Rethinking the role of opioids in the outpatient management of chronic nonmalignant pain.

Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2014.921610

Vol. 30, No. 10, 2014, 2051–2062

Article ST-0067.R1/921610 All rights reserved: reproduction in whole or part not permitted

Curr Med Res Opin Downloaded from informahealthcare.com by Nyu Medical Center on 06/14/15 For personal use only.

Review Rethinking the role of opioids in the outpatient management of chronic nonmalignant pain

David A. Provenzano

Abstract

Edgeworth Medical Commons, Sewickley, PA, USA

Eugene R. Viscusi Thomas Jefferson University, Philadelphia, PA, USA Address for correspondence: David A. Provenzano MD, President, Pain Diagnostics and Interventional Care, 301 Ohio River Boulevard, Suite 203, Edgeworth Medical Commons, Sewickley, PA 15143, USA. Tel.: +1 412 221 7640; Fax: +1 412 490 9850; [email protected] Keywords: Abuse – Analgesic – Chronic pain – Multimodal therapy – Opioids Accepted: 1 May 2014; published online: 18 June 2014 Citation: Curr Med Res Opin 2014; 30:2051–62

Objective: Opioid analgesics are commonly and increasingly prescribed by physicians for the management of chronic pain. However, strong evidence supports the need for strategies that reduce opioid use. The objective of this review is to outline limitations associated with opioid use and discuss therapeutic techniques that can be adopted to optimize the use of opioids in the management of chronic nonmalignant pain. Scope: Literature searches through MEDLINE and Cochrane databases were used to identify relevant journal articles. The search was limited to articles published from January 1980 to January 2014. Additional references were obtained from articles extracted during the database search. Relevant search terms included opioid, opioid abuse, chronic pain management, written care agreements, urine drug testing, and multimodal therapy. Findings: Opioids exhibit a well established abuse potential and evidence supporting the efficacy of opioids in chronic pain management is limited. In addition, opioid exposure is associated with adverse effects on multiple organ systems. Effective strategies designed to mitigate opioid abuse and diversion and optimize clinical outcomes should be employed. Conclusions: Appropriate patient selection through identification of risk factors, urine drug testing, and access to prescription monitoring programs has been shown to effectively improve care. Structured opioid therapy in a multimodal platform, including use of a low initial dose, prescription of alternative non-opioid analgesics including non-steroidal anti-inflammatory drugs and acetaminophen, as well as development of written care agreements to individualize and guide therapy has also been shown to improve patient outcomes. Implementation of opioid allocation strategies has the potential to encourage appropriate opioid use and improve patient care.

Introduction Over 75 million people in the United States suffer from chronic pain, a figure that exceeds the prevalence of heart disease and cancer combined1,2. The resultant healthcare expenses and occupational financial losses cost the United States $560 to $635 billion a year3,4. Patterns of analgesic medication use mirror the prevalence of chronic pain, as analgesics compose 17% to 23% of United States’ over-the-counter drug use – the highest use of any drug class5. Moreover, a significant and increasing proportion of drug use is attributable to opioid analgesics6–9. The rising prevalence of opioid use presents a serious public health concern. In an epidemiologic study of outpatients receiving long-term opioid therapy, approximately 35% of opioid users were opioid abusers10, and an ! 2014 Informa UK Ltd www.cmrojournal.com

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estimated 75% of drug overdoses were related to opioids11,12. In addition, chronic opioid therapy adversely affects multiple organ systems13, and has limited data supporting its long-term effectiveness for the management of chronic nonmalignant pain14. Despite evidence suggesting that current opioid prescription and use practices are problematic, opioid prescription rates are on the rise15, and American Geriatric Society guidelines advocate first-line use of opioids in the management of chronic, nonmalignant pain in individuals over the age of 6516. The influence of primary care physicians (PCPs) on the dissemination of opioids is substantial. For example, in 2004, 61% of ambulatory care patients in the Kaiser Permanente Northwest healthcare system received opioids for lower-back pain17. Furthermore, approximately 40% of the immediate-release and extended-release opioids prescribed in the United States are written by PCPs18 and 81% of Americans who abuse opioids receive a prescription from a single physician. Furthermore, diversion of prescribed opioids by patients from legal distribution and dispensing channels is a major contributing factor to abuse, suggesting that PCPs can have a widespread impact on opioid use and abuse19. Taken together, the compelling data on opioid abuse, concerning side effects, and the role of PCPs in opioid prescriptions establish the need to reassess opioid use in pain management. This review discusses opioid risk profiles and efficacy concerns, and identifies alternative analgesics and practices that can mitigate opioid misuse and diversion in the outpatient setting.

Methods Automated literature searches through the MEDLINE and Cochrane databases were used to identify relevant journal articles published from January 1980 to January 2014. Key search terms included opioid, opioid abuse, chronic pain management, written care agreements, urine drug testing, and multimodal therapy. We obtained additional references from articles discovered during the database search.

Defining the problem: challenges of pain management in the primary care setting High rates of opioid use in the ambulatory care setting are a product of several contributing factors. During the 1990s, new opioid regulations by state medical boards promoted the use of opioids for nonmalignant pain, relaxing prescription practices20. In 2000, the Joint Commission heightened awareness of pain management by releasing new standards for the treatment of pain21,22. These changes encouraged liberal opioid use and influenced prescription 2052


patterns21. Furthermore, pharmaceutical companies heavily promoted opioids in the late 1990s, while minimizing the risk for addiction23, but their rising commercial availability was not accompanied by an increase in physician education15. The scarcity of literature generated on opioid use in the long-term management of chronic pain complicates evidence-based decision making. As a whole, these elements eased patient access to opioids, prompting increased rates of opioid abuse. The analgesic efficacy of opioids in the management of acute pain is well documented, but the net clinical benefit of chronic opioid exposure remains uncertain. Due to a lack of extensive evaluation, it remains unclear whether opioid use promotes significant long-term gains in the management of chronic nonmalignant pain24–26. In a systematic review of 41 randomized trials, Furlan et al.26 reported that weak opioids were not superior to the nonopioid alternative analgesic drugs studied (non-steroidal anti-inflammatory drugs [NSAIDs] and tricyclic antidepressants). Efficacy concerns do not fully encapsulate the limitations of opioid use; tolerance, opioid-induced hyperalgesia, and opioid-associated adverse events (AEs) can contribute to suboptimal disease management13,27. Tolerance is characterized by an increase in opioid dose required to achieve a desired analgesic response. Frequent tolerance-driven dose adjustments can complicate management. Furthermore, high-potency opioid use is associated with higher rates of opioid abuse than low-dose opioid use28. Opioid-induced hyperalgesia may also occur and is an increased sensitivity to noxious stimuli with a lowered pain threshold secondary to opioid use27.

The negative impact of opioid use across multiple organ systems A majority of guidelines advocate the use of opioids only after patients have failed non-opioid analgesic therapy (Table 1)29–34. This is largely a reflection of the prognostic implications of chronic opioid use. Opioid exposure is associated with negative multi-organ system effects (Table 2)13,57–70, and chronic opioid use increases the risk of AEs. Fatal overdose occurs in only 0.04% of patients exposed to opioids71, but opioids are involved in 75% of drug-overdose-related deaths11. Intentional misuse and abuse of opioids contributes significantly to the frequency of opioid-related adverse effects71.

Cognition and brain function The interrelationship between opioids and cognition is well characterized72,73. Acute exposure to opioids can www.cmrojournal.com ! 2014 Informa UK Ltd

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Table 1. Oral analgesic alternatives to opioids26,29–56.


Drug class

Benefits

Major limitation(s)

Acetaminophen

Well-documented efficacy in the management of mild-to-moderate nociceptive pain Effective in moderate-to-severe pain if used in conjunction with opioids Benign side-effect profile relative to opioids

Hepatotoxicity (44 g/day)

Non-steroidal anti-inflammatory drugs

Well documented efficacy in the management of nociceptive pain

Dose-related gastrointestinal, cardiovascular, and renal adverse events

Antiepileptics

Demonstrated efficacy in the management of neuropathic pain

AEs are drug specific but can include blood dyscarias and hepatotoxicity

Antidepressants (tricyclic antidepressants [TCAs] and serotonin–norepinephrine reuptake inhibitors [SNRIs])

Effective in the management of nociceptive and neuropathic pain

TCAs * Anticholinergic effects (e.g., hypotension, constipation, and blurred vision) * Cardiac arrhythmias SNRIs * Hepatotoxicity * Serotonin syndromea

Non-benzodiazepine muscle relaxants

Enhance analgesic effects of other drugs

AEs are drug specific but can include hepatotoxicity Drug dependence Unclear long-term efficacy

AE ¼ adverse event. a Condition characterized by confusion, autonomic hyperactivity, and neuromuscular dysfunction secondary to excess levels of serotonin.

induce transient sedation57. Sedation can present concomitantly with opioid-induced somnolence and cognitive impairment but generally subsides within days57,72. Delirium can develop following initial opioid administration or following a switch to high-dose opioid treatment57,72,73. Occasionally, generalized involuntary twitches and spasms (myoclonus) can develop secondary to high-dose opioid ingestion. Treatment of opioidinduced myoclonus frequently involves dose reduction and may require an opioid rotation to improve symptoms57,72. The natural history of opioid-associated AEs of the central nervous system may be related to opioid-induced structural changes in gray matter73. In 2011, an observational study used magnetic resonance imaging to track morphologic changes in the cortex of patients receiving dose-titrated oral morphine over a 1-month period. Investigators reported that shortly following morphine exposure, structural changes were apparent in multiple regions of the brain, including areas involved in reward processing. The degree of change was proportional to the morphine dose. In addition, many of the gray matter changes persisted on follow-up scans that were performed on average 4.7 months after opioids had been discontinued73. In the setting of chronic opioid use, the presence of comorbidities such as dementia can increase susceptibility to delirium72; as opioid dose is increased, the cognitive effects become more pronounced57,72. In addition, a study of 1883 patients published in 2012 reported a

dose-dependent association between depression rates and opioid dose74. A growing body of evidence suggests that patients with mood disorders are more likely to receive opioids, and at higher doses, than the general population75–77. Increased opioid use in a population in which these drugs may have a pathophysiological role in disease progression is clearly problematic.

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Respiratory Respiratory complications are the most extensively evaluated opioid-related AEs13,57–62. Opioids directly reduce sensitivity at the brain stem’s respiratory center, reducing respiration rate, blunting the cough response, and inducing irregular breathing that can lead to hypercapnia, hypoxia, apnea and, in some cases, death13,62,78,79. Respiratory arrest is the most common cause of opioid-related death13,79 and opioids induce respiratory depression at doses commonly prescribed to provide pain relief62,78. Opioid activity on the respiratory centers of the brain can exhibit a dose-related association with the development of central and obstructive sleep apnea59,61,62,80. Obstructive sleep apnea is a breathing disorder characterized by pauses in breathing during sleep as a result of mechanical upper airway obstruction. Central sleep apnea is defined as repeated stops in breathing during sleep in the absence of upper airway obstruction81–83. In addition, patients do not develop tolerance to the development of central apnea; it has been shown to continue to occur even in patients taking opioids chronically for a minimum of 6 2053


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Table 2. Adverse events related to opioid use13,57–70. Organ system

Adverse event

Central nervous system

Sedation Somnolence Cognitive impairment Delirium Myoclonus Disordered sleep Increased fall risk Depression

(REM) and non-REM sleep63,85. Based on animal models, it is hypothesized that opioids disrupt sleep due to their ability to antagonize adenosine A1 receptors within the basal forebrain and pontine reticular formation – locations where adenosine levels modulate consciousness and sleep64. However, further exploration of the effects of opioids on sleep is required because current evidence is contradictory, as some studies have indicated that opioids improve sleep quality in patients experiencing pain, especially in patients with osteoarthritic pain61,65.


Respiratory system Respiratory depression * Hypoxia * Hypercapnia * Apnea Central sleep apnea Obstructive sleep apnea Ataxic breathing Respiratory arrest and death Cardiovascular system

Bradycardia Vasodilatation Orthostatic hypotension Increased risk of cardiovascular events

Nausea/vomiting Gastric reflux Delayed gastric emptying Intestinal anti-secretory activity Constipation Abdominal cramping Abdominal distention

Gastrointestinal system

Endocrine system GnRH inhibition * Decreased testosterone * Decreased androstendedione * Decreased dehydroepiandosterone sulfate Decreased libido Testicular atrophy Sexual dysfunction Early menopause Immune system Increased histamine release Inhibited macrophage and neutrophil recruitment Altered cytokine production Inhibited macrophage and natural killer cell activity Decreased wound healing Cancer progression Pruritus Increased HIV replication (e.g., increased expression of CCR5 and alteration of chemokine production) GnRH ¼ gonadotropin-releasing hormone; HIV ¼ human immunodeficiency virus.

months62. Interestingly, although being overweight is a risk factor for obstructive sleep apnea in the general population84, it has been reported that low-weight patients receiving opioids are at the highest risk of developing central sleep apnea62. Limited data indicate that opioid exposure can also lead to sleep disturbances through interruption of restorative stages of rapid eye movement 2054


Cardiovascular The impact of opioids on the cardiovascular (CV) system can result in negative patient outcomes13,66,86,87. Opioids can induce vasodilation, bradycardia, and baroreceptor inhibition, producing orthostatic hypotension13. Orthostatic hypotension may facilitate the development of dizziness, an oft-reported side effect of opioid ingestion26,72. Evidence also suggests that opioid use significantly elevates myocardial infarction (MI) risk66,86,87. A retrospective study of 1.7 million patients identified an odds ratio of 1.28 for MI in patients using opioids compared with non-opioid users86. Furthermore, in a case–control study by Solomon and colleagues87, codeine was associated with a 1.62 relative risk (RR) of CV events at 180 days in patients 465 years of age. This relationship appears to be dose dependent. In a study by Carman et al.66, investigators identified a 1.21 incidence rate ratio (IRR) in patients exposed to low-dose opioids and an IRR of 1.89 in patients receiving high-dose opioids compared with opioid-naı¨ve patients.

Gastrointestinal Opioids induce drastic changes in gastrointestinal (GI) function that can impact quality of life and influence adequacy of pain management. Opioids increase upper GI tract smooth muscle tone, act upon the chemoreceptor trigger zone, and increase vestibular sensitivity. These physiological disturbances contribute to the generation of nausea and vomiting13,88. Patients report nausea and vomiting as some of the most bothersome complications of opioid use57. Avouac et al.24 reported that 30% of patients receiving opioids develop nausea and 13% develop vomiting. Commonly, episodes of nausea and vomiting resolve without treatment, although significant vomiting requiring therapeutic intervention may occur89. Increased muscle tone in the lower GI tract can slow motility, a contributing factor to the development of constipation, the most common complication of opioid use13,88. Opioids also delay gastric emptying and reduce intestinal secretory activity and blood flow, further increasing intestinal transit time13,90. In an www.cmrojournal.com ! 2014 Informa UK Ltd



epidemiological study of 2055 patients conducted in 2008, 57% of patients ingesting opioids complained of constipation and 33% reported that, of all opioid-related complications, constipation had the greatest impact on their quality of life91. High-dose opioid treatment elevates constipation risk and intensifies symptom severity. The significance of constipation cannot be overlooked. Opioid-induced constipation does not respond well to laxative administration92,93. Furthermore, tolerance does not develop to opioidinduced constipation and, if left untreated, it can result in intestinal perforation, ileus, colonic distention, and obstipation91. Additional GI AEs associated with opioid use include abdominal cramping and pain, bloating, gastric reflux, and abdominal distention. The net result of these diverse GI complications is poor treatment adherence and decreased quality of life93,94. For example, in the Patient Reports of Opioid-related Bothersome Effects study, patients missed, decreased, or stopped using opioids to avoid opioid-induced AEs93.


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CCR5 expression97. The effects of opioids on immunomodulation do not appear to be subject to tolerance, although this has not been explored extensively in humans98. In addition, laboratory studies suggest that indirect immunoinhibitory and direct tumorigenic opioid activity may promote cancer progression99,100. Preclinical results have been supported by data from retrospective studies in various postoperative patient populations100–102. However, to date, no prospective human studies have been conducted to confirm this association103.

Injury and disability

Pruritus is a distressing AE associated with opioid use, and research suggests that histamine release from mast cells contributes to its development. Histamine release may also account, at least partly, for opioid-induced peripheral vasodilation57. Opioids have demonstrated the ability to cause immunologic impairment by limiting macrophage and neutrophil sequestration, modifying the synthesis of cytokines, and impairing macrophage and natural killer cell activity70. In a retrospective analysis of 1039 cases of pneumonia, opioids were associated with a two-fold increased risk for pneumonia. Investigators hypothesized that opioid-induced immunosuppression, in conjunction with sedation and blunting of the cough response, increased pneumonia risk70. Inhibition of angiogenesis and immune cell activity by opioid-induced immunosuppression can retard wound healing95,96. Opioids have been implicated in the progression of HIV infection; they facilitate immune-cell invasion by HIV through various mechanisms, including increased

Sedation, dizziness, and cognitive impairment resulting from opioid use can cause substantial psychomotor deficits that can elevate fall risk and have devastating repercussions104–107. A meta-analysis of six prospective studies performed by Takkouche et al.104 identified a 1.38 RR for the development of fractures in patients receiving opioids compared with non-opioid users. In a retrospective cohort study of 17,310 patients published in 2011, opioid use was associated with 120 fractures per 1000 personyears, compared with 25 fractures per 1000 person-years for patients receiving NSAIDs105. A nested case–control study evaluated the impact of opioid use on motor vehicle accident rates. Investigators reported that low-, moderate-, and high-dose opioid use among drivers was associated with a 21%, 29%, and 42% increase, respectively, in risk for motor vehicle accidents compared with non-opioid users108. These results are consistent with numerous studies indicating that patients exposed to opioids are at increased risk for motor vehicle accidents108–113. Buckeridge et al.113 investigated the association between opioids and injury (a composite of soft-tissue laceration or subluxations due to falls or motor vehicle accidents, or fractures, excluding vertebrae, in patients aged 65 years and older) and reported that low- and medium-dose opioids increase the risk of injury. In addition, opioids may complicate therapy in patients with chronic nonmalignant pain by increasing susceptibility to disability114–119. A prospective study of 715 patients with low-back pain concluded that, after 6 months, opioids were associated with higher rates of disability compared with other treatment modalities as measured by the Roland–Morris Disability Questionnaire114. An epidemiologic study of approximately 17,000 patients by Eriksen et al. reported that opioid use did not improve functional capacity or quality of life in patients experiencing chronic nonmalignant pain119. Multiple prospective and epidemiological studies have reported similar findings, suggesting a link between opioid use and disability116–118.



Endocrine Opioids act on the hypothalamus to inhibit release of gonadotropin-releasing hormone, preventing production of gonadal hormones such as testosterone67,68. In men, decreased libido, testicular atrophy, and subsequent sexual dysfunction can result from persistently low testosterone levels67–69. Women with opioid-induced androgen deficiency present with sexual dysfunction and can develop menopause at a younger age relative to opioidnaı¨ve women69.

Immunologic

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Post surgical Although opioids are used frequently in the postoperative setting, results of recent studies indicate that they may ultimately be responsible for poor patient outcomes. In a retrospective analysis of compensation claimants from 1994 to 2001, analgesic-related deaths accounted for an increase in postoperative mortality rates compared with the general population120. In addition, perioperative opioid administration lengthens postoperative hospital stay, and these patients are more likely to be readmitted than patients managed with alternative therapies121,122. Postoperative opioid use is also associated with an increase in prolonged opioid use, putting patients at risk for AEs associated with chronic opioid use122,123.

Shifting the paradigm The prognostic implications of inappropriate opioid use are significant. As noted above, the efficacy of opioids in chronic disease management is uncertain. Opioid-related AEs reduce quality of life and, in a minority of cases, have devastating consequences. In addition, failure to clearly address the limitations of opioid use can have legal repercussions. Fitzgibbon et al. reported that the percentage of chronic pain management claims increased from 2% in the period between 1977 and 1999 to 8% in the period from 1999 to 2004124. In a separate analysis, Fitzgibbon and colleagues reported that from 2005 to 2008, the most common reasons for medication management claims in patients treated for chronic pain were failure by the prescribing physician to communicate a care plan, inadequate monitoring and documentation of care, inappropriately high doses of opioids, and unethical or illegal clinical practices125. These data stress the importance of appropriate opioid allocation to potentially reduce both abuse rates and the at-risk population. An effective balance between adequate pain control and appropriate opioid dissemination can be achieved through measures that require the concerted efforts of institutions, pharmaceutical companies, physicians, and patients (Figure 1).

Patient selection Patient selection is a critical step in the opioid prescription process and a thorough history, physical examination, and appropriate laboratory testing can assist in patient stratification and the identification of patients who will gain the greatest net clinical benefit from exposure to opioids. Patients under consideration for opioid use should be selected following a thorough review of risk factors for abuse, psychosocial factors, mood, pain severity, and functional capacity18,126–128. 2056


A retrospective study by Boscarino et al.129 identified young age, pain impairment, higher drug-dependence severity, a greater number of opioid prescriptions, and history of antisocial personality as risk factors for the development of opioid addiction. Additional risk factors identified by others include a personal or family history of abuse, poor social support, and a comorbid psychiatric disorder130. Determination of these risk factors is achievable with a thorough history. In addition, screening tools such as the Screener and Opioid Assessment for Patients with Pain131 and the Opioid Risk Tool132 incorporate evaluations of psychosocial factors and historical data that are designed to provide physicians with validated risk-assessment tools. Assessing quality of pain through a history and physical examination can provide critical information regarding etiology and guide analgesic agent choice133. In a cohort study of postoperative patients conducted from 2007 to 2009, investigators noted that psychosocial factors (e.g., anxiety and preoperative opioid use) and not pain intensity were correlated with long-term opioid use123. The analgesic landscape is varied and each agent is associated with specific pharmacologic benefits (Table 1) and adverse effects. For example, opioid therapy alone is unlikely to optimize benefit in patients with neuropathic pain134. Opioid initiation should be preceded by a trial of non-opioid therapy and opioid use should be limited to patients whose symptomatology and disease processes most benefit from opioid exposure. In some cases, consultation may be required to identify the most appropriate therapeutic option18,128. Increased physician awareness of risk factors and knowledge of pain presentations most amenable to opioid therapy could inform prescription practices and divert opioid use to patients who receive the greatest benefit and are at low risk for developing opioid addiction. A review of prescription monitoring program (PMP) data, if available prior to prescribing opioids, can provide additional historical patient information18. PMPs provide physicians with tools to identify and track patients receiving opioid prescriptions across states and monitor who dispenses them135,136. In states as diverse as New York, Idaho, and Texas, the implementation of PMPs led to 50% reductions in opioid prescribing136. However, these statistics should be assessed cautiously. When physicians perceive difficulty in prescribing an agent, they are less likely to use it – even if it is the most efficacious and potentially beneficial treatment option137. Furthermore, reductions in prescription rates do not necessarily reflect a reduction in abuse rates. Therefore, although it is clear that PMPs can effectively alter prescription practices, they must be used in concordance with other measures for curbing abuse. Urine drug testing (UDT) can aid in patient evaluation and facilitate positive patient behaviors. Addiction treatment centers have become increasingly reliant on www.cmrojournal.com ! 2014 Informa UK Ltd


Patient selection


Initiating opioid therapy

Opioid therapy maintenance


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• Identification of risk factors for abuse • Identification of psychological factors that influence duration of use and efficacy Consultation for treatment if necessary • Identification of etiology and quality of pain • Prescription monitoring program • Urine/serum drug testing • Consultation if necessary (pain medicine specialist and psychologist)

• • • • •

Use of low initial opioid dose Informed consent Written care agreement Multimodal therapy Consultation if necessary

• Physician-patient dialogue • Monitoring for adverse event development and treatment goal progress • Assessment of analgesia, activities of daily living, adverse events and potential for aberrant drug behavior (4As) • Abuse screening Abuse screening questionnaires Random pill counting Urine/serum drug testing • Prescription monitoring program • Multimodal therapy • Consultation if necessary

Figure 1. Opioid abuse mitigation strategies.

UDT, but these tests are used sparingly in the chronic pain management setting. UDTs are reliable and accurate evaluation tools that are simple to perform on patients under consideration for opioid use138. Patients with positive UDT results should be counseled on their current opioid use and evaluated for alternative analgesics (Table 1)18,138,139. However, alternative analgesics can be associated with class-specific AEs (Table 1). NSAIDs are associated with serious dose-related GI, CV, and renal AEs140,141. Although observational studies have indicated that NSAIDs may reduce all-cause mortality, and there is conflicting evidence regarding their CV safety profile, there remains a need for safer NSAID drug products141,142. However, topical and lower-dose submicron particle NSAIDs exhibit the potential to reduce the risk of AEs associated with NSAID use143,144.

treatment efficacy over the course of weeks and months127. Guidance also supports the use of informed consent in initial therapy, providing patients with an understanding of the risks and benefits of opioid therapy126–128. The use of written care agreements prior to initiating therapy has been shown to be beneficial126–128. Written care agreements present patients with a set of rules that they must adhere to in order to continue opioid therapy. The content of written care agreements is not universal, but they frequently contain stipulations that outline proper use; define abuse; require use of alternative therapies, urine or blood testing and random pill counting; and prohibit the selling or sharing of opioids (Table 3)139,145. However, it is important to note that data regarding the efficacy of written care agreements in reducing opioid abuse rates are sparse and definitive conclusions cannot be drawn from current data139.

Initiation of therapy Guidelines indicate that initiation of opioid therapy should be approached cautiously with a low opioid dose and only following a trial of non-opioid analgesics127,128. Current guidance from some authorities also states that initial therapy should be viewed as a trial to evaluate ! 2014 Informa UK Ltd www.cmrojournal.com

Monitoring patients during therapy Managing chronic pain with opioids requires frequent physician–patient engagement to assess for treatment goal progress (e.g., improvement of functional status and/ Rethinking the role of opioids in chronic nonmalignant pain Provenzano & Viscusi

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Table 3. Contents of a written care agreement18.


Definitions of opioid abuse, dependence, addiction, and other risks associated with use Description of appropriate opioid use An understanding that random urine/serum drug testing, pill counts, and other methods to screen for abuse may occur An understanding that patients must make physician aware of all drugs they are currently using Stipulations noting patients can only use a single physician and a single pharmacy Restrictions on alcohol and illicit drug use Consequences of failure to follow the contract Patients are participating in other forms of care

or relief of pain), signs of abuse and AEs, and need for opioid titration or discontinuation. Regular assessment of the analgesia, activities of daily living, AEs, and potential for aberrant drug-related behavior (4As), as outlined in the Pain Assessment and Documentation Tool described by Passik et al.146, can help standardize and streamline patient monitoring. The Pain Assessment and Documentation Tool is a questionnaire that can be completed during a patient visit, providing clinicians with a simple documented record of patient progress across four domains146. Several standardized screening tools have been developed or adapted to assess patients and help detect developing or ongoing opioid addiction123,130. The CAGE– Adapted to Include Drugs, Cyr-Wartman, Screener and Opioid Assessment for Patients with Pain, Opioid Risk Tool, and Skinner Trauma History screens are the most easily applicable screening tests in the clinical setting128,131–133; however, documentation regarding their efficacy in risk reduction is limited and these tests are nonspecific and not diagnostic. Therefore, they should only be used as components of a comprehensive screening program135. Urine drug testing can be implemented as an adjunct to screening questionnaires to help identify concomitant illicit drug use138. The discovery of illicit drug use in patients receiving opioids can help diagnose addiction and identify patients who need inpatient treatment or opioid detoxification. High-risk patients may benefit greatly from a multidisciplinary approach that incorporates urine/serum drug screening, checklists, and counseling146. Multimodal therapy may be beneficial in a subset of patients receiving opioids for management of chronic nonmalignant pain. Using agents with additive or synergistic effects may allow for reduced opioid dose and usage. Tramadol/acetaminophen combinations have demonstrated efficacy in the management of pain and functional impairment147–150. Initiating muscle relaxants has been shown to supplement the pain-alleviating effects of other analgesics151; however, evidence supporting the long-term use of muscle relaxants is limited36. Although no definitive conclusions could be drawn, a systematic review performed 2058


by Windmill and colleagues evaluating opioid-sparing strategies highlighted strategies such as cognitive behavioral therapy that can be used to reduce opioid use while maintaining adequate analgesia37. Administered alone, opioids demonstrate poor efficacy in the treatment of neuropathic pain; however, dual opioid–anticonvulsant drug combinations may allow for safer and more efficacious pain management. Keskinbora et al.134 investigated the efficacy and safety of a gabapentin and opioid combination versus opioids alone in 75 patients with neuropathic pain. Opioids administered with gabapentin produced pain relief that was sustained for a longer duration, reduced AE rates, and lowered opioid dose requirements compared with opioids alone.

Discontinuation of therapy Guidelines suggest that opioids should be discontinued in patients with lack of analgesic response, lack of functional improvement, AEs, and/or opioid abuse or misuse18,126,127. The Departments of Veteran Affairs and Defenses’ guidelines on the management of chronic pain suggest that opioid tapering should be individualized to achieve patient treatment goals. In general, the guidelines suggest tapering opioids by 20% to 50% of the original dose each week, while providing physician and psychosocial support throughout the tapering process126. The American Society of Interventional Pain Physicians advocates a tapering rate of 10% of the original dose each week and suggests the use of clonidine to relieve physical withdrawal symptoms (e.g., diarrhea and myoclonus)18. Antidepressants can be added to the treatment regimen during tapering to manage the mood changes associated with opioid abstinence. Following discontinuation, patients require long-term follow-up to ensure quality of care18,126. Tapering techniques may also be incorporated into programs to wean patients off of opioids. In a pain rehabilitation program study, patients transitioning from opioids on a tapered regimen reported improvements in mood and pain severity152. Tapering to the lowest effective dose can provide adequate analgesia while reducing risk of sedation, confusion, and delirium in elderly patients145. Improvements in patient and physician education on the above mitigation strategies may reduce opioid abuse rates. However, it is important to note that in a comprehensive systematic review, Chou et al.153 reported that there is limited evidence that opioid abuse mitigation and identification strategies impact opioid abuse and use patterns.

Conclusion It is clear that opioid prescription and abuse patterns share a symbiotic relationship that is influenced by an array of www.cmrojournal.com ! 2014 Informa UK Ltd



contributing factors. As PCPs are often the front line in managing patients with chronic pain, increased awareness may promote appropriate opioid use and mitigate abuse. Opioids are important tools that can effectively address pain, but they should not be the foundation of pain management. Opioids exhibit a concerning abuse potential and can lead to life-altering events affecting multiple organ systems, often as a result of misuse and abuse. Opioid mitigation and diversion reduction strategies are rarely practiced by PCPs. Physician-led societies and government agencies recognize the concern opioids pose and have provided proposals such as the FDA’s Risk Evaluation and Mitigation Strategy to alter opioid prescription patterns. Given these considerations, a clear benefit must be demonstrated if opioid therapy is initiated. Alternative analgesics can be effectively used to manage pain when applicable, further limiting opioid use to patients who will receive the highest net clinical benefit. Although alternatives to opioids are associated with risks, new formulations, such as topical and submicron-particle capsule NSAIDs, can improve the risk:benefit profile of drugs with well documented efficacy. In addition, if opioid therapy is initiated, steps should be undertaken to monitor for abuse and assess whether opioid discontinuation should be considered. The adoption of these strategies could reduce opioid abuse and its societal repercussions.

Transparency Declaration of funding Editorial support was sponsored by Iroko Pharmaceuticals LLC. Declaration of financial/other relationships D.A.P. has disclosed that he is a consultant for Medtronic Inc., St. Jude Medical S.C. Inc., Kimberly-Clark Worldwide Inc., and Janssen Pharmaceuticals Inc. E.R.V. has disclosed that he is a consultant for AcelRx Pharmaceuticals Inc., Cadence Pharmaceuticals Inc., Cubist Pharmaceuticals Inc., Mallinckrodt Pharmaceuticals, Pacira Pharmaceuticals Inc., and Salix Pharmaceuticals Inc. His university has received research funding from AcelRx Pharmaceuticals Inc., Cumberland Pharmaceuticals Inc., and Pacira Pharmaceuticals Inc. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Acknowledgments Editorial assistance was provided by Colville Brown, MD of AlphaBioCom LLC.

References 1. Institute of Medicine Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press (US), 2011



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2. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Health, United States, 2006: With Chartbook on Trends in the Health of Americans. Hyattsville, MD, 2006 3. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain 2012;13:715-24 4. Turk DC. Clinical effectiveness and cost-effectiveness of treatments for patients with chronic pain. Clin J Pain 2002;18:355-65 5. Kaufman DW, Kelly JP, Rosenberg L, et al. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002;287:337-44 6. Caudill-Slosberg MA, Schwartz LM, Woloshin S. Office visits and analgesic prescriptions for musculoskeletal pain in US: 1980 vs. 2000. Pain 2004;109:514-19 7. Thielke SM, Simoni-Wastila L, Edlund MJ, et al. Age and sex trends in longterm opioid use in two large American health systems between 2000 and 2005. Pain Med 2010;11:248-56 8. Wilson RD. Analgesic prescribing for musculoskeletal complaints in the ambulatory care setting after the introduction and withdrawal of cyclooxygenase-2 inhibitors. Arch Phys Med Rehab 2009;90:1147-51 9. Boudreau D, Von Korff M, Rutter CM, et al. Trends in long-term opioid therapy for chronic non-cancer pain. Pharmacoepidemiol Drug Saf 2009;18:1166-75 10. Boscarino JA, Rukstalis MR, Hoffman SN, et al. Prevalence of prescription opioid-use disorder among chronic pain patients: comparison of the DSM-5 vs. DSM-4 diagnostic criteria. J Addict Dis 2011;30:185-94 11. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA 2013;309:657-9 12. Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers – United States, 1999–2008. MMWR 2011;60:1487-92 13. Moallem SA, Balali-Mood K, Balali-Mood M. In: Mozayani A, Raymon L, eds. Handbook of Drug Interactions Opioids and Opiates. New York, NY: Humana Press, 2012:159-91 14. Alford DP, Liebschutz J, Chen IA, et al. Update in pain medicine. J Gen Intern Med 2008;23:841-5 15. Bollinger L. Under the Counter: The Diversion of Abuse of Controlled Prescription Drugs in the U.S. New York, NY: Columbia University, 2005 16. American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc 2009;57:1331-46 17. Deyo RA, Smith DHM, Johnson ES, et al. Opioids for back pain patients: primary care prescribing patterns and use of services. J Am Board Fam Med 2011;24:717-27 18. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part 2 – guidance. Pain Phys 2012;15(3 Suppl):S67-116 19. Bates C, Laciak R, Southwick A, Bishoff J. Overprescription of postoperative narcotics: a look at postoperative pain medication delivery, consumption and disposal in urological practice. J Urol 2011;185:551-5 20. Joranson DE, Gilson AM, Dahl JL, Haddox JD. Pain management, controlled substances, and state medical board policy – a decade of change. J Pain Symptom Manag 2002;23:138-47 21. Manchikanti L, Fellows B, Ailinani H, Pampati V. Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. Pain Phys 2010;13:401-35 22. Phillips DM. JCAHO pain management standards are unveiled. Joint Commission on Accreditation of Healthcare Organizations. JAMA 2000;284:428-9 23. Van Zee A. The promotion and marketing of oxycontin: commercial triumph, public health tragedy. Am J Public Health 2009;99:221-7 24. Avouac J, Gossec L, Dougados M. Efficacy and safety of opioids for osteoarthritis: a meta-analysis of randomized controlled trials. Osteoarthritis Cartilage 2007;15:957-65


2059



October 2014

25. Chou R, Ballantyne JC, Fanciullo GJ, et al. Research gaps on use of opioids for chronic noncancer pain: findings from a review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline. J Pain 2009;10:147-59 26. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. Can Med Assoc J 2006;174:1589-94 27. Chu LF, Clark DJ, Angst MS. Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study. J Pain 2006;7:43-8 28. Martin BC, Fan MY, Edlund MJ, et al. Long-term chronic opioid therapy discontinuation rates from the TROUP study. J Gen Intern Med 2011;26:1450-7 29. Conaghan PG, Dickson J, Grant RL, Guideline Development Group. Care and management of osteoarthritis in adults: summary of NICE guidance. BMJ 2008;336:502-3 30. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2012;64:455-74 31. Zhang W, Doherty M, Arden N, et al. EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2005;64:669-81 32. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16:137-62 33. Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage 2010;18:476-99 34. American Academy of Orthopaedic Surgeons. Treatment of Osteoarthritis of the Knee (non-arthroplasy). Rosemont, IL: American Academy of Orthopaedic Surgeons, 2008 35. Coxib and traditional NSAID Trialists (CNT) Collaboration, Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal antiinflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013;382:769-79 36. Dillon C, Paulose-Ram R, Hirsch R, Gu Q. Skeletal muscle relaxant use in the United States: data from the Third National Health and Nutrition Examination Survey (NHANES III). Spine 2004;29:892-6 37. Windmill J, Fisher E, Eccleston C, et al. Interventions for the reduction of prescribed opioid use in chronic non-cancer pain. Cochrane Database Syst Rev 2013;9:CD010323 38. Bhamb B, Brown D, Hariharan J, et al. Survey of select practice behaviors by primary care physicians on the use of opioids for chronic pain. Curr Med Res Opin 2006;22:1859-65 39. Krenzelok EP, Royal MA. Confusion: acetaminophen dosing changes based on NO evidence in adults. Drugs R D 2012;12:45-8 40. Towheed TE, Maxwell L, Judd MG, et al. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;1:CD004257 41. Rao P, Knaus EE. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J Pharm Pharm Sci 2008;11:81-110s 42. Carr DB, Goudas LC. Acute pain. Lancet 1999;353:2051-8 43. McGettigan P, Henry D. Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med 2013;10:e1001388 44. Wolfe F, Zhao S, Lane N. Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients: a survey of 1,799 patients with osteoarthritis, rheumatoid arthritis, and fibromyalgia. Arthritis Rheum 2000;43:378-85 45. Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev 2009;3:CD007076

2060


46. Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011;3:CD007938 47. Selph S, Carson S, Fu R, et al. Drug Class Review: Neuropathic Pain: Final Update 1 Report. Portland (OR): Oregon Health & Science University, 2011 48. Parsons B, Tive L, Huang S. Gabapentin: a pooled analysis of adverse events from three clinical trials in patients with postherpetic neuralgia. Am J Geriatr Phamacother 2004;2:157-62 49. Pilowsky I, Hallett EC, Bassett DL, et al. A controlled study of amitriptyline in the treatment of chronic pain. Pain 1982;14:169-79 50. Chappell AS, Ossanna MJ, Liu-Seifert H, et al. Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13week, randomized, placebo-controlled trial. Pain 2009;146:253-60 51. Chappell AS, Desaiah D, Liu-Seifert H, et al. A double-blind, randomized, placebo-controlled study of the efficacy and safety of duloxetine for the treatment of chronic pain due to osteoarthritis of the knee. Pain Pract 2011;11:33-41 52. Hochberg MC, Wohlreich M, Gaynor P, et al. Clinically relevant outcomes based on analysis of pooled data from 2 trials of duloxetine in patients with knee osteoarthritis. J Rheumatol 2012;39:352-8 53. Trindade E, Menon D, Topfer L-A, Coloma C. Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a metaanalysis. Can Med Assoc J 1998;159:1245-52 54. Vuppalanchi R, Hayashi PH, Chalasani N, et al. Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network. Aliment Pharmacol Ther 2010;32:1174-83 55. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20 56. Kuehn BM. Serotonin syndrome update. JAMA 2011;306:2661 57. McNicol E, Horowicz-Mehler N, Fisk RA, et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain 2003;4:231-56 58. Camı´ J, Farre´ M. Drug addiction. N Engl J Med 2003;349:975-86 59. Mogri M, Khan MI, Grant BJ, Mador MJ. Central sleep apnea induced by acute ingestion of opioids. Chest 2008;133:1484-8 60. Wang D, Teichtahl H, Drummer O, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest 2005;128:1348-56 61. Webster LR, Choi Y, Desai H, et al. Sleep-disordered breathing and chronic opioid therapy. Pain Med 2008;9:425-32 62. Walker JM, Farney RJ, Rhondeau SM, et al. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med 2007;3:455-61 63. Wang D, Teichtahl H. Opioids, sleep architecture and sleep-disordered breathing. Sleep Med Rev 2007;11:35-46 64. Moore JT, Kelz MB. Opiates, sleep, and pain: the adenosinergic link. Anesthesiology 2009;111:1175-6 65. Turk DC, Cohen MJ. Sleep as a marker in the effective management of chronic osteoarthritis pain with opioid analgesics. Semin Arthritis Rheum 2010;39:477-90 66. Carman WJ, Su S, Cook SF, et al. Coronary heart disease outcomes among chronic opioid and cyclooxygenase-2 users compared with a general population cohort. Pharmacoepidemiol Drug Saf 2011;20:754-62 67. Kalyani RR, Gavini S, Dobs AS. Male hypogonadism in systemic disease. Endocrinol Metab Clin North Am 2007;36:333-48 68. Daniell HW, Lentz R, Mazer NA. Open-label pilot study of testosterone patch therapy in men with opioid-induced androgen deficiency. J Pain 2006;7:200-10 69. Smith HS, Elliott JA. Opioid-induced androgen deficiency (OPIAD). Pain Phys 2012;15(3 Suppl):ES145-56 70. Dublin S, Walker RL, Jackson ML, et al. Use of opioids or benzodiazepines and risk of pneumonia in older adults: a population-based case-control study. J Am Geriatr Soc 2011;59:1899-907 71. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA 2011;305:1315-21

www.cmrojournal.com ! 2014 Informa UK Ltd




October 2014

72. O’Neil CK, Hanlon JT, Marcum ZA. Adverse effects of analgesics commonly used by older adults with osteoarthritis: focus on non-opioid and opioid analgesics. Am J Geriatr Pharmacother 2012;10:331-42 73. Younger JW, Chu LF, D’Arcy NT, et al. Prescription opioid analgesics rapidly change the human brain. Pain 2011;152:1803-10 74. Merrill JO, Von Korff M, Banta-Green CJ, et al. Prescribed opioid difficulties, depression and opioid dose among chronic opioid therapy patients. Gen Hosp Psychiatry 2012;34:581-7 75. Bohnert ASB, Ilgen MA, Ignacio RV, et al. Risk of death from accidental overdose associated with psychiatric and substance use disorders. Am J Psychiatry 2012;169:64-70 76. Gomes T, Mamdani MM, Dhalla IA, et al. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med 2011;171:686-91 77. Wasan AD, Davar G, Jamison R. The association between negative affect and opioid analgesia in patients with discogenic low back pain. Pain 2005;117:450-61 78. White JM, Irvine RJ. Mechanisms of fatal opioid overdose. Addiction 1999;94:961-72 79. Pattinson KTS. Opioids and the control of respiration. Brit J Anaesth 2008;100:747-58 80. Teichtahl H, Prodromidis A, Miller B, et al. Sleep-disordered breathing in stable methadone programme patients: a pilot study. Addiction 2001;96:395-403 81. Park JG, Ramar K, Olson EJ. Updates on definition, consequences, and management of obstructive sleep apnea. Mayo Clin Proc 2011;86:549-54 82. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 1999;22:667-89 83. American Academy of Sleep Medicine. International classification of sleep disorders: diagnostic and coding manual. Westchester, IL: American Academy of Sleep Medicine, 2005 84. Dealberto MJ, Ferber C, Garma L, et al. Factors related to sleep apnea syndrome in sleep clinic patients. Chest 1994;105:1753-8 85. Wenk M, Po¨pping D, Chapman G, et al. Long-term quality of sleep after remifentanil-based anaesthesia: a randomized controlled trial. Br J Anaesth 2013;110:250-7 86. Li L, Setoguchi S, Cabral H, Jick S. Opioid use for noncancer pain and risk of myocardial infarction amongst adults. J Intern Med 2013; 273:511-26 87. Solomon DH, Rassen JA, Glynn RJ, et al. The comparative safety of opioids for nonmalignant pain in older adults. Arch Intern Med 2010;170:1979-86 88. Swegle JM, Logemann C. Management of common opioid-induced adverse effects. Am Fam Phys 2006;74:1347-54 89. Flake ZA, Scalley RD, Bailey AG. Practical selection of antiemetics. Am Fam Phys 2004;69:1169-74 90. De Luca A, Coupar IM. Insights into opioid action in the intestinal tract. Pharmacol Ther 1996;69:103-15 91. Cook SF, Lanza L, Zhou X, et al. Gastrointestinal side effects in chronic opioid users: results from a population-based survey. Aliment Pharmacol Ther 2008;27:1224-32 92. Davies EC, Green CF, Mottram DR, Pirmohamed M. The use of opioids and laxatives, and incidence of constipation, in patients requiring neck-of-femur (NOF) surgery: a pilot study. J Clin Pharm Ther 2008;33:561-6 93. Bell TJ, Panchal SJ, Miaskowski C, et al. The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European patient survey (PROBE 1). Pain Med 2009;10:35-42 94. Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg 2001;182(5A Suppl):11-18S 95. Martin JL, Charboneau R, Barke RA, Roy S. Chronic morphine treatment inhibits LPS-induced angiogenesis: implications in wound healing. Cell Immunol 2010;265:139-45 96. Martin JL, Koodie L, Krishnan AG, et al. Chronic morphine administration delays wound healing by inhibiting immune cell recruitment to the wound site. Am J Pathol 2010;176:786-99

97. Ho WZ, Guo CJ, Yuan CS, et al. Methylnaltrexone antagonizes opioidmediated enhancement of HIV infection of human blood mononuclear phagocytes. J Pharmacol Exp Ther 2003;307:1158-62 98. Martucci C, Panerai AE, Sacerdote P. Chronic fentanyl or buprenorphine infusion in the mouse: similar analgesic profile but different effects on immune responses. Pain 2004;110:385-92 99. Mathew B, Lennon FE, Siegler J, et al. The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth Analg 2011;112:558-67 100. Lennon FE, Moss J, Singleton PA. The m-opioid receptor in cancer progression: is there a direct effect? Anesthesiology 2012;116:940-5 101. Gupta K, Kshirsagar S, Chang L, et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 2002;62:4491-8 102. Bortsov AV, Millikan RC, Belfer I, et al. mu-Opioid receptor gene A118G polymorphism predicts survival in patients with breast cancer. Anesth 2012;116:896-902 103. Exadaktylos AK, Buggy DJ, Moriarty DC, et al. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesth 2006;105:660-4 104. Takkouche B, Montes-Martinez A, Gill SS, Etminan M. Psychotropic medications and the risk of fracture: a meta-analysis. Drug Saf 2007;30:171-84 105. Miller M, Sturmer T, Azrael D, et al. Opioid analgesics and the risk of fractures in older adults with arthritis. J Am Geriatr Soc 2011;59:430-8 106. French DD, Campbell R, Spehar A, et al. National outpatient medication profiling: medications associated with outpatient fractures in communitydwelling elderly veterans. Br J Clin Pharmacol 2007;63:238-44 107. Kamal-Bahl SJ, Stuart BC, Beers MH. Propoxyphene use and risk for hip fractures in older adults. Am J Geriatr Pharmacother 2006;4:219-26 108. Gomes T, Redelmeier DA, Juurlink DN, et al. Opioid dose and risk of road trauma in Canada: a population-based study. JAMA Intern Med 2013;173:196-201 109. Gibson JE, Hubbard RB, Smith CJP, et al. Use of self-controlled analytical techniques to assess the association between use of prescription medications and the risk of motor vehicle crashes. Am J Epidemiol 2009;169:761-8 110. Engeland A, Skurtveit S, Mørland J. Risk of road traffic accidents associated with the prescription of drugs: a registry-based cohort study. Ann Epidemiol 2007;17:597-602 111. Verster JC, Veldhuijzen DS, Volkerts ER. Effects of an opioid (oxycodone/ paracetamol) and an NSAID (bromfenac) on driving ability, memory functioning, psychomotor performance, pupil size, and mood. Clin J Pain 2006;22:499-504 112. Zacny JP. A review of the effects of opioids on psychomotor and cognitive functioning in humans. Exp Clin Psychopharmacol 1995;3:432-466 113. Buckeridge D, Huang A, Hanley J, et al. Risk of injury associated with opioid use in older adults. J Am Geriatr Soc 2010;58:1664-70 114. Ashworth J, Green DJ, Dunn KM, Jordan KP. Opioid use among low back pain patients in primary care: is opioid prescription associated with disability at 6 month follow-up? Pain 2013;154:1038-44 115. Kidner CL, Mayer TG, Gatchel RJ. Higher opioid doses predict poorer functional outcome in patients with chronic disabling occupational musculoskeletal disorders. J Bone Joint Surg Am 2009;91:919-27 116. Franklin GM, Stover BD, Turner JA, et al. Early opioid prescription and subsequent disability among workers with back injuries: the Disability Risk Identification Study Cohort. Spine 2008;33:199-204 117. Gross DP, Stephens B, Bhambhani Y, et al. Opioid prescriptions in Canadian workers’ compensation claimants: prescription trends and associations between early prescription and future recovery. Spine 2009;34:525-31 118. Webster BS, Verma SK, Gatchel RJ. Relationship between early opioid prescribing for acute occupational low back pain and disability duration, medical costs, subsequent surgery and late opioid use. Spine 2007;32:2127-32 119. Eriksen J, Sjogren P, Bruera E, et al. Critical issues on opioids in chronic noncancer pain: an epidemiological study. Pain 2006;125:172-9 120. Juratli SM, Mirza SK, Fulton-Kehoe D, et al. Mortality after lumbar fusion surgery. Spine 2009;34:740-7



2061



October 2014

121. Ordera G, Gan TJ, Johnson BH, Robinson SB. Effect of opioid-related adverse events on outcomes in selected surgical patients. J Pain Palliat Care Pharmacother 2013;27:62-70 122. Alam A, Gomes T, Zheng H, et al. Long-term analgesic use after low-risk surgery: a retrospective cohort study. Arch Intern Med 2012;172:425-30 123. Carroll I, Barelka P, Wang CKM, et al. A pilot cohort study of the determinants of longitudinal opioid use after surgery. Anesth Analg 2012;115:694-702 124. Fitzgibbon DR, Posner KL, Domino KB, et al. Chronic pain management: American Society of Anesthesiologists Closed Claims Project. Anesthesiology 2004;100:98-105 125. Fitzgibbon DR, Rathmell JP, Michna E, et al. Malpractice claims associated with medication management for chronic pain. Anesthesiology 2010;112:948-56 126. The Management of Opioid Therapy for Chronic Pain Working Group. Departments of Veteran Affairs and Defense. Clinical Practice Guideline for Management of Opioid Therapy for Chronic Pain. Washington, DC: Departments of Veteran Affairs and Defense, 2010 127. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009;10:113-30 128. Savage SR. Assessment for addiction in pain-treatment settings. Clin J Pain 2002;18(4 Suppl):S28-38 129. Boscarino JA, Rukstalis M, Hoffman SN, et al. Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care system. Addiction 2010;105:1776-82 130. Højsted J, Sjøgren P. Addiction to opioids in chronic pain patients: a literature review. Eur J Pain 2007;11:490-518 131. Butler SF, Budman SH, Fernandez K, Jamison RN. Validation of a screener and opioid assessment measure for patients with chronic pain. Pain 2004;112:65-75 132. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the opioid risk tool. Pain Med 2005;6:43242 133. Jamison RN, Clark JD. Opioid medication management: clinician beware! Anesthesiology 2010;112:777-8 134. Keskinbora K, Pekel AF, Aydinli I. Gabapentin and an opioid combination versus opioid alone for the management of neuropathic cancer pain: a randomized open trial. J Pain Symptom Manag 2007;34:183-9 135. Solanki DR, Koyyalagunta D, Shah RV, et al. Monitoring opioid adherence in chronic pain patients: assessment of risk of substance misuse. Pain Phys 2011;14:E119-31 136. Manchikanti L, Whitfield E, Pallone F. Evolution of the National All Schedules Prescription Electronic Reporting Act (NASPER): a public law for balancing treatment of pain and drug abuse and diversion. Pain Phys 2005;8:335-47 137. Fishman SM. Commentary in response to Paulozzi et al.: prescription drug abuse and safe pain management. Pharmacoepidemiol Drug Saf 2006;15:628-31 138. Christo PJ, Manchikanti L, Ruan X, et al. Urine drug testing in chronic pain. Pain Phys 2011;14:123-43

2062


139. Starrels JL, Becker WC, Alford DP, et al. Systematic review: treatment agreements and urine drug testing to reduce opioid misuse in patients with chronic pain. Ann Intern Med 2010;152:712-20 140. Brater DC. Anti-inflammatory agents and renal function. Semin Arthritis Rheum 2002;32(3 Suppl 1):33-42 141. Mangoni AA, Woodman RJ, Gaganis P, et al. Use of non-steroidal antiinflammatory drugs and risk of incident myocardial infarction and heart failure, and all-cause mortality in the Australian veteran community. Br J Clin Pharmacol 2010;69:689-700 142. Andrew R, Derry S, Taylor RS, et al. The costs and consequences of adequately managed chronic non-cancer pain and chronic neuropathic pain. Pain Practice 2014;14:79-94 143. Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev 2012;9:CD007400 144. Gibofsky A, Silberstein S, Argoff C, et al. Lower-dose diclofenac submicron particle capsules provide early and sustained acute patient pain relief in a phase 3 study. Postgrad Med 2013;125:130-8 145. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part I – evidence assessment. Pain Phys 2012;15(3 Suppl):S1-65 146. Passik SD, Kirsh KL, Whitcomb L, et al. A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy. Clin Ther 2004;26:552-61 147. Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane Database Syst Rev 2006;3:CD005522 148. Emkey R, Rosenthal N, Wu S-C, CAPSS-114 Study Group. Efficacy and safety of tramadol/acetaminophen tablets (Ultracet) as add-on therapy for osteoarthritis pain in subjects receiving a COX-2 nonsteroidal antiinflammatory drug: a multicenter, randomized, double-blind, placebo-controlled trial. J Rheumatol 2004;31:150-6 149. Park K-S, Choi J-J, Kim W-U, et al. The efficacy of tramadol/acetaminophen combination tablets (Ultracetâ ) as add-on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID). Clin Rheumatol 2012;31:317-23 150. Rosenthal NR, Silverfield JC, Wu S-C, CAPSS-105 Study Group. Tramadol/ acetaminophen combination tablets for the treatment of pain associated with osteoarthritis flare in an elderly patient population. J Am Geriatr Soc 2004;52:374-80 151. van Tulder MW, Touray T, Furlan AD, et al.; Cochrane Back Review Group. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane collaboration. Spine 2003;28:1978-92 152. Townsend CO, Kerkvliet JL, Bruce BK, et al. A longitudinal study of the efficacy of a comprehensive pain rehabilitation program with opioid withdrawal: comparison of treatment outcomes based on opioid use status at admission. Pain 2008;140:177-89 153. Chou R, Fanciullo GJ, Fine PG, et al. Opioids for chronic noncancer pain: prediction and identification of aberrant drug-related behaviors: a review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline. J Pain 2009;10:131-46

www.cmrojournal.com ! 2014 Informa UK Ltd

Opioids Resistance in Chronic Pain Management.

Opioids Resistance in Chronic Pain Management.

Spinal opioids in the management of obstetric pain.

The management of chronic osteoarticular pain in the outpatient setting: results of an ASON audit.

Spinal opioids in the management of acute and postoperative pain.

Opioids for the management of breakthrough pain in cancer patients.

Response to pain management among patients with active cancer, no evidence of disease, or chronic nonmalignant pain in an outpatient palliative care clinic.

Sex differences in chronic pain management practices for patients receiving opioids from the Veterans Health Administration.

Only modest long-term opioid dose escalation occurs over time in chronic nonmalignant pain management.

Pediatric pain management and opioids: the baby and the bathwater.

The Pain and Opioids IN Treatment study: characteristics of a cohort using opioids to manage chronic non-cancer pain.

Adherence to pharmacological pain therapy in patients with nonmalignant pain: the role of patients' knowledge of pain medication.

Transdermal Opioids for Cancer Pain Management.

Management of acute pain in patients on treatment with opioids.

The role of rehabilitation medicine in the management of chronic pain: description of a pain control program and longitudinal outcomes.

Outpatient management of chronic heart failure.

[Cancer pain management: good clinical practices, use of strong opioids].

Long-term use of opioids for complex chronic pain.

Availability and utilization of opioids for pain management: global issues.

Monitoring sedation in patients receiving opioids for pain management.

Combined use of intrathecal opioids and dexmedetomidine in the management of neuropathic pain.

Reflections on the role of opioids in the treatment of chronic pain: a shared solution for prescription opioid abuse and pain.

Interactions of Opioids and HIV Infection in the Pathogenesis of Chronic Pain.

Resident Decision Making: Opioids in the Outpatient Setting.