Depts. of Radiology and Neurosurgery, lantic Spine & Pain Physicians of Newark, DE, Director, Massachusetts General Hospital and Associate Profes Pain Medicine Fellowship, Temple University Hospi sor of Radiology, Harvard Medical School, Boston, tal, Philadelphia, PA, and Associate Professor, Depart MA. [email protected] ment of PM&R, Temple University Medical School, 34. Jeffrey W. Janata, PhD is Associate Professor of Psy Philadelphia, PA. [email protected] chiatry, Director, Behavioral Medicine Program Uni 22. Bert Fellows, MA is Director Emeritus of Psychological versity Hospitals of Cleveland Case Western Reserve Services at the Pain Management Center of Paducah, University, Cleveland, OH [email protected] Paducah, KY [email protected] 35. Adam M. Kaye, PharmD is Clinical Professor, Thomas 23. Stephanie Geffert, MLIS is Director of Research and Ed J. Long School of Pharmacy and Health Sciences, Uni ucation and Administrative Assistant at Mid Atlantic versity of the Pacific, Stockton, CA. [email protected] Spine & Pain Physicians of Newark, DE and Fellowship 36. Alan D. Kaye, MD, PhD is Chairman and Professor, Coordinator at Temple University Hospital, Philadel Dept of Anesthesia LSU Health Science Center, New phia, PA [email protected] Orleans, LA [email protected] 24. Christopher G. Gharibo, MD is Medical Director of 37. David S. Kloth, MD is Medical Director of Connecticut Pain Medicine and Associate Professor of Anesthesi Pain Care, Danbury, CT. [email protected] ology and Orthopedics, Department of Anesthesiol 38. Dhanalakshmi Koyyalagunta, MD is Associate Profes ogy, NYU Langone-Hospital for Joint Diseases, NYU sor, Medical Director, Pain Management Center Uni School of Medicine, New York, NY. [email protected] versity of Texas, MD Anderson Cancer Center, Dept. 25. Scott E. Glaser, MD is the Medical Director of Pain Spe of Anesthesiology & Pain Medicine, Houston, TX cialists of Greater Chicago, Burr Ridge, IL. sglaser@ [email protected] painchicago.com 39. Marion Lee, MD is Director of Centers for Pain Man 26. Jay S. Grider, DO, PhD is Medical Director, UK Health agement, Tifton, GA [email protected] care Pain Services, Division Chief, Pain and Regional 40. Yogesh Malla, MD is an Interventional Pain Physician at Anesthesia and Associate Professor, Department of the Pain Management Center of Paducah, Paducah, Anesthesiology, University of Kentucky, Lexington, KY. [email protected] KY [email protected] 41. Kavita N. Manchikanti, MD is a second year resident in 27. Haroon Hameed, MD is with the Department of Physi Physical Medicine and Rehabilitation at the Univer cal Medicine and Rehabilitation, The Johns Hopkins sity of Kentucky, Lexington, KY kavita. manchikanti@ University School of Medicine, Baltimore, MD. hha- gmail.com [email protected] 42. Carla D. McManus, RN, BSN is a Nursing Administra 28. Mariam Hameed, MD is with the Department of Physi tor at the Pain Management Center of Paducah, cal Medicine and Rehabilitation, The Johns Hopkins Paducah, KY [email protected] University School of Medicine, Baltimore, MD mha- 43. Vidyasagar Pampati, MSc is a Statistician at the Pain [email protected] Management Center of Paducah, Paducah, KY 29. Hans Hansen, MD is the Medical Director of The Pain [email protected] Relief Centers, Conover, NC. [email protected] 44. Allan T. Parr, MD is Medical Director, Premier Pain Cen 30. Michael E. Harned, MD is Assistant Professor, Depart ter, Covington, LA [email protected]

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45. Ramarao Pasupuleti, MD is Medical Director, Center Department of Anesthesiology, Albany, NY for Pain Management, Bowling Green, KY rampasu- 51. Lee T. Snook, MD is Medical Director of Metropolitan [email protected] Pain Management Consultants, Inc., Sacramento, CA. 46. Vikram Patel, MD is Medical Director of ACMI Pain [email protected] Care, Algonquin, IL. [email protected] 52. Daneshvari R. Solanki, MD is Professor of Anesthesia 47. Nalini Sehgal, MD is Medical Director, Interventional and Pain Management, University of Texas Medical Pain Program, University of Wisconsin School of Branch, Galveston, TX. [email protected] Medicine and Public Health and Associate Professor, 53. Deborah H. Tracy, MD is Medical Director, Institute Department of Orthopedics and Rehabilitation Med of Interventional Pain Management, Brooksville, FL. icine, Madison, Wl. [email protected] [email protected] 48. Sanford M. Silverman, MD is Medical Director of Com 54. Ricardo Vallejo, MD, PhD is Director of Research, Mil prehensive Pain Medicine, Pompano Beach, FL san- lennium Pain Center, Bloomington, IL; and Adjunct [email protected] Professor of Biology, Illinois State University, Normal, 49. Vijay Singh, MD is Medical Director, Spine Pain Diag IL. [email protected] nostics Associates, Niagara, Wl. [email protected] 55. Bradley W. Wargo, DO is an interventional pain physi 50. Howard S. Smith, MD is Professor and Academic Direc cian at the McFarland Clinic, Mary Greeley Medical tor of Pain Management for Albany Medical College Center, Ames, IA. [email protected]

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