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Opioid Analgesics

  • Robert N. Jamison
    Correspondence
    Correspondence: Address to Robert N. Jamison, PhD, Department of Anesthesiology, Perioperative and Pain Medicine and Department of Psychiatry, Pain Management Center, Brigham and Women’s Hospital, 850 Boylston St, Ste 320, Chestnut Hill, MA 02467.
    Affiliations
    Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
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  • Jianren Mao
    Affiliations
    Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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      Abstract

      Chronic pain is an international health issue of immense importance that is influenced by both physical and psychological factors. Opioids are useful in treating chronic pain but have accompanying complications. It is important for clinicians to understand the basics of opioid pharmacology, the benefits and adverse effects of opioids, and related problematic issues of tolerance, dependence, and opioid-induced hyperalgesia. In this article, the role of psychiatric comorbidity and the use of validated assessment tools to identify individuals who are at the greatest risk for opioid misuse are discussed. Additionally, interventional treatment strategies for patients with chronic pain who are at risk for opioid misuse are presented. Specific behavioral interventions designed to improve adherence with prescription opioids among persons treated for chronic pain, such as frequent monitoring, periodic urine screens, opioid therapy agreements, opioid checklists, and motivational counseling, are also reviewed. Use of state-sponsored prescription drug monitoring programs is also encouraged. Areas requiring additional investigation are identified, and the future role of abuse-deterrent opioids and innovative technology in addressing issues of opioid therapy and pain are presented.

      Abbreviations and Acronyms:

      OIH (opioid-induced hyperalgesia), PDMP (prescription drug monitoring program)
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      Learning Objectives: On completion of this article, you should be able to (1) identify the major issues associated with opioid analgesics, (2) critically appraise the current literature about opioid analgesics, and (3) examine how opioids can be safely monitored in managing acute and chronic pain.
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      Chronic pain is a serious international problem of immense proportion that can negatively impact every facet of daily living.
      • Goldberg D.S.
      • McGee S.J.
      Pain as a global public health priority.
      • Jamison R.N.
      • Edwards R.R.
      Risk factor assessment for problematic use of opioids for chronic pain.
      It has been estimated that annually more than 100 million Americans have chronic pain.
      Institute of Medicine
      Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.
      Chronic pain affects more individuals than diabetes, cancer, and heart disease combined and is the major reason people visit their primary care physicians. Chronic pain can interfere with sleep, employment, social life, daily activities, and overall quality of life. Chronic pain can also have a negative effect on mood, appetite, energy level, and sexual activities and can contribute to recurrent worried thoughts about finances, family interactions, and future disability.
      • Ohman M.
      • Söderberg S.
      • Lundman B.
      Hovering between suffering and enduring: the meaning of living with serious chronic illness.
      • Söderberg S.
      • Strand M.
      • Haapala M.
      • Lundman B.
      Living with a woman with fibromyalgia from the perspective of the husband.
      • Otis J.D.
      • Cardella L.A.
      • Kerns R.D.
      The influence of family and culture on pain.
      The usefulness of opioids in the treatment of acute and cancer-related pain has been confirmed by several studies.
      • Kalso E.
      • Edwards J.E.
      • Moore R.A.
      • McQuay H.J.
      Opioids in chronic non-cancer pain: systematic review of efficacy and safety.
      An estimated 5 to 8 million Americans use opioids for chronic pain.

      National Institutes of Health. Pathways to Prevention Workshop: The Role of Opioids in the Treatment of Chronic Pain; Executive Summary Final Report. National Institutes of Health website. https://prevention.nih.gov/docs/programs/p2p/ODPPainPanelStatementFinal_10-02-14.pdf. Published September 2014. Accessed April 8, 2015.

      Yet, many physicians and other health care professionals are reluctant to support the use of opioid medication for patients with chronic noncancer pain because of concerns regarding adverse effects, tolerance, and addiction.
      • Bhamb B.
      • Brown D.
      • Hariharan J.
      • Anderson J.
      • Balousek S.
      • Fleming M.F.
      Survey of select practice behaviors by primary care physicians on the use of opioids for chronic pain.
      • Furlan A.D.
      • Sandoval J.A.
      • Mailis-Gagnon A.
      • Tunks E.
      Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects.
      Addiction, in particular, is of prime concern given its intensely negative consequences and its relatively broad prevalence. Over the past decade, there has been a steady increase in use of prescription opioids in the United States, which has been the main contributing factor to the skyrocketing incidence of opioid abuse. The number of opioid prescriptions written for pain increased from 76 million in 1991 to an estimated 219 million in 2011.
      • Olsen Y.
      • Daumit G.L.
      • Ford D.E.
      Opioid prescriptions by U.S. primary care physicians from 1992 to 2001.
      This increase has paralleled the increase in opioid-related overdoses and hospitalizations.

      Centers for Disease Control and Prevention. Prescription Painkiller Overdoses:Use and Abuse of Methadone as a Painkiller. Centers for Disease Control and Prevention website. http://www.cdc.gov/vitalsigns/pdf/2012-07-vitalsigns.pdf. Published July 2012. Accessed April 8, 2015.

      Because of increased availability, prescription opioids have become the most abused class of drug in the United States, with more deaths related to opioid abuse than to cocaine and heroin combined.

      Centers for Disease Control and Prevention. Prescription Painkiller Overdoses:Use and Abuse of Methadone as a Painkiller. Centers for Disease Control and Prevention website. http://www.cdc.gov/vitalsigns/pdf/2012-07-vitalsigns.pdf. Published July 2012. Accessed April 8, 2015.

      Many drug abusers prefer prescription opioids not only for their easier availability compared with street drugs but also for their greater purity due to their regulated manufacture.

      Centers for Disease Control and Prevention. Prescription Painkiller Overdoses:Use and Abuse of Methadone as a Painkiller. Centers for Disease Control and Prevention website. http://www.cdc.gov/vitalsigns/pdf/2012-07-vitalsigns.pdf. Published July 2012. Accessed April 8, 2015.

      • Jamison R.N.
      • Sheehan K.A.
      • Scanlan E.
      • Matthews M.
      • Ross E.L.
      Beliefs and attitudes about opioid prescribing and chronic pain management: survey of primary care providers.
      In fact, patients in the United States consume 80% of all opioid prescriptions worldwide, and prescription drug abuse is perceived to be the fastest growing drug problem in America.

      Centers for Disease Control and Prevention. Prescription Painkiller Overdoses:Use and Abuse of Methadone as a Painkiller. Centers for Disease Control and Prevention website. http://www.cdc.gov/vitalsigns/pdf/2012-07-vitalsigns.pdf. Published July 2012. Accessed April 8, 2015.

      Unfortunately, most clinicians are not adequately prepared to properly diagnose, treat, and closely monitor patients with chronic pain who are prescribed opioids, even though studies have shown that those patients who are at greater risk for misuse of opioids are most likely to be prescribed opioids.
      • Jamison R.N.
      • Sheehan K.A.
      • Scanlan E.
      • Matthews M.
      • Ross E.L.
      Beliefs and attitudes about opioid prescribing and chronic pain management: survey of primary care providers.
      In this article, we present a current review of the pharmacology of opioids and its uses and discuss misuse and abuse issues that are often present when treating patients prescribed opioids for chronic pain. We will also provide an overview of assessment and treatment strategies designed to improve adherence to opioid prescriptions and briefly explore unresolved clinical questions and future considerations.

      Overview of Opioids for Pain

      Opioid Clinical Pharmacology

      The term opioid analgesics refers to a broad class of drugs including (1) alkaloids extracted from poppy seeds (morphine, codeine) and their semisynthetic derivatives (oxycodone, hydromorphone, oxymorphone) and (2) synthetic phenylpiperidines (meperidine, fentanyl) and synthetic pseudopiperidines such as methadone.
      • Chang G.
      • Chen L.
      • Mao J.
      Opioid tolerance and hyperalgesia.
      Opioid analgesics act on 3 major classes of receptors: μ, δ, and κ receptors. Each of these classes of receptors has its representative endogenous ligand (eg, endorphin for the μ receptor and dynorphin for the κ receptor). These classes of opioid receptors are widely distributed throughout the central and peripheral nervous system as well as other systems such as the gastrointestinal tract. On the basis of their pharmacodynamic profiles, opioid analgesics can also be classified as a full agonist at opioid receptors (eg, morphine, fentanyl) or an agonist-antagonist such as buprenorphine.
      • Chen K.Y.
      • Chen L.
      • Mao J.
      Buprenorphine-naloxone therapy in pain management.

      Benefits and Adverse Effects of Opioids

      Activation of opioid receptors produces profound analgesia mediated through a combined presynaptic and postsynaptic effect. Presynaptically, opioid analgesics act on primary nociceptive afferents (inhibition of calcium channels), resulting in the reduced release of neurotransmitters such as substance P and glutamate implicated in nociceptive transmission. Postsynaptically, opioid analgesics directly inhibit postsynaptic neuronal activity by hyperpolarizing cell membranes via opening potassium channels. Other effects of opioids (eg, antitussive, reducing gastrointestinal tract motility) also have practical therapeutic use.
      • Johnston S.
      Effectiveness and safety of high-dose opioids for chronic pain.
      Because of a widespread distribution of opioid receptors both within and outside the nervous system, opioid analgesics also produce a broad spectrum of adverse effects including euphoria, dysphoria, sedation, respiratory depression, constipation, suppression of endocrine systems, cardiovascular disorders (eg, bradycardia), convulsion, nausea, vomiting, pruritus, and miosis.
      • Ballantyne J.
      • Mao J.
      Opioid therapy for chronic pain.
      Although the extent of these adverse effects may differ among individual opioids depending on dose regimen, these effects substantially narrow the clinical therapeutic window for effective opioid therapy.
      • Ballantyne J.
      • Mao J.
      Opioid therapy for chronic pain.
      Because of these adverse effects, particularly for opioid-naive patients, it is always best to start with a low dose and gradually titrate up.
      • Von Korff M.R.
      Long-term use of opioids for complex chronic pain.
      For patients with chronic persistent moderate to severe pain, short-acting opioids can be converted to long-acting opioids in the belief that long-acting opioids provide less fluctuation in analgesic blood levels, fewer adverse effects, and require less frequent dosing. However, there are ongoing controversies about the comparable benefits of either opioid dosing formula.
      • Argoff C.E.
      • Silvershein D.I.
      A comparison of long- and short-acting opioids for the treatment of chronic noncancer pain: tailoring therapy to meet patient needs.

      Opioid Tolerance and Opioid-Induced Hyperalgesia

      In addition to opioid adverse effects, the development of tolerance to opioid analgesics is a major barrier to clinical opioid therapy. Opioid tolerance is a pharmacological phenomenon caused by repeated opioid exposure that results in decreased analgesic effects.
      • Mao J.
      Opioid-induced abnormal pain sensitivity.
      Although the degree of tolerance may differ for individual opioid analgesics, this incomplete tolerance to individual opioid analgesics is considered as a rationale for opioid rotation in opioid-tolerant patients with pain. Although changing to an alternative drug may yield a better balance between analgesia and adverse effects, this process requires a working knowledge of equianalgesic doses, and the long-term efficacy of opioid rotation is questionable.
      • Indelicato R.A.
      • Portenoy R.K.
      Opioid rotation in the management of refractory cancer pain.
      Excessive opioid exposure may produce a paradoxical increase in pain sensitivity manifested as hyperalgesia (exacerbated painful response to noxious stimulation) and/or allodynia (painful response elicited by innocuous stimulation). This opioid-induced hyperalgesia (OIH) has been linked to both short-term (eg, intraoperative remifentanil infusion) and long-term opioid administration.
      • Mao J.
      Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy.
      • Chen L.
      • Malarick C.
      • Seefeld L.
      • Wang S.
      • Houghton M.
      • Mao J.
      Altered quantitative sensory testing outcome in subjects with opioid therapy.
      Although it may be clinically difficult and controversial to differentiate between opioid tolerance and OIH using subjective pain scores, OIH may be related to exacerbated preexisting pain, new onset of pain, increasing pain with opioid dose escalation, and decreasing pain with opioid dose reduction. Accordingly, opioid tolerance and OIH may be improved and exacerbated, respectively, by opioid dose escalation, although the direct clinical impact to OIH has been questioned.
      • Von Korff M.R.
      Long-term use of opioids for complex chronic pain.
      • Chen L.
      • Malarick C.
      • Seefeld L.
      • Wang S.
      • Houghton M.
      • Mao J.
      Altered quantitative sensory testing outcome in subjects with opioid therapy.

      Definitions of Terms and Clinical Issues

      Defining key terms is important to help minimize confusion and clarify discussion about patients prescribed opioids for pain.

      American Adademy of Pain Medicine. Use of opioids for the treatment of chronic pain. American Academy of Pain Medicine website. http://www.painmed.org/files/use-of-opioids-for-the-treatment-of-chronic-pain.pdf. Published 2013. Accessed, April 6, 2015.

      American Society of Addiction Medicine. Definitions Related to the Use of Opioids for the Treatment of Pain: Consensus Statement of the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine. American Society of Addiction Medicine website. http://www.asam.org/docs/publicy-policy-statements/1opioid-definitions-consensus-2-011.pdf?sfvrsn=0. Accessed February 14, 2015.

      American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders: DSM-5.
      Substance misuse is defined as the use of any drug in a manner other than how it is prescribed and indicated for use. Substance abuse is the unlawful use of a substance or use that results in failure to fulfill major obligations or patterns of legal, social, and interpersonal problems caused by such use. Addiction refers to the compulsive use of a drug resulting in physical, social, and psychological harm to the user. Addiction is generally understood to be a chronic condition with an underlying neurobiological dysfunction that, once manifested, is believed to persist and is characterized by (1) an inability to consistently abstain, (2) impairment in behavioral control, (3) craving, (4) diminished recognition of major problems with one’s behaviors and interpersonal relationships, and (5) a dysfunctional emotional response.
      American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders: DSM-5.
      • Gilson A.M.
      • Kreis P.G.
      The burden of the nonmedical use of prescription opioid analgesics.
      • Trescot A.M.
      • Boswell M.V.
      • Atluri S.L.
      • et al.
      Opioid guidelines in the management of chronic non-cancer pain.
      Physical dependence is a common phenomenon in persons taking opioids for a period of time. It is characterized by physical withdrawal symptoms when the opioid is discontinued. Tolerance is a common consequence of long-term opioid treatment (although individual differences in opioid tolerance vary) that is manifested by a need for increasing doses to maintain the same effect. Physical dependence and tolerance are both commonly found among patients who use opioids for chronic pain, and neither of these phenomena is necessarily related to true addiction. Aberrant drug-related behavior is behavior that is suggestive of a substance abuse and/or addiction disorder. Some of these behaviors include obtaining prescription drugs from nonmedical sources, “borrowing” drugs from others, selling prescriptions, seeking prescriptions from multiple clinicians, forging prescriptions, injecting oral formulations, “losing” prescriptions on multiple occasions, having evidence of deterioration in function at work, home, or in the family, and resisting any change to therapy despite evidence of psychological and physical deterioration. A list of these terms and their definitions are presented in Table 1.
      Table 1Definition of Terms
      Data from the American Academy of Pain Medicine,

      American Adademy of Pain Medicine. Use of opioids for the treatment of chronic pain. American Academy of Pain Medicine website. http://www.painmed.org/files/use-of-opioids-for-the-treatment-of-chronic-pain.pdf. Published 2013. Accessed, April 6, 2015.

      the American Society of Addiction Medicine,

      American Society of Addiction Medicine. Definitions Related to the Use of Opioids for the Treatment of Pain: Consensus Statement of the American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine. American Society of Addiction Medicine website. http://www.asam.org/docs/publicy-policy-statements/1opioid-definitions-consensus-2-011.pdf?sfvrsn=0. Accessed February 14, 2015.

      and the American Psychiatric Association.
      American Psychiatric Association
      Diagnostic and Statistical Manual of Mental Disorders: DSM-5.
      Substance misuse—The use of any drug in a manner other than how it is indicated or prescribed
      Substance abuse—The use of any substance when such use is unlawful or when such use is detrimental to the user or others
      Addiction—A primary, chronic, neurobiological disease that is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Addiction is generally understood to be a chronic condition from which recovery is possible; however, the underlying neurobiological dysfunction, once manifested, is believed to persist
      Physical dependence—A state of adaptation that is manifested by a drug class–specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, or decreasing blood levels of the drug and/or by administration of an antagonist
      Tolerance—A state of adaptation in which exposure to a drug induces changes that result in diminution of one or more of the drug’s effects over time
      Aberrant drug-related behavior—Behavior suggestive of a substance abuse and/or addiction disorder. Examples are selling prescription drugs, prescription forgery, stealing or “borrowing” drugs from others, injecting oral formulations, obtaining prescription drugs from nonmedical sources, multiple episodes of prescription “loss,” repeatedly seeking prescriptions from other clinicians, evidence of deterioration in function (work, home, family), and repeated resistance to change therapy despite evidence of physical and psychological problems
      Several earlier studies suggested that most individuals prescribed opioids for the treatment of pain typically do not develop addiction or substance abuse,
      • Gilson A.M.
      • Kreis P.G.
      The burden of the nonmedical use of prescription opioid analgesics.
      although the reported incidence of addiction from prescription opioids has been variable. Most patients receiving long-term opioid therapy experience physical dependence and tolerance to the medication. It has also been suggested that some persons with chronic pain who are undermedicated manifest drug-seeking behaviors by overusing their prescription medication in an attempt to find relief. This concept, known as pseudoaddiction, identifies those patients who, once adequately relieved from the pain, discontinue all drug-seeking behaviors.
      • Passik S.D.
      • Kirsh K.L.
      • Webster L.
      Pseudoaddiction revisited: a commentary on clinical and historical considerations.

      Risk Factors for Prescription Opioid Misuse

      Efforts to improve health care professionals’ ability to identify abuse and diversion of controlled substances have been strongly recommended by the US Department of Justice.
      Department of Justice
      Dispensing controlled substances for the treatment of pain.
      In particular, seeking prescriptions from multiple physicians, using illicit drugs, snorting or injecting medications, selling and diverting prescription drugs, and using drugs in a manner other than its intended use have been identified as particularly problematic. Despite the need to identify misuse of opioids and limit inappropriate prescribing, health care professionals also struggle with providing appropriate pain relief for patients who present with legitimate pain problems.
      • Hampton T.
      Experts point to lessons learned from controversy over rofecoxib safety.
      • Ballantyne J.C.
      • LaForge K.S.
      Opioid dependence and addiction during opioid treatment of chronic pain.
      There are particular problems associated with long-term use of opioids. Some patients become psychologically dependent on the medication,
      • Darnall B.D.
      • Stacey B.R.
      • Chou R.
      Medical and psychological risks and consequences of long-term opioid therapy in women.
      • Kahan M.
      • Wilson L.
      • Mailis-Gagnon A.
      • Srivastava A.
      National Opioid Use Guideline Group
      Canadian guideline for safe and effective use of opioids for chronic noncancer pain: clinical summary for family physicians, Part 2: special populations.
      while others may have signs of impaired cognition,
      • Veldhuijzen D.S.
      • van Wijck A.J.
      • Verster J.C.
      • et al.
      Acute and subchronic effects of amitriptyline 25mg on actual driving in chronic neuropathic pain patients.
      difficulties with psychomotor performance,
      • Mailis-Gagnon A.
      • Lakha S.F.
      • Ou T.
      • et al.
      Chronic noncancer pain: characteristics of patients prescribed opioids by community physicians and referred to a tertiary pain clinic.
      and over time, development of OIH.
      • Chang G.
      • Chen L.
      • Mao J.
      Opioid tolerance and hyperalgesia.
      • Mao J.
      Opioid-induced abnormal pain sensitivity.
      • Mao J.
      Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy.
      • Cohen S.P.
      • Christo P.J.
      • Wang S.
      • et al.
      The effect of opioid dose and treatment duration on the perception of a painful standardized clinical stimulus.
      • Ram K.C.
      • Eisenberg E.
      • Haddad M.
      • Pud D.
      Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain: new perspective of opioid-induced hyperalgesia.
      • Hooten W.M.
      • Mantilla C.B.
      • Sandroni P.
      • Townsend C.O.
      Associations between heat pain perception and opioid dose among patients with chronic pain undergoing opioid tapering.
      There is some evidence that high-dose opioids, which some define as greater than 180-mg morphine equivalent per day, can be particularly dangerous, leading to increasing risk of respiratory depression, central sleep apnea, and sleep-disordered breathing and with lower long-term efficacy.
      • Johnston S.
      Effectiveness and safety of high-dose opioids for chronic pain.
      There is also evidence that early misuse of opioids can increase the chance of leading to addiction,
      • Quello S.B.
      • Brady K.T.
      • Sonne S.C.
      Mood disorders and substance use disorder: a complex comorbidity.
      supporting the need for early risk assessment, careful monitoring, and strategies to assess and improve compliance when indicated.
      • Jamison R.N.
      • Serraillier J.
      • Michna E.
      Screening before embarking: how to screen for addiction risk in opioid prescribing.
      There are some identifiable factors that are related to lower risk of misuse of opioids, including older age, stable mood, a history of being responsible and keeping appointments, not overusing medication, and, in general, presenting in a rational and pleasant manner.
      • Jamison R.N.
      • Edwards R.R.
      Risk factor assessment for problematic use of opioids for chronic pain.
      Risk factors commonly cited in the literature as being associated with opioid misuse include (1) family or personal history of substance abuse, (2) young age, (3) history of legal problems, (4) frequent contact with high-risk individuals or environments, (5) history of previous problems with employers, family, and friends, (6) history of risk-taking and thrill-seeking behavior, (7) smoking cigarettes and regularly using other substances that lead to dependence, (8) history of major depression or anxiety, (9) multiple psychosocial stressors, (10) history of childhood abuse, and (11) previous drug and/or alcohol rehabilitation (Table 2).
      • Jamison R.N.
      • Edwards R.R.
      Risk factor assessment for problematic use of opioids for chronic pain.
      • Turk D.C.
      • Swanson K.S.
      • Gatchel R.J.
      Predicting opioid misuse by chronic pain patients: a systematic review and literature synthesis.
      • Jamison R.N.
      • Link C.L.
      • Marceau L.D.
      Do pain patients at high risk for substance misuse experience more pain? a longitudinal outcomes study.
      • Jamison R.N.
      • Ross E.L.
      • Michna E.
      • Chen L.Q.
      • Holcomb C.
      • Wasan A.D.
      Substance misuse treatment for high-risk chronic pain patients on opioid therapy: a randomized trial.
      Table 2Risk Factors for Opioid Misuse
      • Family history of substance abuse
      • Personal history of substance abuse
      • Young age
      • History of criminal activity and/or legal problems including DUIs
      • Regular contact with high-risk people or high-risk environments
      • Problems with past employers, family members, and friends (mental disorder)
      • Risk-taking or thrill-seeking behavior
      • Heavy tobacco use
      • History of severe depression or anxiety
      • Psychosocial stressors
      • Prior drug and/or alcohol rehabilitation
      DUI = driving under the influence.
      It is important to understand that the determinants of opioid misuse and addiction rest with the user and that many patient-specific factors may increase susceptibility to these problems. Factors such as preexisting personality traits,
      • Verdejo-García A.
      • Lawrence A.J.
      • Clark L.
      Impulsivity as a vulnerability marker for substance-use disorders: review of findings from high-risk research, problem gamblers and genetic association studies.
      a tendency to self-medicate to alleviate symptoms,
      • Passik S.D.
      • Lowery A.
      Psychological variables potentially implicated in opioid-related mortality as observed in clinical practice.
      and opioid craving
      • Martel M.O.
      • Dolman A.J.
      • Edwards R.R.
      • Jamison R.N.
      • Wasan A.D.
      The association between negative affect and prescription opioid misuse in patients with chronic pain: the mediating role of opioid craving.
      • Wasan A.D.
      • Ross E.L.
      • Michna E.
      • et al.
      Craving of prescription opioids in patients with chronic pain: a longitudinal outcomes trial.
      • Wasan A.D.
      • Butler S.F.
      • Budman S.H.
      • et al.
      Does report of craving opioid medication predict aberrant drug behavior among chronic pain patients?.
      have been identified as individual factors that contribute to opioid abuse.

      Issues of Negative Affect and Opioid Use

      Many patients with chronic pain have accompanying psychiatric comorbidity expressed as depression, anxiety, irritability, and negative affect.
      • Ligthart L.
      • Gerrits M.M.
      • Boomsma D.I.
      • Pennix B.W.
      Anxiety and depression are associated with migraine and pain in general: an investigation of the interrelationships.
      • Hawker G.A.
      • Gignac M.A.
      • Badley E.
      • et al.
      A longitudinal study to explain the pain-depression link in older adults with osteoarthritis.
      • Jamison R.N.
      • Edwards R.R.
      • Liu X.
      • et al.
      Effect of negative affect and outcome of an opioid therapy trial among low back pain patients.
      • Grattan A.
      • Sullivan M.D.
      • Saunders K.W.
      • Campbell C.I.
      • Von Korff M.R.
      Depression and prescription opioid misuse among chronic opioid therapy recipients with no history of substance abuse.
      Also, surveys of patients with chronic pain have revealed a high incidence of physical or sexual abuse and early childhood trauma.
      • Jamison R.N.
      • Craig K.D.
      Psychological assessment of persons with chronic pain.
      • Andersson G.B.
      Epidemiological features of chronic low-back pain.
      • Bair M.J.
      • Robinson R.L.
      • Katon W.
      • Kroenke K.
      Depression and pain comorbidity: a literature review.
      Among patients treated in a specialty pain center, studies suggest that between 50% and 80% of patients with chronic pain have signs of psychopathology, making psychiatric problems the most prevalent comorbidity in these patients.
      • Boersma K.
      • Linton S.J.
      Screening to identify patients at risk: profiles of psychological risk factors for early intervention.
      • Celestin J.
      • Edwards R.R.
      • Jamison R.N.
      Pretreatment psychosocial variables as predictors of outcomes following lumbar surgery and spinal cord stimulation: a systematic review and literature synthesis.
      • Edwards R.R.
      • Smith M.T.
      • Klick B.
      • et al.
      Symptoms of depression and anxiety as unique predictors of pain-related outcomes following burn injury.
      In an earlier survey study conducted by Arkinstall et al,
      • Arkinstall W.
      • Sandler A.
      • Goughnour B.
      • Babul N.
      • Harsanyi Z.
      • Darke A.C.
      Efficacy of controlled-release codeine in chronic non-malignant pain: a randomized, placebo-controlled clinical trial.
      patients prescribed opioids were found to have a 50% prevalence of a mood disorder. It has also been reported that physicians are more likely to prescribe opioids for chronic pain on the basis of pain behavior and increased affective distress rather than the patient’s self-reported pain severity or objective physical pathology.
      • Grattan A.
      • Sullivan M.D.
      • Saunders K.W.
      • Campbell C.I.
      • Von Korff M.R.
      Depression and prescription opioid misuse among chronic opioid therapy recipients with no history of substance abuse.
      Furthermore, patients with chronic pain who have major psychopathology are more likely to report greater pain intensity, more pain-related disability, and higher levels of emotional distress associated with their pain than those who do not have evidence of psychopathology.
      • Moulin D.E.
      • Iezzi A.
      • Amireh R.
      • Sharpe W.K.
      • Boyd D.
      • Merskey H.
      Randomised trial of oral morphine for chronic non-cancer pain.
      • Breckenridge J.
      • Clark J.D.
      Patient characteristics associated with opioid versus nonsteroidal anti-inflammatory drug management of chronic low back pain.
      Follow-up studies of patients with chronic pain who have notable psychopathology have revealed poorer treatment outcomes (eg, greater pain and disability) compared with patients who present with minimal psychopatholgy.
      • Rooks D.S.
      • Huang J.
      • Bierbaum B.E.
      • et al.
      The effect of preoperative exercise on measures of functional status in men and women undergoing total hip and knee arthroplasty.
      • Wasan A.D.
      • Kaptchuk T.J.
      • Davar G.
      • Jamison R.N.
      The association between psychopathology and placebo analgesia in patients with discogenic low back pain.
      In particular, those with elevated ratings of anxiety and depression tend to have considerably worse return-to-work rates 1 year after injury compared with those without any mood disorder.
      • Boersma K.
      • Linton S.J.
      Screening to identify patients at risk: profiles of psychological risk factors for early intervention.
      • Fishbain D.A.
      Approaches to treatment decisions for psychiatric comorbidity in the management of the chronic pain patient.
      One study investigating the effects of intravenous morphine found a 40% greater reduction in pain among patients with minor psychopathology compared with a matched group with major psychopathology.
      • Wasan A.D.
      • Kaptchuk T.J.
      • Davar G.
      • Jamison R.N.
      The association between psychopathology and placebo analgesia in patients with discogenic low back pain.
      Taken together, the literature suggests that patients with chronic pain and a high degree of negative affect benefit less from opioids and any other treatments designed to control their pain compared with those with minimal negative affect.
      • Jamison R.N.
      • Edwards R.R.
      • Liu X.
      • et al.
      Effect of negative affect and outcome of an opioid therapy trial among low back pain patients.
      Many patients with affective disorders also have substance use disorders. Treating an affective disorder may result in decreased substance abuse behaviors, although patients are at risk of relapse.
      • Martel M.O.
      • Dolman A.J.
      • Edwards R.R.
      • Jamison R.N.
      • Wasan A.D.
      The association between negative affect and prescription opioid misuse in patients with chronic pain: the mediating role of opioid craving.
      Some studies have found that patients with high-level negative affect are 2 to 3 times more likely to misuse opioid medications than patients with low-level negative affect.
      • Grattan A.
      • Sullivan M.D.
      • Saunders K.W.
      • Campbell C.I.
      • Von Korff M.R.
      Depression and prescription opioid misuse among chronic opioid therapy recipients with no history of substance abuse.
      • Becker W.C.
      • Sullivan L.E.
      • Tetrault J.M.
      • Desai R.A.
      • Fiellin D.A.
      Non-medical use, abuse and dependence on prescription opioids among U.S. adults: psychiatric, medical and substance use correlates.
      • Wasan A.D.
      • Butler S.F.
      • Budman S.H.
      • Benoit C.
      • Fernandez K.
      • Jamison R.N.
      Psychiatric history and psychologic adjustment as risk factors for aberrant drug-related behavior among patients with chronic pain.
      Hasin et al
      • Hasin D.
      • Liu X.
      • Nunes E.
      • McCloud S.
      • Samet S.
      • Endicott J.
      Effects of major depression on remission and relapse of substance dependence.
      found that some patients abuse their opioid pain medication to alleviate their psychiatric symptoms. Similarly, a study by Wasan et al
      • Wasan A.D.
      • Ross E.L.
      • Michna E.
      • et al.
      Craving of prescription opioids in patients with chronic pain: a longitudinal outcomes trial.
      indicated that comorbid depression and/or anxiety disorders were associated with greater opioid misuse, even in those with no history of a substance use disorder.

      Risk Assessment Tools

      Many physicians struggle with providing appropriate pain relief for patients while minimizing the misuse of opioid analgesics, and in response, concerted efforts have been made to identify individuals at risk for abuse of prescription opioids.
      • Darnall B.D.
      • Stacey B.R.
      • Chou R.
      Medical and psychological risks and consequences of long-term opioid therapy in women.
      • Kahan M.
      • Wilson L.
      • Mailis-Gagnon A.
      • Srivastava A.
      National Opioid Use Guideline Group
      Canadian guideline for safe and effective use of opioids for chronic noncancer pain: clinical summary for family physicians, Part 2: special populations.
      Numerous regulatory and professional organizations have released recommendations and guidelines related to the use of opioids among patients with chronic pain.
      • Furlan A.D.
      • Sandoval J.A.
      • Mailis-Gagnon A.
      • Tunks E.
      Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects.
      • Chou R.
      • Fanciullo G.J.
      • Fine P.
      • et al.
      American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel
      Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.
      • Furlan A.D.
      • Reardon R.
      • Weppler C.
      National Opioid Use Guideline Group Opioids for chronic noncancer pain: a new Canadian practice guideline.
      These guidelines emphasize the importance of opioid risk assessment before initiation of long-term opioid therapy. In addition to obtaining a thorough medical history, reviewing past medical records, and performing a medical examination, an opioid risk assessment using validated screening tools should be conducted. Structured interview measures based on Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria have been useful in assessing alcoholism and substance use disorders,
      • First M.B.
      • Spitzer R.L.
      • Gibbon M.
      • Williams J.B.W.
      Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), Clinician Version, Administration Booklet.
      but often these measures lack validation in persons with chronic pain. Using traditional substance abuse measures increases the likelihood that tolerance and dependence will be identified when no abuse exists. Some of the most commonly recommended tools include the Screener and Opioid Assessment for Patients with Pain – Revised,
      • Butler S.F.
      • Budman S.H.
      • Fernandez K.
      • Jamison R.N.
      Validation of a screener and opioid assessment measure for patients with chronic pain.
      • Butler S.F.
      • Fernandez K.
      • Benoit C.
      • Budman S.H.
      • Jamison R.N.
      Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R).
      • Butler S.F.
      • Budman S.H.
      • Fernandez K.C.
      • Fanciullo G.J.
      • Jamison R.N.
      Cross-validation of a screener to predict opioid misuse in chronic pain patients (SOAPP-R).
      the Opioid Risk Tool,
      • Webster L.R.
      • Webster R.M.
      Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool.
      • Webster L.R.
      • Dove B.
      Avoiding Opioid Abuse While Managing Pain: A Guide for Practitioners.
      the Diagnosis, Intractability, Risk, and Efficacy scale,
      • Belgrade M.J.
      • Schamber C.D.
      • Lindgren B.R.
      The DIRE score: predicting outcomes of opioid prescribing for chronic pain.
      and the Screening Instrument for Substance Abuse Potential.
      • Coambs R.B.
      • Jarry J.L.
      • Santhiapillai A.S.
      • et al.
      The SISAP: a new screening instrument for identifying potential opioid abusers in the management of chronic malignant pain within general medical practice.
      Validated ongoing assessment measures have also been useful in identifying current opioid abuse (Current Opioid Misuse Measure
      • Butler S.F.
      • Budman S.H.
      • Fernandez K.C.
      • et al.
      Development and validation of the Current Opioid Misuse Measure.
      • Butler S.F.
      • Budman S.H.
      • Fanciullo G.J.
      • Jamison R.N.
      Cross validation of the Current Opioid Misuse Measure to monitor chronic pain patients on opioid therapy.
      and Opioid Compliance Checklist
      • Jamison R.N.
      • Martel M.O.
      • Edwards R.R.
      • Qian J.
      • Sheehan K.A.
      • Ross E.L.
      Validation of a brief Opioid Compliance Checklist for patients with chronic pain.
      ). Scores on any of these measures are not necessarily a reason to deny opioids but instead allow clinicians to identify patients in whom close monitoring might be required to minimize their likelihood of opioid abuse and addiction. Brief descriptions of these assessments and other tools are provided in Table 3.
      Table 3Opioid and Medication Abuse Screening Assessments Tools
      Name of questionnaireReferencesPurpose of questionnaire
      Screener and Opioid Assessment for Patients with Pain – RevisedButler et al,
      • Butler S.F.
      • Budman S.H.
      • Fernandez K.
      • Jamison R.N.
      Validation of a screener and opioid assessment measure for patients with chronic pain.
      2004; Butler et al,
      • Butler S.F.
      • Fernandez K.
      • Benoit C.
      • Budman S.H.
      • Jamison R.N.
      Validation of the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R).
      2008; Butler et al,
      • Butler S.F.
      • Budman S.H.
      • Fernandez K.C.
      • Fanciullo G.J.
      • Jamison R.N.
      Cross-validation of a screener to predict opioid misuse in chronic pain patients (SOAPP-R).
      2009
      24- Item self-administered screening tool designed to predict aberrant medication-related behaviors for patients with chronic pain being considered for long-term opioid therapy. Opioid risk cutoff score is 18. The reliability and predictive validity were high
      Current Opioid Misuse MeasureButler et al,
      • Butler S.F.
      • Budman S.H.
      • Fernandez K.C.
      • et al.
      Development and validation of the Current Opioid Misuse Measure.
      2007; Butler et al,
      • Butler S.F.
      • Budman S.H.
      • Fanciullo G.J.
      • Jamison R.N.
      Cross validation of the Current Opioid Misuse Measure to monitor chronic pain patients on opioid therapy.
      2010
      17-Item self-report assessment developed for identifying patients with chronic pain who are currently misusing prescription opioids. Opioid risk cutoff score is 9. The reliability and predictive validity were high
      Opioid Risk ToolWebster and Webster,
      • Webster L.R.
      • Webster R.M.
      Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool.
      2005; Webster and Dove,
      • Webster L.R.
      • Dove B.
      Avoiding Opioid Abuse While Managing Pain: A Guide for Practitioners.
      2007
      5-Item checklist that allows the physician to determine if a patient will display aberrant drug-related behaviors. Opioid risk cutoff score is 8
      Diagnosis, Intractability, Risk, and Efficacy scoreBelgrade et al,
      • Belgrade M.J.
      • Schamber C.D.
      • Lindgren B.R.
      The DIRE score: predicting outcomes of opioid prescribing for chronic pain.
      2006
      Predicts the feasibility of long-term opioid treatment for noncancer pain. Also used to pinpoint beneficial factors, if any, of an individual’s opioid use. Opioid risk cutoff score is 14
      Screening Instrument for Substance Abuse PotentialCoambs et al,
      • Coambs R.B.
      • Jarry J.L.
      • Santhiapillai A.S.
      • et al.
      The SISAP: a new screening instrument for identifying potential opioid abusers in the management of chronic malignant pain within general medical practice.
      1996
      5-Item self-report screening questionnaire for substance abuse potential intended mostly for alcohol abuse
      Opioid Compliance ChecklistJamison et al,
      • Jamison R.N.
      • Martel M.O.
      • Edwards R.R.
      • Qian J.
      • Sheehan K.A.
      • Ross E.L.
      Validation of a brief Opioid Compliance Checklist for patients with chronic pain.
      2014
      12-Item questionnaire developed to assess adherence in patients with chronic pain receiving long-term prescription opioids. Five items were found to best predict subsequent aberrant behaviors based on multivariate logistic regression analyses
      Pain Assessment and Documentation ToolPassik et al,
      • Passik S.D.
      • Kirsch K.L.
      • Whitcomb L.
      • et al.
      A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy.
      2004
      41-Item questionnaire that provides extensive documentation of the patient’s progress and objectively monitors the patient’s care. There is no numerical scoring method for this assessment
      Prescription Drug Use QuestionnaireCompton et al,
      • Compton P.A.
      • Wu S.M.
      • Schieffer B.
      • Pham Q.
      • Naliboff B.D.
      Introduction of a self-report version of the Prescription Drug Use Questionnaire and relationship to medication agreement noncompliance.
      2008
      42-Item questionnaire used to identify patients who are likely to be nonaddicted, substance abusing, or substance-dependent

      Interventions for High-Risk Patients

      Opioid Therapy Agreements

      Controlled substance agreements have been used in clinics to document the expectations and roles of patients and physicians concerning the use of prescription opioids. The goal of these agreements is to use informed consent in order to address potential problems with opioid use and to improve patient adherence with opioid medication. Often, these documented agreements are used to educate patients as well as inform them of their responsibilities when using prescribed pain medication.
      An opioid therapy agreement identifies the conditions required of patients to be prescribed opioids for pain. Patients are often aware of the risks and complications associated with opioids, and termed conditions are needed to document that the patients are being responsible and benefiting from prescription opioids for pain.
      • Jamison R.N.
      • Martel M.O.
      • Edwards R.R.
      • Qian J.
      • Sheehan K.A.
      • Ross E.L.
      Validation of a brief Opioid Compliance Checklist for patients with chronic pain.
      Typical sample conditions state that (1) patients should only use their prescribed medications as directed by their physician, (2) they agree to only receive prescription pain medication from one physician, (3) they will only use one pharmacy to fill prescriptions, (4) they will not receive additional medication if their prescription runs out early, (5) they will be unable to receive replacement medication if lost or stolen, (6) they agree to submit to periodic urine screens and pill counts to verify adherence, (7) they will be responsible in maintaining their appointments, (8) they agree to participate in all aspects of treatment (eg, physical therapy, psychotherapy, and behavioral medicine), and (9) if pain and daily function have not improved with their prescription pain medication, the physician has the right to taper the patient off the medication.
      • Jamison R.N.
      • Edwards R.R.
      Risk factor assessment for problematic use of opioids for chronic pain.
      • Jamison R.N.
      • Ross E.L.
      • Michna E.
      • Chen L.Q.
      • Holcomb C.
      • Wasan A.D.
      Substance misuse treatment for high-risk chronic pain patients on opioid therapy: a randomized trial.
      • Jamison R.N.
      • Martel M.O.
      • Edwards R.R.
      • Qian J.
      • Sheehan K.A.
      • Ross E.L.
      Validation of a brief Opioid Compliance Checklist for patients with chronic pain.
      Each of the elements of the opioid therapy agreement should be clarified so that patients know exactly what is expected of them. By signing the agreement, they are acknowledging their consent to the proposed treatment plan and agree to adhere to the specific conditions and responsibilities set by the clinic. It is recommended that every patient prescribed opioids for pain read and sign a controlled substance agreement. Periodic use of an opioid adherence checklist can also be used to remind patients of their responsibilities when using opioids.
      • Jamison R.N.
      • Martel M.O.
      • Edwards R.R.
      • Qian J.
      • Sheehan K.A.
      • Ross E.L.
      Validation of a brief Opioid Compliance Checklist for patients with chronic pain.
      For some, a violation of this agreement would mean tapering and eventually discontinuing prescription opioids. Unfortunately, violations of this agreement can go unreported, and often, the treating physician has difficulty in tracking and verifying adherence.
      • Jamison R.N.
      • Edwards R.R.
      Risk factor assessment for problematic use of opioids for chronic pain.
      A rational systematic approach in the treatment and management of chronic pain with opioid therapy known as universal precautions has received strong support from pain societies and clinicians alike.
      • Gourlay D.
      • Heit H.A.
      • Almahrezi A.
      Universal precautions in pain medicine: a rational approach to the treatment of chronic pain.
      This approach, borrowed from infectious disease paradigms, includes a means of identifying and monitoring patients at risk for misusing prescription opioids. Gourlay et al
      • Gourlay D.
      • Heit H.A.
      • Almahrezi A.
      Universal precautions in pain medicine: a rational approach to the treatment of chronic pain.
      recommended the following steps when considering a patient for long-term opioid therapy: (1) establish a diagnosis with the appropriate differential, (2) obtain a psychological assessment, including risk potential for addictive disorder, (3) complete an informed consent and treatment agreement, (4) assess level of pain and function, (5) begin an opioid therapy trial if indicated, (6) periodically reassess pain, function, and behavior (eg, analgesia, activities of daily living, adverse events), (7) obtain at least annual urine screens, (8) review the primary diagnosis and comorbidities on every follow-up visit, and (9) thoroughly document all information. Additional evaluation and treatment planning can be provided by members of a comprehensive pain management center and communicated to the referring physician. Some pain management specialists prefer to incorporate a trilateral agreement with the patient’s primary care physician. After the patients have been followed up by a pain specialist and their condition stabilized with a particular opioid regimen, they may be referred back to the primary care physician. If issues of opioid nonadherence occur or there is a change in the pain diagnosis, the pain specialists could offer a reevaluation and consider additional treatments or changes in the medication regimen if necessary.

      Urine Toxicology Screening

      Urine toxicology screens are particularly useful in determining patients’ adherence to their prescribed opioid medication. Immunoassay urine screens can be helpful in determining if a particular class of drug is present in the urine, but gas chromatography/mass spectrometry is the most sensitive and specific type of urine screen and is particularly helpful in quantifying a particular prescription medication. Gas chromatography/mass spectrometry screens are also helpful in determining creatinine levels used to identify possible drug tampering/adulteration as well as the presence of illegal substances and/or absence of prescribed medications. Objectively documenting adherence by obtaining a urine screen for every patient receiving opioid therapy at least yearly is recommended.
      • Reisfield G.M.
      • Salazar E.
      • Bertholf R.L.
      Rational use and interpretation of urine drug testing in chronic opioid therapy.
      Random urine toxicology screening in patients with chronic pain who have been prescribed opioids has revealed a high incidence of abnormal results. In a study of 122 patients, 43% of the sample had an abnormal result.
      • Fishbain D.A.
      • Cutler R.B.
      • Rosomoff H.L.
      • Rosomoff R.S.
      Validity of self-reported drug use in chronic pain patients.
      Another study found that 21% of the study patients had evidence of an illicit drug or a nonprescribed medication even though no obvious behavioral issues had been observed by their physicians.
      • Katz N.
      • Fanciullo G.J.
      Role of urine toxicology testing in the management of chronic opioid therapy.
      These results were replicated in a study of 226 patients with chronic pain, which revealed that 46.5% of the sample taking prescribed opioids had abnormal urine toxicology screen results.
      • Michna E.
      • Jamison R.N.
      • Pham L.D.
      • et al.
      Urine toxicology screening among chronic pain patients on opioid therapy: frequency and predictability of abnormal findings.
      These studies suggest that risk assessment alone may not always identify patients who misuse pain medication and underscore the importance of regular urine toxicology screening along with behavioral observation and incorporation of self-report measures. Many clinics use immunoassay urine screens as the first line of analysis and then obtain results from gas chromatography/mass spectrometry testing when it is important to detect the specific level of drug metabolite in the urine.
      • Michna E.
      • Jamison R.N.
      • Pham L.D.
      • et al.
      Urine toxicology screening among chronic pain patients on opioid therapy: frequency and predictability of abnormal findings.

      Prescription Drug Monitoring Programs

      Potential solutions to the continuing increase in opioid abuse, misuse, and diversion have become an ongoing focus in regulatory, legal, and governmental action. Prescription drug monitoring programs (PDMPs), one of the first diversion control tools established, monitor and analyze electronic prescription data transferred from pharmacies and practitioners. Prescription drug monitoring programs are one facet of a universal precautions approach that has been implemented clinically over recent years. Universal precautions assume a degree of risk for each patient and include risk assessment strategies as well as close patient monitoring in order to initiate and modify therapy in a safe and controlled manner.
      • Gourlay D.
      • Heit H.A.
      • Almahrezi A.
      Universal precautions in pain medicine: a rational approach to the treatment of chronic pain.
      For instance, if a patient is screened and deemed to be at higher risk for opioid misuse, more frequent follow-up may be indicated as well as signing an opioid treatment agreement, prescribing fewer doses of opioids per prescription, requiring frequent urine screening, using pill counts, and regularly checking the PDMP. The goals of this plan also include an expansion of PDMPs among states and an objective to achieve consensus standards for prescribing of opioids.

      Office of National Drug Control Policy. National drug control strategy. whitehouse.gov website. https://www.whitehouse.gov/ondcp. Accessed February12, 2015.

      Behavioral Interventions for Opioid Adherence

      Patients with chronic pain who have evidence of nonadherence with prescription opioids are sometimes dismissed from clinical practice. Being “fired” as a patient at a clinic is not optimal because these patients often seek treatment elsewhere by going to the emergency department of a local hospital or engaging in illegal activity. A randomized study was conducted to examine the benefits of close monitoring and cognitive behavioral motivational counseling in improving adherence with prescription opioid use among patients with noncancer back pain at high risk for opioid misuse.
      • Jamison R.N.
      • Ross E.L.
      • Michna E.
      • Chen L.Q.
      • Holcomb C.
      • Wasan A.D.
      Substance misuse treatment for high-risk chronic pain patients on opioid therapy: a randomized trial.
      The results revealed that adherence training paired with careful monitoring of high-risk patients can be incorporated into a multidisciplinary pain program. Additionally, opioid adherence among high-risk patients could be improved to that of low-risk patients. This encouraging study documents the value and importance of risk assessment, frequent monitoring with monthly urine screens and opioid adherence checklists, and motivational counseling to help improve adherence with opioids. An ancillary component of this trial was the reduced number of patients who were discharged from treatment because of the attention and measures taken among patients prone to misuse of prescription opioids.
      The recommended criterion standard of care for all patients considered for long-term opioid therapy includes a comprehensive assessment with a thorough history and physical examination, a mandatory opioid agreement, and regular monitoring. For those patients at greatest risk for misuse of their medication, more frequent visits with urine toxicology screens, use of an adherence checklist, motivational counseling, and pill counts, if indicated, would be recommended.
      • Jamison R.N.
      • Edwards R.R.
      Risk factor assessment for problematic use of opioids for chronic pain.
      Even though risk of opioid misuse and addiction remains, greater focus on risk screening and documentation of outcome will help to mitigate the misuse of prescription opioids.
      • Jamison R.N.
      • Serraillier J.
      • Michna E.
      Screening before embarking: how to screen for addiction risk in opioid prescribing.

      Unsolved Questions and Future Considerations

      In anticipation of an ever-aging population, future emphasis will be given to adequately managing chronic pain and other medical comorbidities within the health care system. Abuse-deterrent opioids will continue to be developed, and greater attention will be given to educating physicians and patients about obtaining, storing, and disposing of opioids. Abuse-deterrent formulations are those that are hard to crush and may contain substances that are designed to make the formulation less attractive to abusers. Some products combine an opioid agonist with an antagonist released when the pills are adulterated. Several new opioid formulations that are designed to prevent or deter the abuse of opioids have been developed,
      • Butler S.F.
      • Cassidy T.A.
      • Chilcoat H.
      • et al.
      Abuse rates and routes of administration of reformulated extended-release oxycodone: initial findings from a sentinel surveillance sample of individuals assessed for substance abuse treatment.

      Yap D. FDA approves final ER/LA opioid analgesic REMS. Pharmacy Today website. http://www.pharmacist.com/fda-approves-final-erla-opioid-analgesic-rems. Published August 1, 2012. Accessed February 15, 2015.

      • Lourenço L.M.
      • Matthews M.
      • Jamison R.N.
      Abuse-deterrent and tamper-resistant opioids: how valuable are novel formulations in thwarting non-medical use?.
      and many more are expected to be approved for marketing in years to come. The future incorporation of abuse-deterrent opioids will hopefully decrease the abuse potential of prescribed opioids.
      In the future, innovative technology will play a more active role in health care. Interactive and dynamic software programs that are designed to educate physicians, pharmacists, and patients will continue to be developed. Recently, there has been rapid growth of mobile and electronic health (mHealth and eHealth) applications in pain assessment and management.
      • Vardeh D.
      • Edwards R.R.
      • Jamison R.N.
      • Eccleston C.
      There’s an app for that: mobile technology is a new advantage in managing chronic pain.
      The advent of mHealth, which refers specifically to the use of mobile and wireless applications (eg, text messaging, apps, movement monitors, social media), has increasingly become a viable option for managing chronic pain. It is hoped that eHealth and mHealth applications will reduce barriers to availability and accessibility for individuals with pain. With ever-expanding technology, larger segments of the population will have access to information and personal data designed to improve pain and coping, which hopefully will lead to reduced costs and more efficient health care utilization.
      Another hopeful area of investigation will be genome research and genetics testing. This area of study holds much promise for the identification of markers for potential opioid misuse. Single-nucleotide polymorphisms have been identified that seem to affect drug metabolism and opioid reception (eg, cytochrome P450, catechol-O-methyltransferase, and ABCB1) as well as other allelic variants.
      • Rakvåg T.T.
      • Klepstad P.
      • Baar C.
      • et al.
      The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients.
      Future identification of markers for opioid benefit and abuse within endogenous chemical-reactive systems will also shed light on our understanding of tolerance, OIH, craving, and potential opioid misuse. Longitudinal studies investigating demographic variables or sex, ethnic origin, and personality characteristics will also help in creating empirically based practice guidelines.
      Ongoing investigations into cannabinoids and cannabinoid receptors will likely impact pain treatment strategies of the future and offer understanding into new mechanisms for symptom reduction. Nanotechnology used to deliver treatment to a specific targeted area and development of other delivery strategies like topical preparations will add to the treatment armamentarium. Lastly, a mechanistic understanding behind how an acute pain problem develops into a chronic pain syndrome and the effects this process has on centralized mechanisms will help to expand the scope of interventions for pain. The ultimate long-range goal would be to offer effective, affordable, and acceptable treatments for those who suffer the most from chronic pain.

      Conclusion

      Chronic pain is a multifaceted global health problem that requires multiple modes of intervention. Despite the apparent physical pathology of pain, it has been implicated that psychiatric comorbidities such as depression and anxiety disorders substantially affect pain intensity, level of functioning, and pain outcome. Corresponding to the dramatic increase in opioid prescriptions, psychiatric comorbidity is now associated with opioid misuse, abuse, and/or diversion. Many screening assessments are useful for evaluating a patient’s risk for opioid misuse. Additionally, opioid therapy agreements, urine toxicology screens, use of tamper-resistant opioids, implementation of PDMPs, and other behavioral interventions have been established to improve opioid adherence. Unfortunately, there is a paucity of studies on long-term opioid therapy and little empirical support to instruct clinicians in the best strategies for treating pain with opioids. Sponsorship of continued research in this area is critically needed.

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