Clinical Review

CASE Sam M., age 48, is in your office for the first time in more than two years. He has gained a considerable amount of weight and appears a bit sluggish, and you wonder whether he's depressed. As you take a history, Sam reminds you that he was laid off 16 months ago and had been caring for his wife, who sustained a debilitating back injury. When you saw her recently, she told you she's back to work and pain-free. So you're taken aback when Sam asks you to refill his wife's oxycodone prescription for lingering pain that often keeps her up at night.

If Sam were your patient, would you suspect opioid dependence?

Dependence on opioid analgesics and the adverse consequences associated with it have steadily increased during the past decade. Consider the following:

• Between 2004 and 2008, the number of emergency department visits related to nonmedical prescription opioid use more than doubled, rising by 111%.¹

• The increasing prevalence of opioid abuse has led to a recent spike in unintentional deaths,² with the number of lives lost to opioid analgesic overdose now exceeding that of heroin or cocaine.³

• More than 75% of opioids used for nonmedical purposes were prescribed for someone else.⁴

The course of opioid use is highly variable. Some people start with a legitimate medical prescription for an opioid analgesic, then continue taking it after the pain subsides. Others experiment briefly with nonmedical prescription opioids or use them intermittently without adverse effect. Some progress from prescription opioids to heroin, despite its dangers.⁵ Still others experience a catastrophic outcome, such as an overdose or severe accident, the first time they use opioids.⁶ Rapid progression from misuse of opioids to dependence is most likely to occur in vulnerable populations, such as those with concurrent mental illness, other substance use disorders, or increased sensitivity to pain.⁷

Understanding the terms. Before we continue, a word about terminology is in order. Misuse generally refers to the use of a medication in a manner (ie, purpose, dose, or frequency) other than its intended use, whereas drug addiction is the repeated use of a drug despite resulting harm. Here we will use opioid dependence to mean a pattern of increasing use characterized by significant impairment and distress and an inability to stop, and opioid withdrawal to reflect a constellation of symptoms, such as insomnia, nausea, diarrhea, and muscle aches, that can follow physiological dependence (though not necessarily opioid dependence). Our definitions of these terms are consistent with those of the American Psychiatric Association (APA).⁸ Worth noting, however, is the fact that as the APA prepares for the publication of the 5th edition of its Diagnostic and Statistical Manual of Mental Disorders, its Substance Disorder Work Group has proposed replacing the term opioid dependence with opioid use disorder to reduce the confusion associated with these definitions.⁹

Assessing Illicit Opioid Use: Start With a Targeted Question
Most patients who are opioid dependent do not seek treatment for it¹⁰ and are typically free of medical sequelae associated with drug addiction when they see family practitioners. The absence of self-reporting and obvious physical signs and symptoms, coupled with the increase in illicit use of prescription opioids, underscores the need for clinicians to identify patients who are abusing opioids and ensure that they get the help they need.

Screening tools. There are a number of screening tools you can use for this purpose—eg, CAGE-Adapted to Include Drugs (CAGE-AID) and Drug Abuse Screening Test (DAST)^11,12—but they have not been found to be significantly better than a careful substance abuse history.¹³

Straightforward questions. You can start by asking, "Do you take any medications for pain?" If the answer is Yes, get the name of the drug and inquire about the frequency of use and the route, the amount typically taken, and the duration of the current use pattern. Ask specifically about opioids when taking a substance abuse history. After a question about alcohol use, you can say, "Do you use any other drugs in a serious way? Marijuana? Opioids, like Percocet, Vicodin, or Oxycontin?" Although it can be very difficult to detect opioid dependence if the patient is not forthcoming, other likely indicators of drug-seeking behavior should trigger additional questions. (See "Opioid dependence: Red Flags to Keep in Mind."^14-16)

"Brief" protocols. Recent studies of Screening, Brief Intervention, and Referral to Treatment (SBIRT) programs have found that the simple, time-limited interventions they offer (visit www.samhsa.gov/prevention/sbirt/SBIRTwhitepaper.pdf to learn more) lead to a reduction in self-reported illicit opioid use.^17,18 Clinicians can readily incorporate SBIRT protocols into routine practice, as an evidence-based and often reimbursable approach to substance abuse.¹⁷

Additional Steps Before Initiating Treatment
After screening and diagnostic evaluation provide evidence that a patient is opioid dependent, you can take several steps to guide him or her to the appropriate treatment.

A thorough biopsychosocial assessment covering co-occurring psychiatric illnesses, pain, psychosocial stressors contributing to opioid use, and infectious disease screening is required to gain a clear picture of the patient's situation. In every case, acute emergencies such as suicidal ideation require immediate intervention, which may include hospitalization.¹⁹

Assess the patient's desire for help. After the initial assessment, it is often helpful to categorize the patient's "stage of change" (precontemplation, contemplation, preparation, action, or maintenance)²⁰ and to tailor your next step accordingly. A patient who denies that opioid use is a problem or who is clearly ambivalent about seeking treatment may require a conversation that uses principles of motivational interviewing—a collaborative approach that aims to evoke and strengthen personal motivation for change.²¹ Consider a question that encourages him or her to express reasons for change, such as: "How would you like your current situation to be different?" As almost everyone abusing opioids has thoughts about stopping, such a question may help the patient focus on specific changes.

CASE When you question Sam about his interest in oxycodone, he breaks down. He's been unable to find work or to lose the excess weight he gained during the many months he cared for his wife. He tells you that soon after his wife stopped taking the pain pills, he started taking them. At first, he took one occasionally. Then he started taking the opioids every day, and finally, whenever he awakened at night. Now, Sam says, he has no more pills, and he's nauseous, depressed, and unable to sleep—and looking to you for help.

Sam fits the criteria for opioid withdrawal as a result of physiological dependence; further questioning reveals that he also suffers from opioid dependence, and that he is receptive to treatment.

Recommending Treatment and Following Up
Several options are available for patients who, like Sam, have signs and symptoms of opioid withdrawal as a result of physiological dependence. You can provide a referral to a clinician who specializes in addiction, recommend detoxification and/or treatment in an inpatient facility, or initiate pharmacologic treatment and provide a referral to a behavioral therapist. Whatever the initial approach, most patients will ultimately be treated as outpatients, with a combination of pharmacotherapy and behavioral therapy—often, with monitoring and oversight by a primary care provider. Which approach to pursue should be guided by evidence-based recommendations (see table^17,22-27) and jointly decided by provider and patient.

Medication Plays a Key Role in Recovery
Recommend medication-assisted treatment, either with an agonist (buprenorphine or methadone) or an antagonist (naltrexone), for every patient with physiological opioid dependence. The goals of pharmacotherapy are to prevent or reduce withdrawal symptoms and craving, avoid relapse, and restore to a normal state any physiological functions (eg, sleep, bowel habits) that have been disrupted by opioid use.²⁸ When continued for at least three months, medication has been shown to improve outcomes.^23,24,29 In one recent study, 49% of opioid-dependent participants who were still taking buprenorphine-naloxone at 12 weeks had successful outcomes (minimal or no opioid use), compared with 7% of those undergoing a brief buprenorphine-naloxone taper.²⁴

There are risks associated with medication-assisted therapy, however. Those of greatest concern are a potential increase in drug interactions, the risk of diversion (a concern with both buprenorphine and methadone), and the potential for accidental overdose.^2,30

Buprenorphine, a partial m-opioid receptor agonist, is a Schedule III controlled substance and can be dispensed by a pharmacist, making inpatient opioid detoxification unnecessary for many opioid-dependent patients. Clinicians who wish to prescribe buprenorphine for the treatment of opioid dependence must complete an 8-hour course, offered by the American Medical Association and the APA, among other medical groups, and obtain a Drug Enforcement Administration (code "X") license.³¹

Buprenorphine has a high affinity for, and a slow dissociation from, m-opioid receptors, resulting in the displacement of other opioids from the m receptor and less severe withdrawal.³² As a partial agonist, buprenorphine attenuates opioid withdrawal symptoms with a ceiling, or near-maximal, effect at 16 mg, thereby lowering the risk for overdose.³³ A sublingual formulation that combines buprenorphine with naloxone, an opioid antagonist that exerts its full effect when injected but is minimally absorbed sublingually, reduces the potential for abuse of buprenorphine without interfering with its effectiveness.³⁴

Compared with methadone, buprenorphine is less likely to interact with antiretroviral medications or to cause QTc prolongation, erectile dysfunction, or cognitive or psychomotor impairment.^31,35-37 Limitations include the ceiling effect, which can be a problem for cases in which more agonist is needed; cost (approximately $12/d); and the lack of approval by the FDA for use during pregnancy.

Buprenorphine maintenance involves three phases: induction, stabilization, and maintenance.³⁸ Induction takes place in a clinician's office at the time the patient experiences opioid withdrawal symptoms, typically 6 to 48 hours after taking the last opioid. Extended treatment improves clinical outcomes,^23,24 and longer-term maintenance (of indefinite duration) is frequently required.

Naltrexone is a m-receptor antagonist, and therefore does not cause physical dependence or have agonist effects such as euphoria and sedation. As a result, it has no diversion value and may appeal to those who view opioid-agonist pharmacotherapy as simply trading one drug for another.³⁹ Naltrexone is not a controlled substance and is not subject to the regulatory requirements that buprenorphine and methadone face.

Although agonists can be started in the first day or two after a patient decides to stop using opioids, patients must be opioid-free for at least seven days before starting naltrexone. That's because its antagonist properties will precipitate withdrawal if another opioid is present on the opioid receptors. During the seven-day "washout" period, opioid withdrawal symptoms can be treated with medications such as clonidine and dicyclomine, but such symptoms make patients especially vulnerable to relapse while waiting to start naltrexone.

Oral naltrexone's effectiveness as a treatment for opioid dependence has been limited by poor patient adherence. But a long-acting intramuscular form of the drug, approved by the FDA in 2010 and requiring once-a-month injection, mitigates this concern.^40,41

Methadone is a full m-opioid agonist, administered daily at specialized clinics, as a maintenance therapy for opioid dependence. Although office-based physicians can prescribe methadone for pain, the drug can only be used for opioid dependence under the auspices of state- and federally regulated opioid treatment programs (http://findtreatment.samhsa.gov/TreatmentLocator/faces/quickSearch.jspx; a mobile phone application is also available at www.samhsa.gov/mobile/treat mentlocator.aspx).

Methadone, a Schedule III controlled substance with a half-life averaging 24 to 36 hours, requires daily dosing.⁴² Its slow metabolism and long half-life increase the risk for overdose.

Methadone is best for patients who are highly dependent on opioids and likely to benefit from a structured treatment environment with daily supervision (although patients who are doing well may earn take-home privileges so they don't have to come to the clinic every day).⁴³ New patients should receive an initial dose of 30 mg or less, and a maximum first-day dose of 40 mg.⁴⁴

Methadone use remains the standard of care for pregnant women being treated for opioid dependence, while studies of the effects of buprenorphine and naltrexone on a developing fetus continue. Although methadone's efficacy, particularly in lower doses, is similar to that of buprenorphine,⁴⁵ its adverse effect profile is worse. Adverse effects include drug interactions, the potential for respiratory depression (especially in combination with alcohol or sedatives), QTc prolongation (which requires monitoring by ECG), sedation, and weight gain, and should be considered before methadone is selected as a maintenance pharmacotherapy.^30,37,46 And, because relapse rates within 12 months of tapering off methadone have been reported to exceed 80%,⁴⁷ both the clinician and the patient need to consider the likelihood of long-term, even lifelong, maintenance before initiating treatment.

Behavioral Interventions Are a Vital Part of the Picture
Studies evaluating the extent to which various types and amounts of counseling improve outcomes compared with pharmacotherapy alone have had conflicting results.^24,48 Nonetheless, most clinicians consider counseling a critical component of treatment for opioid dependence and recommend, at a minimum, either individual or group counseling (various modalities have been shown to be effective) and regular attendance at a self-help group like Narcotics Anonymous. Contingency management, a type of therapy that uses prizes as incentives for desired behaviors; and family therapy, individual counseling, and community-based programs have all been found to improve outcomes.^6,49 

CASE You refer Sam to an addiction psychiatrist, who stabilizes him on 16 mg/d buprenorphine/naloxone as part of an outpatient treatment program. Sam is enrolled in a weekly buprenorphine stabilization group, where he gives a urine sample each week. He also begins seeing a social worker weekly for counseling and attends Narcotics Anonymous meetings two to three times a week. At a follow-up appointment with you six months later, he reports that he has been abstinent from oxycodone for six months, his sleep is improved, and he feels better about his chances of finding another job.

Your Role in Safeguarding the Patient
With the rising prevalence of opioid overdose, patient education aimed at crisis prevention is crucial as well. Warn patients of the risk for accidental overdose, often associated with relapse, stressing the importance of continuing treatment and taking their maintenance medication exactly as prescribed.

There are other steps that can be taken to safeguard patients—for example, providing naloxone rescue kits to patients and their families when appropriate. The clinician can also institute diversion and overdose prevention measures for patients taking buprenorphine or methadone—providing a lock box for take-home medication, implementing treatment contracts, and using a designated pharmacy to dispense buprenorphine, for example.^26,27,50

Regular monitoring, urine drug screens, and random pill counts, in which patients are typically given 24 hours to bring in their prescribed medication so it can be counted, can also help keep patients on track. Treatment for concurrent psychiatric disorders—depression, anxiety, and personality disorders are common among patients with opioid dependence—is also likely to improve treatment outcomes.

References
1. CDC. Emergency department visits involving nonmedical use of selected prescription drugs - United States, 2004-2008. MMWR Morb Mortal Wkly Rep. 2010;59:705-709.

2. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305:1315-1321.

3. Warner M, Chen LH, Makuc DM. Increase in fatal poisonings involving opioid analgesics in the United States, 1999-2006. NCHS Data Brief. 2009;22:1-8.

4. Substance Abuse and Mental Health Services Administration. Results From the 2009 National Survey on Drug Use and Health: Volume I. Summary of National Findings. Rockville, Md: SAMHSA, Office of Applied Studies; 2010. NSDUH Series H-38A, HHS publication SMA 10-4856. www.samhsa.gov/dataNSDUH/2k9NSDUH/2k9Results.htm. Accessed August 22, 2012.

5. Hser YI, Huang D, Brecht ML, et al. Contrasting trajectories of heroin, cocaine, and methamphetamine use. J Addict Dis. 2008;27:13-21.

6. Veilleux JC, Colvin PJ, Anderson J, et al. A review of opioid dependence treatment: pharmacological and psychosocial interventions to treat opioid addiction. Clin Psychol Rev. 2011;30:155-166.

7. George O, Koob GF. Individual differences in prefrontal cortex function and the transition from drug use to drug dependence. Neurosci Biobehav Rev. 2011;35:232-247.

8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev (DSM-IV-TR). Arlington, VA: American Psychiatric Association; 2000.

9. American Psychiatric Association. R 19 opioid use disorder (2012). www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=460. Accessed June 20, 2012.

10. Substance Abuse and Mental Health Services Administration. Results From the 2008 National Survey on Drug Use and Health: National Findings. Rockville, MD: SAMHSA, Office of Applied Studies; 2009. NSDUH Series H-36, HHS publication SMA 09-4434. www.samhsa.gov/data/nsduh/2k8nsduh/2k8Results.htm. Accessed August 22, 2012.

11. Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and other drug abuse: criterion validity in a primary care practice. Wis Med J. 1995;94:135-140.

12. Skinner HA. The drug abuse screening test. Addict Behav. 1982;7:363-371.

13. US Preventive Services Task Force. Screening for Illicit Drug Use: US Preventive Services Task Force Recommendation Statement. January 2008. www.uspreventiveservicestaskforce.org/uspstf08/druguse/drugrs.htm. Accessed May 7, 2012.

14. Gourlay D, Caplan Y, Heit H. Urine Drug Testing in Clinical Practice: Dispelling the Myths and Designing Strategies. San Francisco, Calif: California Academy of Family Physicians; 2006.

15. Jackman R, Purvis J, Mallett B. Chronic nonmalignant pain in primary care. Am Fam Physician. 2008;78:1155-1162.

16. McBane S, Weigle N. Is it time to drug test your chronic pain patient? J Fam Pract. 2010;59:628-633.

17. Madras BK, Compton WM, Avula D, et al. Screening, brief interventions, referral to treatment (SBIRT) for illicit drug and alcohol use at multiple healthcare sites: comparison at intake and 6 months later. Drug Alcohol Depend. 2009;99:280-295.

18. The InSight Project Research Group. SBIRT outcomes in Houston: final report on InSight, a hospital district-based program for patients at risk for alcohol or drug use problems. Alcohol Clin Exp Res. 2009;33:1374-1381.

19. Borges G, Walters EE, Kessler RC. Associations of substance use, abuse, and dependence with subsequent suicidal behavior. Am J Epidemiol. 2000;151:781-789.

20. Prochaska JO, DiClemente CC. Stages and processes of self-change of smoking: toward an integrative model of change. J Consult Clin Psychol. 1983;51:390-395.

21. Smedslund G, Berg RC, Hammerstrom KT, et al. Motivational interviewing for substance abuse. Cochrane Database Syst Rev. 2011;(5):CD008063.

22. Gryczynski J, Mitchell SG, Peterson TR, et al. The relationship between services delivered and substance use outcomes in New Mexico's Screening, Brief Intervention, Referral and Treatment (SBIRT) Initiative. Drug Alcohol Depend. 2011;118:152-157.

23. Woody GE, Poole SA, Subramaniam G, et al. Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial. JAMA. 2008;300:2003-2011.

24. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry. 2011;68:1238-1246.

25. Johansson BA, Berglund M, Lindgren A. Efficacy of maintenance treatment with naltrexone for opioid dependence: a meta-analytical review. Addiction. 2006;101:491-503.

26. Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008;300:2613-2620.

27. Zacny J, Bigelow G, Compton P, et al. College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug Alcohol Depend. 2003;69:215-232.

28. Kreek MJ. Rationale for maintenance pharmacotherapy of opiate dependence. Res Publ Assoc Res Nerv Ment Dis. 1992;70:205-230.

29. Mattick RP, Breen C, Kimber J, et al. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2009;(3):CD002209.

30. McCance-Katz EF, Sullivan LE, Nallani S. Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review. Am J Addict. 2010;19:4-16.

31. Office of National Drug Control Policy Reauthorization Act of 2006 (ONDCPRA), HR 6344, 109th Cong, 2nd Sess (2006).

32. Lewis JW, Walter D. Buprenorphine—background to its development as a treatment for opiate dependence. In: Blaine JD, ed. Buprenorphine: An Alternative Treatment for Opioid Dependence. Rockville, MD: National Institute on Drug Abuse; 1992:5-11. NIDA Research Monograph, No. 121. http://archives.drugabuse.gov/pdf/monographs/121.pdf. Accessed August 22, 2012.

33. Walsh SL, Preston KL, Stitzer ML, et al. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55:569-580.

34. Alho H, Sinclair D, Vuori E, et al. Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. Drug Alcohol Depend. 2007;88:75-78.

35. Hallinan R, Byrne A, Agho K, et al. Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment. J Sex Med. 2008;5:684-692.

36. Rapeli P, Fabritius C, Alho H, et al. Methadone vs. buprenorphine/naloxone during early opioid substitution treatment: a naturalistic comparison of cognitive performance relative to healthy controls. BMC Clin Pharmacol. 2007;7:5.

37. Wedam EF, Bigelow GE, Johnson RE, et al. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007;167:2469-2475.

38. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2004. Treatment Improvement Protocol (TIP) Series 40. DHHS publication SMA 04‐3939.

39. Kleber HD. Methadone maintenance 4 decades later: thousands of lives saved but still controversial. JAMA. 2008;300:2303-2305.

40. Hulse GK, Morris N, Arnold-Reed D, et al. Improving clinical outcomes in treating heroin dependence: randomized, controlled trial of oral or implant naltrexone. Arch Gen Psychiatry. 2009;66:1108-1115.

41. FDA. FDA approves injectable drug to treat opioid-dependent patients. October 12, 2010. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm229109.htm. Accessed September 11, 2012.

42. Inturrisi CE, Verebely K. The levels of methadone in the plasma in methadone maintenance. Clin Pharmacol Ther. 1972;13(5 pt 1):633-637.

43. Stitzer M, Bigelow G, Lawrence C, et al. Medication take-home as a reinforcer in a methadone maintenance program. Addict Behav. 1977;2:9-14.

44. Code of Federal Regulations. Title 42.8.12. Federal Opioid Treatment Standards. October 2010.

45. Johnson RE. Chutuape MA, Strain EC, et al. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000;343:1290-1297.

46. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387-395.

47. Ball JC, Lange WR, Myers CP, et al. Reducing the risk of AIDS through methadone maintenance treatment. J Health Soc Behav. 1988;29:214-226.

48. Fiellin DA, Pantalon MV, Chawarski MC, et al. Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence. N Engl J Med. 2006;355:365-374.

49. Defulio A, Everly JJ, Leoutsakos JM, et al. Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone in opioid-dependent adults: a randomized controlled trial. Drug Alcohol Depend. 2012;120:48-54.

50. Savage SR. Management of opioid medications in patients with chronic pain and risk of substance misuse. Curr Psychiatry Rep. 2009;11:377-384.

This article was originally published in the Journal of Family Practice. 2012;61:588-597.

CASE Sam M., age 48, is in your office for the first time in more than two years. He has gained a considerable amount of weight and appears a bit sluggish, and you wonder whether he's depressed. As you take a history, Sam reminds you that he was laid off 16 months ago and had been caring for his wife, who sustained a debilitating back injury. When you saw her recently, she told you she's back to work and pain-free. So you're taken aback when Sam asks you to refill his wife's oxycodone prescription for lingering pain that often keeps her up at night.

If Sam were your patient, would you suspect opioid dependence?

Dependence on opioid analgesics and the adverse consequences associated with it have steadily increased during the past decade. Consider the following:

• Between 2004 and 2008, the number of emergency department visits related to nonmedical prescription opioid use more than doubled, rising by 111%.¹

• The increasing prevalence of opioid abuse has led to a recent spike in unintentional deaths,² with the number of lives lost to opioid analgesic overdose now exceeding that of heroin or cocaine.³

• More than 75% of opioids used for nonmedical purposes were prescribed for someone else.⁴

The course of opioid use is highly variable. Some people start with a legitimate medical prescription for an opioid analgesic, then continue taking it after the pain subsides. Others experiment briefly with nonmedical prescription opioids or use them intermittently without adverse effect. Some progress from prescription opioids to heroin, despite its dangers.⁵ Still others experience a catastrophic outcome, such as an overdose or severe accident, the first time they use opioids.⁶ Rapid progression from misuse of opioids to dependence is most likely to occur in vulnerable populations, such as those with concurrent mental illness, other substance use disorders, or increased sensitivity to pain.⁷

Understanding the terms. Before we continue, a word about terminology is in order. Misuse generally refers to the use of a medication in a manner (ie, purpose, dose, or frequency) other than its intended use, whereas drug addiction is the repeated use of a drug despite resulting harm. Here we will use opioid dependence to mean a pattern of increasing use characterized by significant impairment and distress and an inability to stop, and opioid withdrawal to reflect a constellation of symptoms, such as insomnia, nausea, diarrhea, and muscle aches, that can follow physiological dependence (though not necessarily opioid dependence). Our definitions of these terms are consistent with those of the American Psychiatric Association (APA).⁸ Worth noting, however, is the fact that as the APA prepares for the publication of the 5th edition of its Diagnostic and Statistical Manual of Mental Disorders, its Substance Disorder Work Group has proposed replacing the term opioid dependence with opioid use disorder to reduce the confusion associated with these definitions.⁹

Assessing Illicit Opioid Use: Start With a Targeted Question
Most patients who are opioid dependent do not seek treatment for it¹⁰ and are typically free of medical sequelae associated with drug addiction when they see family practitioners. The absence of self-reporting and obvious physical signs and symptoms, coupled with the increase in illicit use of prescription opioids, underscores the need for clinicians to identify patients who are abusing opioids and ensure that they get the help they need.

Screening tools. There are a number of screening tools you can use for this purpose—eg, CAGE-Adapted to Include Drugs (CAGE-AID) and Drug Abuse Screening Test (DAST)^11,12—but they have not been found to be significantly better than a careful substance abuse history.¹³

Straightforward questions. You can start by asking, "Do you take any medications for pain?" If the answer is Yes, get the name of the drug and inquire about the frequency of use and the route, the amount typically taken, and the duration of the current use pattern. Ask specifically about opioids when taking a substance abuse history. After a question about alcohol use, you can say, "Do you use any other drugs in a serious way? Marijuana? Opioids, like Percocet, Vicodin, or Oxycontin?" Although it can be very difficult to detect opioid dependence if the patient is not forthcoming, other likely indicators of drug-seeking behavior should trigger additional questions. (See "Opioid dependence: Red Flags to Keep in Mind."^14-16)

"Brief" protocols. Recent studies of Screening, Brief Intervention, and Referral to Treatment (SBIRT) programs have found that the simple, time-limited interventions they offer (visit www.samhsa.gov/prevention/sbirt/SBIRTwhitepaper.pdf to learn more) lead to a reduction in self-reported illicit opioid use.^17,18 Clinicians can readily incorporate SBIRT protocols into routine practice, as an evidence-based and often reimbursable approach to substance abuse.¹⁷

Additional Steps Before Initiating Treatment
After screening and diagnostic evaluation provide evidence that a patient is opioid dependent, you can take several steps to guide him or her to the appropriate treatment.

A thorough biopsychosocial assessment covering co-occurring psychiatric illnesses, pain, psychosocial stressors contributing to opioid use, and infectious disease screening is required to gain a clear picture of the patient's situation. In every case, acute emergencies such as suicidal ideation require immediate intervention, which may include hospitalization.¹⁹

Assess the patient's desire for help. After the initial assessment, it is often helpful to categorize the patient's "stage of change" (precontemplation, contemplation, preparation, action, or maintenance)²⁰ and to tailor your next step accordingly. A patient who denies that opioid use is a problem or who is clearly ambivalent about seeking treatment may require a conversation that uses principles of motivational interviewing—a collaborative approach that aims to evoke and strengthen personal motivation for change.²¹ Consider a question that encourages him or her to express reasons for change, such as: "How would you like your current situation to be different?" As almost everyone abusing opioids has thoughts about stopping, such a question may help the patient focus on specific changes.

CASE When you question Sam about his interest in oxycodone, he breaks down. He's been unable to find work or to lose the excess weight he gained during the many months he cared for his wife. He tells you that soon after his wife stopped taking the pain pills, he started taking them. At first, he took one occasionally. Then he started taking the opioids every day, and finally, whenever he awakened at night. Now, Sam says, he has no more pills, and he's nauseous, depressed, and unable to sleep—and looking to you for help.

Sam fits the criteria for opioid withdrawal as a result of physiological dependence; further questioning reveals that he also suffers from opioid dependence, and that he is receptive to treatment.

Recommending Treatment and Following Up
Several options are available for patients who, like Sam, have signs and symptoms of opioid withdrawal as a result of physiological dependence. You can provide a referral to a clinician who specializes in addiction, recommend detoxification and/or treatment in an inpatient facility, or initiate pharmacologic treatment and provide a referral to a behavioral therapist. Whatever the initial approach, most patients will ultimately be treated as outpatients, with a combination of pharmacotherapy and behavioral therapy—often, with monitoring and oversight by a primary care provider. Which approach to pursue should be guided by evidence-based recommendations (see table^17,22-27) and jointly decided by provider and patient.

Medication Plays a Key Role in Recovery
Recommend medication-assisted treatment, either with an agonist (buprenorphine or methadone) or an antagonist (naltrexone), for every patient with physiological opioid dependence. The goals of pharmacotherapy are to prevent or reduce withdrawal symptoms and craving, avoid relapse, and restore to a normal state any physiological functions (eg, sleep, bowel habits) that have been disrupted by opioid use.²⁸ When continued for at least three months, medication has been shown to improve outcomes.^23,24,29 In one recent study, 49% of opioid-dependent participants who were still taking buprenorphine-naloxone at 12 weeks had successful outcomes (minimal or no opioid use), compared with 7% of those undergoing a brief buprenorphine-naloxone taper.²⁴

There are risks associated with medication-assisted therapy, however. Those of greatest concern are a potential increase in drug interactions, the risk of diversion (a concern with both buprenorphine and methadone), and the potential for accidental overdose.^2,30

Buprenorphine, a partial m-opioid receptor agonist, is a Schedule III controlled substance and can be dispensed by a pharmacist, making inpatient opioid detoxification unnecessary for many opioid-dependent patients. Clinicians who wish to prescribe buprenorphine for the treatment of opioid dependence must complete an 8-hour course, offered by the American Medical Association and the APA, among other medical groups, and obtain a Drug Enforcement Administration (code "X") license.³¹

Buprenorphine has a high affinity for, and a slow dissociation from, m-opioid receptors, resulting in the displacement of other opioids from the m receptor and less severe withdrawal.³² As a partial agonist, buprenorphine attenuates opioid withdrawal symptoms with a ceiling, or near-maximal, effect at 16 mg, thereby lowering the risk for overdose.³³ A sublingual formulation that combines buprenorphine with naloxone, an opioid antagonist that exerts its full effect when injected but is minimally absorbed sublingually, reduces the potential for abuse of buprenorphine without interfering with its effectiveness.³⁴

Compared with methadone, buprenorphine is less likely to interact with antiretroviral medications or to cause QTc prolongation, erectile dysfunction, or cognitive or psychomotor impairment.^31,35-37 Limitations include the ceiling effect, which can be a problem for cases in which more agonist is needed; cost (approximately $12/d); and the lack of approval by the FDA for use during pregnancy.

Buprenorphine maintenance involves three phases: induction, stabilization, and maintenance.³⁸ Induction takes place in a clinician's office at the time the patient experiences opioid withdrawal symptoms, typically 6 to 48 hours after taking the last opioid. Extended treatment improves clinical outcomes,^23,24 and longer-term maintenance (of indefinite duration) is frequently required.

Naltrexone is a m-receptor antagonist, and therefore does not cause physical dependence or have agonist effects such as euphoria and sedation. As a result, it has no diversion value and may appeal to those who view opioid-agonist pharmacotherapy as simply trading one drug for another.³⁹ Naltrexone is not a controlled substance and is not subject to the regulatory requirements that buprenorphine and methadone face.

Although agonists can be started in the first day or two after a patient decides to stop using opioids, patients must be opioid-free for at least seven days before starting naltrexone. That's because its antagonist properties will precipitate withdrawal if another opioid is present on the opioid receptors. During the seven-day "washout" period, opioid withdrawal symptoms can be treated with medications such as clonidine and dicyclomine, but such symptoms make patients especially vulnerable to relapse while waiting to start naltrexone.

Oral naltrexone's effectiveness as a treatment for opioid dependence has been limited by poor patient adherence. But a long-acting intramuscular form of the drug, approved by the FDA in 2010 and requiring once-a-month injection, mitigates this concern.^40,41

Methadone is a full m-opioid agonist, administered daily at specialized clinics, as a maintenance therapy for opioid dependence. Although office-based physicians can prescribe methadone for pain, the drug can only be used for opioid dependence under the auspices of state- and federally regulated opioid treatment programs (http://findtreatment.samhsa.gov/TreatmentLocator/faces/quickSearch.jspx; a mobile phone application is also available at www.samhsa.gov/mobile/treat mentlocator.aspx).

Methadone, a Schedule III controlled substance with a half-life averaging 24 to 36 hours, requires daily dosing.⁴² Its slow metabolism and long half-life increase the risk for overdose.

Methadone is best for patients who are highly dependent on opioids and likely to benefit from a structured treatment environment with daily supervision (although patients who are doing well may earn take-home privileges so they don't have to come to the clinic every day).⁴³ New patients should receive an initial dose of 30 mg or less, and a maximum first-day dose of 40 mg.⁴⁴

Methadone use remains the standard of care for pregnant women being treated for opioid dependence, while studies of the effects of buprenorphine and naltrexone on a developing fetus continue. Although methadone's efficacy, particularly in lower doses, is similar to that of buprenorphine,⁴⁵ its adverse effect profile is worse. Adverse effects include drug interactions, the potential for respiratory depression (especially in combination with alcohol or sedatives), QTc prolongation (which requires monitoring by ECG), sedation, and weight gain, and should be considered before methadone is selected as a maintenance pharmacotherapy.^30,37,46 And, because relapse rates within 12 months of tapering off methadone have been reported to exceed 80%,⁴⁷ both the clinician and the patient need to consider the likelihood of long-term, even lifelong, maintenance before initiating treatment.

Behavioral Interventions Are a Vital Part of the Picture
Studies evaluating the extent to which various types and amounts of counseling improve outcomes compared with pharmacotherapy alone have had conflicting results.^24,48 Nonetheless, most clinicians consider counseling a critical component of treatment for opioid dependence and recommend, at a minimum, either individual or group counseling (various modalities have been shown to be effective) and regular attendance at a self-help group like Narcotics Anonymous. Contingency management, a type of therapy that uses prizes as incentives for desired behaviors; and family therapy, individual counseling, and community-based programs have all been found to improve outcomes.^6,49 

CASE You refer Sam to an addiction psychiatrist, who stabilizes him on 16 mg/d buprenorphine/naloxone as part of an outpatient treatment program. Sam is enrolled in a weekly buprenorphine stabilization group, where he gives a urine sample each week. He also begins seeing a social worker weekly for counseling and attends Narcotics Anonymous meetings two to three times a week. At a follow-up appointment with you six months later, he reports that he has been abstinent from oxycodone for six months, his sleep is improved, and he feels better about his chances of finding another job.

Your Role in Safeguarding the Patient
With the rising prevalence of opioid overdose, patient education aimed at crisis prevention is crucial as well. Warn patients of the risk for accidental overdose, often associated with relapse, stressing the importance of continuing treatment and taking their maintenance medication exactly as prescribed.

There are other steps that can be taken to safeguard patients—for example, providing naloxone rescue kits to patients and their families when appropriate. The clinician can also institute diversion and overdose prevention measures for patients taking buprenorphine or methadone—providing a lock box for take-home medication, implementing treatment contracts, and using a designated pharmacy to dispense buprenorphine, for example.^26,27,50

Regular monitoring, urine drug screens, and random pill counts, in which patients are typically given 24 hours to bring in their prescribed medication so it can be counted, can also help keep patients on track. Treatment for concurrent psychiatric disorders—depression, anxiety, and personality disorders are common among patients with opioid dependence—is also likely to improve treatment outcomes.

References
1. CDC. Emergency department visits involving nonmedical use of selected prescription drugs - United States, 2004-2008. MMWR Morb Mortal Wkly Rep. 2010;59:705-709.

2. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305:1315-1321.

3. Warner M, Chen LH, Makuc DM. Increase in fatal poisonings involving opioid analgesics in the United States, 1999-2006. NCHS Data Brief. 2009;22:1-8.

4. Substance Abuse and Mental Health Services Administration. Results From the 2009 National Survey on Drug Use and Health: Volume I. Summary of National Findings. Rockville, Md: SAMHSA, Office of Applied Studies; 2010. NSDUH Series H-38A, HHS publication SMA 10-4856. www.samhsa.gov/dataNSDUH/2k9NSDUH/2k9Results.htm. Accessed August 22, 2012.

5. Hser YI, Huang D, Brecht ML, et al. Contrasting trajectories of heroin, cocaine, and methamphetamine use. J Addict Dis. 2008;27:13-21.

6. Veilleux JC, Colvin PJ, Anderson J, et al. A review of opioid dependence treatment: pharmacological and psychosocial interventions to treat opioid addiction. Clin Psychol Rev. 2011;30:155-166.

7. George O, Koob GF. Individual differences in prefrontal cortex function and the transition from drug use to drug dependence. Neurosci Biobehav Rev. 2011;35:232-247.

8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev (DSM-IV-TR). Arlington, VA: American Psychiatric Association; 2000.

9. American Psychiatric Association. R 19 opioid use disorder (2012). www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=460. Accessed June 20, 2012.

10. Substance Abuse and Mental Health Services Administration. Results From the 2008 National Survey on Drug Use and Health: National Findings. Rockville, MD: SAMHSA, Office of Applied Studies; 2009. NSDUH Series H-36, HHS publication SMA 09-4434. www.samhsa.gov/data/nsduh/2k8nsduh/2k8Results.htm. Accessed August 22, 2012.

11. Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and other drug abuse: criterion validity in a primary care practice. Wis Med J. 1995;94:135-140.

12. Skinner HA. The drug abuse screening test. Addict Behav. 1982;7:363-371.

13. US Preventive Services Task Force. Screening for Illicit Drug Use: US Preventive Services Task Force Recommendation Statement. January 2008. www.uspreventiveservicestaskforce.org/uspstf08/druguse/drugrs.htm. Accessed May 7, 2012.

14. Gourlay D, Caplan Y, Heit H. Urine Drug Testing in Clinical Practice: Dispelling the Myths and Designing Strategies. San Francisco, Calif: California Academy of Family Physicians; 2006.

15. Jackman R, Purvis J, Mallett B. Chronic nonmalignant pain in primary care. Am Fam Physician. 2008;78:1155-1162.

16. McBane S, Weigle N. Is it time to drug test your chronic pain patient? J Fam Pract. 2010;59:628-633.

17. Madras BK, Compton WM, Avula D, et al. Screening, brief interventions, referral to treatment (SBIRT) for illicit drug and alcohol use at multiple healthcare sites: comparison at intake and 6 months later. Drug Alcohol Depend. 2009;99:280-295.

18. The InSight Project Research Group. SBIRT outcomes in Houston: final report on InSight, a hospital district-based program for patients at risk for alcohol or drug use problems. Alcohol Clin Exp Res. 2009;33:1374-1381.

19. Borges G, Walters EE, Kessler RC. Associations of substance use, abuse, and dependence with subsequent suicidal behavior. Am J Epidemiol. 2000;151:781-789.

20. Prochaska JO, DiClemente CC. Stages and processes of self-change of smoking: toward an integrative model of change. J Consult Clin Psychol. 1983;51:390-395.

21. Smedslund G, Berg RC, Hammerstrom KT, et al. Motivational interviewing for substance abuse. Cochrane Database Syst Rev. 2011;(5):CD008063.

22. Gryczynski J, Mitchell SG, Peterson TR, et al. The relationship between services delivered and substance use outcomes in New Mexico's Screening, Brief Intervention, Referral and Treatment (SBIRT) Initiative. Drug Alcohol Depend. 2011;118:152-157.

23. Woody GE, Poole SA, Subramaniam G, et al. Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial. JAMA. 2008;300:2003-2011.

24. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry. 2011;68:1238-1246.

25. Johansson BA, Berglund M, Lindgren A. Efficacy of maintenance treatment with naltrexone for opioid dependence: a meta-analytical review. Addiction. 2006;101:491-503.

26. Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008;300:2613-2620.

27. Zacny J, Bigelow G, Compton P, et al. College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug Alcohol Depend. 2003;69:215-232.

28. Kreek MJ. Rationale for maintenance pharmacotherapy of opiate dependence. Res Publ Assoc Res Nerv Ment Dis. 1992;70:205-230.

29. Mattick RP, Breen C, Kimber J, et al. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2009;(3):CD002209.

30. McCance-Katz EF, Sullivan LE, Nallani S. Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review. Am J Addict. 2010;19:4-16.

31. Office of National Drug Control Policy Reauthorization Act of 2006 (ONDCPRA), HR 6344, 109th Cong, 2nd Sess (2006).

32. Lewis JW, Walter D. Buprenorphine—background to its development as a treatment for opiate dependence. In: Blaine JD, ed. Buprenorphine: An Alternative Treatment for Opioid Dependence. Rockville, MD: National Institute on Drug Abuse; 1992:5-11. NIDA Research Monograph, No. 121. http://archives.drugabuse.gov/pdf/monographs/121.pdf. Accessed August 22, 2012.

33. Walsh SL, Preston KL, Stitzer ML, et al. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55:569-580.

34. Alho H, Sinclair D, Vuori E, et al. Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. Drug Alcohol Depend. 2007;88:75-78.

35. Hallinan R, Byrne A, Agho K, et al. Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment. J Sex Med. 2008;5:684-692.

36. Rapeli P, Fabritius C, Alho H, et al. Methadone vs. buprenorphine/naloxone during early opioid substitution treatment: a naturalistic comparison of cognitive performance relative to healthy controls. BMC Clin Pharmacol. 2007;7:5.

37. Wedam EF, Bigelow GE, Johnson RE, et al. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007;167:2469-2475.

38. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2004. Treatment Improvement Protocol (TIP) Series 40. DHHS publication SMA 04‐3939.

39. Kleber HD. Methadone maintenance 4 decades later: thousands of lives saved but still controversial. JAMA. 2008;300:2303-2305.

40. Hulse GK, Morris N, Arnold-Reed D, et al. Improving clinical outcomes in treating heroin dependence: randomized, controlled trial of oral or implant naltrexone. Arch Gen Psychiatry. 2009;66:1108-1115.

41. FDA. FDA approves injectable drug to treat opioid-dependent patients. October 12, 2010. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm229109.htm. Accessed September 11, 2012.

42. Inturrisi CE, Verebely K. The levels of methadone in the plasma in methadone maintenance. Clin Pharmacol Ther. 1972;13(5 pt 1):633-637.

43. Stitzer M, Bigelow G, Lawrence C, et al. Medication take-home as a reinforcer in a methadone maintenance program. Addict Behav. 1977;2:9-14.

44. Code of Federal Regulations. Title 42.8.12. Federal Opioid Treatment Standards. October 2010.

45. Johnson RE. Chutuape MA, Strain EC, et al. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000;343:1290-1297.

46. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387-395.

47. Ball JC, Lange WR, Myers CP, et al. Reducing the risk of AIDS through methadone maintenance treatment. J Health Soc Behav. 1988;29:214-226.

48. Fiellin DA, Pantalon MV, Chawarski MC, et al. Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence. N Engl J Med. 2006;355:365-374.

49. Defulio A, Everly JJ, Leoutsakos JM, et al. Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone in opioid-dependent adults: a randomized controlled trial. Drug Alcohol Depend. 2012;120:48-54.

50. Savage SR. Management of opioid medications in patients with chronic pain and risk of substance misuse. Curr Psychiatry Rep. 2009;11:377-384.

This article was originally published in the Journal of Family Practice. 2012;61:588-597.

CASE Sam M., age 48, is in your office for the first time in more than two years. He has gained a considerable amount of weight and appears a bit sluggish, and you wonder whether he's depressed. As you take a history, Sam reminds you that he was laid off 16 months ago and had been caring for his wife, who sustained a debilitating back injury. When you saw her recently, she told you she's back to work and pain-free. So you're taken aback when Sam asks you to refill his wife's oxycodone prescription for lingering pain that often keeps her up at night.

If Sam were your patient, would you suspect opioid dependence?

Dependence on opioid analgesics and the adverse consequences associated with it have steadily increased during the past decade. Consider the following:

• Between 2004 and 2008, the number of emergency department visits related to nonmedical prescription opioid use more than doubled, rising by 111%.¹

• The increasing prevalence of opioid abuse has led to a recent spike in unintentional deaths,² with the number of lives lost to opioid analgesic overdose now exceeding that of heroin or cocaine.³

• More than 75% of opioids used for nonmedical purposes were prescribed for someone else.⁴

The course of opioid use is highly variable. Some people start with a legitimate medical prescription for an opioid analgesic, then continue taking it after the pain subsides. Others experiment briefly with nonmedical prescription opioids or use them intermittently without adverse effect. Some progress from prescription opioids to heroin, despite its dangers.⁵ Still others experience a catastrophic outcome, such as an overdose or severe accident, the first time they use opioids.⁶ Rapid progression from misuse of opioids to dependence is most likely to occur in vulnerable populations, such as those with concurrent mental illness, other substance use disorders, or increased sensitivity to pain.⁷

Understanding the terms. Before we continue, a word about terminology is in order. Misuse generally refers to the use of a medication in a manner (ie, purpose, dose, or frequency) other than its intended use, whereas drug addiction is the repeated use of a drug despite resulting harm. Here we will use opioid dependence to mean a pattern of increasing use characterized by significant impairment and distress and an inability to stop, and opioid withdrawal to reflect a constellation of symptoms, such as insomnia, nausea, diarrhea, and muscle aches, that can follow physiological dependence (though not necessarily opioid dependence). Our definitions of these terms are consistent with those of the American Psychiatric Association (APA).⁸ Worth noting, however, is the fact that as the APA prepares for the publication of the 5th edition of its Diagnostic and Statistical Manual of Mental Disorders, its Substance Disorder Work Group has proposed replacing the term opioid dependence with opioid use disorder to reduce the confusion associated with these definitions.⁹

Assessing Illicit Opioid Use: Start With a Targeted Question
Most patients who are opioid dependent do not seek treatment for it¹⁰ and are typically free of medical sequelae associated with drug addiction when they see family practitioners. The absence of self-reporting and obvious physical signs and symptoms, coupled with the increase in illicit use of prescription opioids, underscores the need for clinicians to identify patients who are abusing opioids and ensure that they get the help they need.

Screening tools. There are a number of screening tools you can use for this purpose—eg, CAGE-Adapted to Include Drugs (CAGE-AID) and Drug Abuse Screening Test (DAST)^11,12—but they have not been found to be significantly better than a careful substance abuse history.¹³

Straightforward questions. You can start by asking, "Do you take any medications for pain?" If the answer is Yes, get the name of the drug and inquire about the frequency of use and the route, the amount typically taken, and the duration of the current use pattern. Ask specifically about opioids when taking a substance abuse history. After a question about alcohol use, you can say, "Do you use any other drugs in a serious way? Marijuana? Opioids, like Percocet, Vicodin, or Oxycontin?" Although it can be very difficult to detect opioid dependence if the patient is not forthcoming, other likely indicators of drug-seeking behavior should trigger additional questions. (See "Opioid dependence: Red Flags to Keep in Mind."^14-16)

"Brief" protocols. Recent studies of Screening, Brief Intervention, and Referral to Treatment (SBIRT) programs have found that the simple, time-limited interventions they offer (visit www.samhsa.gov/prevention/sbirt/SBIRTwhitepaper.pdf to learn more) lead to a reduction in self-reported illicit opioid use.^17,18 Clinicians can readily incorporate SBIRT protocols into routine practice, as an evidence-based and often reimbursable approach to substance abuse.¹⁷

Additional Steps Before Initiating Treatment
After screening and diagnostic evaluation provide evidence that a patient is opioid dependent, you can take several steps to guide him or her to the appropriate treatment.

A thorough biopsychosocial assessment covering co-occurring psychiatric illnesses, pain, psychosocial stressors contributing to opioid use, and infectious disease screening is required to gain a clear picture of the patient's situation. In every case, acute emergencies such as suicidal ideation require immediate intervention, which may include hospitalization.¹⁹

Assess the patient's desire for help. After the initial assessment, it is often helpful to categorize the patient's "stage of change" (precontemplation, contemplation, preparation, action, or maintenance)²⁰ and to tailor your next step accordingly. A patient who denies that opioid use is a problem or who is clearly ambivalent about seeking treatment may require a conversation that uses principles of motivational interviewing—a collaborative approach that aims to evoke and strengthen personal motivation for change.²¹ Consider a question that encourages him or her to express reasons for change, such as: "How would you like your current situation to be different?" As almost everyone abusing opioids has thoughts about stopping, such a question may help the patient focus on specific changes.

CASE When you question Sam about his interest in oxycodone, he breaks down. He's been unable to find work or to lose the excess weight he gained during the many months he cared for his wife. He tells you that soon after his wife stopped taking the pain pills, he started taking them. At first, he took one occasionally. Then he started taking the opioids every day, and finally, whenever he awakened at night. Now, Sam says, he has no more pills, and he's nauseous, depressed, and unable to sleep—and looking to you for help.

Sam fits the criteria for opioid withdrawal as a result of physiological dependence; further questioning reveals that he also suffers from opioid dependence, and that he is receptive to treatment.

Recommending Treatment and Following Up
Several options are available for patients who, like Sam, have signs and symptoms of opioid withdrawal as a result of physiological dependence. You can provide a referral to a clinician who specializes in addiction, recommend detoxification and/or treatment in an inpatient facility, or initiate pharmacologic treatment and provide a referral to a behavioral therapist. Whatever the initial approach, most patients will ultimately be treated as outpatients, with a combination of pharmacotherapy and behavioral therapy—often, with monitoring and oversight by a primary care provider. Which approach to pursue should be guided by evidence-based recommendations (see table^17,22-27) and jointly decided by provider and patient.

Medication Plays a Key Role in Recovery
Recommend medication-assisted treatment, either with an agonist (buprenorphine or methadone) or an antagonist (naltrexone), for every patient with physiological opioid dependence. The goals of pharmacotherapy are to prevent or reduce withdrawal symptoms and craving, avoid relapse, and restore to a normal state any physiological functions (eg, sleep, bowel habits) that have been disrupted by opioid use.²⁸ When continued for at least three months, medication has been shown to improve outcomes.^23,24,29 In one recent study, 49% of opioid-dependent participants who were still taking buprenorphine-naloxone at 12 weeks had successful outcomes (minimal or no opioid use), compared with 7% of those undergoing a brief buprenorphine-naloxone taper.²⁴

There are risks associated with medication-assisted therapy, however. Those of greatest concern are a potential increase in drug interactions, the risk of diversion (a concern with both buprenorphine and methadone), and the potential for accidental overdose.^2,30

Buprenorphine, a partial m-opioid receptor agonist, is a Schedule III controlled substance and can be dispensed by a pharmacist, making inpatient opioid detoxification unnecessary for many opioid-dependent patients. Clinicians who wish to prescribe buprenorphine for the treatment of opioid dependence must complete an 8-hour course, offered by the American Medical Association and the APA, among other medical groups, and obtain a Drug Enforcement Administration (code "X") license.³¹

Buprenorphine has a high affinity for, and a slow dissociation from, m-opioid receptors, resulting in the displacement of other opioids from the m receptor and less severe withdrawal.³² As a partial agonist, buprenorphine attenuates opioid withdrawal symptoms with a ceiling, or near-maximal, effect at 16 mg, thereby lowering the risk for overdose.³³ A sublingual formulation that combines buprenorphine with naloxone, an opioid antagonist that exerts its full effect when injected but is minimally absorbed sublingually, reduces the potential for abuse of buprenorphine without interfering with its effectiveness.³⁴

Compared with methadone, buprenorphine is less likely to interact with antiretroviral medications or to cause QTc prolongation, erectile dysfunction, or cognitive or psychomotor impairment.^31,35-37 Limitations include the ceiling effect, which can be a problem for cases in which more agonist is needed; cost (approximately $12/d); and the lack of approval by the FDA for use during pregnancy.

Buprenorphine maintenance involves three phases: induction, stabilization, and maintenance.³⁸ Induction takes place in a clinician's office at the time the patient experiences opioid withdrawal symptoms, typically 6 to 48 hours after taking the last opioid. Extended treatment improves clinical outcomes,^23,24 and longer-term maintenance (of indefinite duration) is frequently required.

Naltrexone is a m-receptor antagonist, and therefore does not cause physical dependence or have agonist effects such as euphoria and sedation. As a result, it has no diversion value and may appeal to those who view opioid-agonist pharmacotherapy as simply trading one drug for another.³⁹ Naltrexone is not a controlled substance and is not subject to the regulatory requirements that buprenorphine and methadone face.

Although agonists can be started in the first day or two after a patient decides to stop using opioids, patients must be opioid-free for at least seven days before starting naltrexone. That's because its antagonist properties will precipitate withdrawal if another opioid is present on the opioid receptors. During the seven-day "washout" period, opioid withdrawal symptoms can be treated with medications such as clonidine and dicyclomine, but such symptoms make patients especially vulnerable to relapse while waiting to start naltrexone.

Oral naltrexone's effectiveness as a treatment for opioid dependence has been limited by poor patient adherence. But a long-acting intramuscular form of the drug, approved by the FDA in 2010 and requiring once-a-month injection, mitigates this concern.^40,41

Methadone is a full m-opioid agonist, administered daily at specialized clinics, as a maintenance therapy for opioid dependence. Although office-based physicians can prescribe methadone for pain, the drug can only be used for opioid dependence under the auspices of state- and federally regulated opioid treatment programs (http://findtreatment.samhsa.gov/TreatmentLocator/faces/quickSearch.jspx; a mobile phone application is also available at www.samhsa.gov/mobile/treat mentlocator.aspx).

Methadone, a Schedule III controlled substance with a half-life averaging 24 to 36 hours, requires daily dosing.⁴² Its slow metabolism and long half-life increase the risk for overdose.

Methadone is best for patients who are highly dependent on opioids and likely to benefit from a structured treatment environment with daily supervision (although patients who are doing well may earn take-home privileges so they don't have to come to the clinic every day).⁴³ New patients should receive an initial dose of 30 mg or less, and a maximum first-day dose of 40 mg.⁴⁴

Methadone use remains the standard of care for pregnant women being treated for opioid dependence, while studies of the effects of buprenorphine and naltrexone on a developing fetus continue. Although methadone's efficacy, particularly in lower doses, is similar to that of buprenorphine,⁴⁵ its adverse effect profile is worse. Adverse effects include drug interactions, the potential for respiratory depression (especially in combination with alcohol or sedatives), QTc prolongation (which requires monitoring by ECG), sedation, and weight gain, and should be considered before methadone is selected as a maintenance pharmacotherapy.^30,37,46 And, because relapse rates within 12 months of tapering off methadone have been reported to exceed 80%,⁴⁷ both the clinician and the patient need to consider the likelihood of long-term, even lifelong, maintenance before initiating treatment.

Behavioral Interventions Are a Vital Part of the Picture
Studies evaluating the extent to which various types and amounts of counseling improve outcomes compared with pharmacotherapy alone have had conflicting results.^24,48 Nonetheless, most clinicians consider counseling a critical component of treatment for opioid dependence and recommend, at a minimum, either individual or group counseling (various modalities have been shown to be effective) and regular attendance at a self-help group like Narcotics Anonymous. Contingency management, a type of therapy that uses prizes as incentives for desired behaviors; and family therapy, individual counseling, and community-based programs have all been found to improve outcomes.^6,49 

CASE You refer Sam to an addiction psychiatrist, who stabilizes him on 16 mg/d buprenorphine/naloxone as part of an outpatient treatment program. Sam is enrolled in a weekly buprenorphine stabilization group, where he gives a urine sample each week. He also begins seeing a social worker weekly for counseling and attends Narcotics Anonymous meetings two to three times a week. At a follow-up appointment with you six months later, he reports that he has been abstinent from oxycodone for six months, his sleep is improved, and he feels better about his chances of finding another job.

Your Role in Safeguarding the Patient
With the rising prevalence of opioid overdose, patient education aimed at crisis prevention is crucial as well. Warn patients of the risk for accidental overdose, often associated with relapse, stressing the importance of continuing treatment and taking their maintenance medication exactly as prescribed.

There are other steps that can be taken to safeguard patients—for example, providing naloxone rescue kits to patients and their families when appropriate. The clinician can also institute diversion and overdose prevention measures for patients taking buprenorphine or methadone—providing a lock box for take-home medication, implementing treatment contracts, and using a designated pharmacy to dispense buprenorphine, for example.^26,27,50

Regular monitoring, urine drug screens, and random pill counts, in which patients are typically given 24 hours to bring in their prescribed medication so it can be counted, can also help keep patients on track. Treatment for concurrent psychiatric disorders—depression, anxiety, and personality disorders are common among patients with opioid dependence—is also likely to improve treatment outcomes.

References
1. CDC. Emergency department visits involving nonmedical use of selected prescription drugs - United States, 2004-2008. MMWR Morb Mortal Wkly Rep. 2010;59:705-709.

2. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA. 2011;305:1315-1321.

3. Warner M, Chen LH, Makuc DM. Increase in fatal poisonings involving opioid analgesics in the United States, 1999-2006. NCHS Data Brief. 2009;22:1-8.

4. Substance Abuse and Mental Health Services Administration. Results From the 2009 National Survey on Drug Use and Health: Volume I. Summary of National Findings. Rockville, Md: SAMHSA, Office of Applied Studies; 2010. NSDUH Series H-38A, HHS publication SMA 10-4856. www.samhsa.gov/dataNSDUH/2k9NSDUH/2k9Results.htm. Accessed August 22, 2012.

5. Hser YI, Huang D, Brecht ML, et al. Contrasting trajectories of heroin, cocaine, and methamphetamine use. J Addict Dis. 2008;27:13-21.

6. Veilleux JC, Colvin PJ, Anderson J, et al. A review of opioid dependence treatment: pharmacological and psychosocial interventions to treat opioid addiction. Clin Psychol Rev. 2011;30:155-166.

7. George O, Koob GF. Individual differences in prefrontal cortex function and the transition from drug use to drug dependence. Neurosci Biobehav Rev. 2011;35:232-247.

8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev (DSM-IV-TR). Arlington, VA: American Psychiatric Association; 2000.

9. American Psychiatric Association. R 19 opioid use disorder (2012). www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=460. Accessed June 20, 2012.

10. Substance Abuse and Mental Health Services Administration. Results From the 2008 National Survey on Drug Use and Health: National Findings. Rockville, MD: SAMHSA, Office of Applied Studies; 2009. NSDUH Series H-36, HHS publication SMA 09-4434. www.samhsa.gov/data/nsduh/2k8nsduh/2k8Results.htm. Accessed August 22, 2012.

11. Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and other drug abuse: criterion validity in a primary care practice. Wis Med J. 1995;94:135-140.

12. Skinner HA. The drug abuse screening test. Addict Behav. 1982;7:363-371.

13. US Preventive Services Task Force. Screening for Illicit Drug Use: US Preventive Services Task Force Recommendation Statement. January 2008. www.uspreventiveservicestaskforce.org/uspstf08/druguse/drugrs.htm. Accessed May 7, 2012.

14. Gourlay D, Caplan Y, Heit H. Urine Drug Testing in Clinical Practice: Dispelling the Myths and Designing Strategies. San Francisco, Calif: California Academy of Family Physicians; 2006.

15. Jackman R, Purvis J, Mallett B. Chronic nonmalignant pain in primary care. Am Fam Physician. 2008;78:1155-1162.

16. McBane S, Weigle N. Is it time to drug test your chronic pain patient? J Fam Pract. 2010;59:628-633.

17. Madras BK, Compton WM, Avula D, et al. Screening, brief interventions, referral to treatment (SBIRT) for illicit drug and alcohol use at multiple healthcare sites: comparison at intake and 6 months later. Drug Alcohol Depend. 2009;99:280-295.

18. The InSight Project Research Group. SBIRT outcomes in Houston: final report on InSight, a hospital district-based program for patients at risk for alcohol or drug use problems. Alcohol Clin Exp Res. 2009;33:1374-1381.

19. Borges G, Walters EE, Kessler RC. Associations of substance use, abuse, and dependence with subsequent suicidal behavior. Am J Epidemiol. 2000;151:781-789.

20. Prochaska JO, DiClemente CC. Stages and processes of self-change of smoking: toward an integrative model of change. J Consult Clin Psychol. 1983;51:390-395.

21. Smedslund G, Berg RC, Hammerstrom KT, et al. Motivational interviewing for substance abuse. Cochrane Database Syst Rev. 2011;(5):CD008063.

22. Gryczynski J, Mitchell SG, Peterson TR, et al. The relationship between services delivered and substance use outcomes in New Mexico's Screening, Brief Intervention, Referral and Treatment (SBIRT) Initiative. Drug Alcohol Depend. 2011;118:152-157.

23. Woody GE, Poole SA, Subramaniam G, et al. Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial. JAMA. 2008;300:2003-2011.

24. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry. 2011;68:1238-1246.

25. Johansson BA, Berglund M, Lindgren A. Efficacy of maintenance treatment with naltrexone for opioid dependence: a meta-analytical review. Addiction. 2006;101:491-503.

26. Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008;300:2613-2620.

27. Zacny J, Bigelow G, Compton P, et al. College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug Alcohol Depend. 2003;69:215-232.

28. Kreek MJ. Rationale for maintenance pharmacotherapy of opiate dependence. Res Publ Assoc Res Nerv Ment Dis. 1992;70:205-230.

29. Mattick RP, Breen C, Kimber J, et al. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev. 2009;(3):CD002209.

30. McCance-Katz EF, Sullivan LE, Nallani S. Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review. Am J Addict. 2010;19:4-16.

31. Office of National Drug Control Policy Reauthorization Act of 2006 (ONDCPRA), HR 6344, 109th Cong, 2nd Sess (2006).

32. Lewis JW, Walter D. Buprenorphine—background to its development as a treatment for opiate dependence. In: Blaine JD, ed. Buprenorphine: An Alternative Treatment for Opioid Dependence. Rockville, MD: National Institute on Drug Abuse; 1992:5-11. NIDA Research Monograph, No. 121. http://archives.drugabuse.gov/pdf/monographs/121.pdf. Accessed August 22, 2012.

33. Walsh SL, Preston KL, Stitzer ML, et al. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55:569-580.

34. Alho H, Sinclair D, Vuori E, et al. Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. Drug Alcohol Depend. 2007;88:75-78.

35. Hallinan R, Byrne A, Agho K, et al. Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment. J Sex Med. 2008;5:684-692.

36. Rapeli P, Fabritius C, Alho H, et al. Methadone vs. buprenorphine/naloxone during early opioid substitution treatment: a naturalistic comparison of cognitive performance relative to healthy controls. BMC Clin Pharmacol. 2007;7:5.

37. Wedam EF, Bigelow GE, Johnson RE, et al. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007;167:2469-2475.

38. Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2004. Treatment Improvement Protocol (TIP) Series 40. DHHS publication SMA 04‐3939.

39. Kleber HD. Methadone maintenance 4 decades later: thousands of lives saved but still controversial. JAMA. 2008;300:2303-2305.

40. Hulse GK, Morris N, Arnold-Reed D, et al. Improving clinical outcomes in treating heroin dependence: randomized, controlled trial of oral or implant naltrexone. Arch Gen Psychiatry. 2009;66:1108-1115.

41. FDA. FDA approves injectable drug to treat opioid-dependent patients. October 12, 2010. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm229109.htm. Accessed September 11, 2012.

42. Inturrisi CE, Verebely K. The levels of methadone in the plasma in methadone maintenance. Clin Pharmacol Ther. 1972;13(5 pt 1):633-637.

43. Stitzer M, Bigelow G, Lawrence C, et al. Medication take-home as a reinforcer in a methadone maintenance program. Addict Behav. 1977;2:9-14.

44. Code of Federal Regulations. Title 42.8.12. Federal Opioid Treatment Standards. October 2010.

45. Johnson RE. Chutuape MA, Strain EC, et al. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000;343:1290-1297.

46. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387-395.

47. Ball JC, Lange WR, Myers CP, et al. Reducing the risk of AIDS through methadone maintenance treatment. J Health Soc Behav. 1988;29:214-226.

48. Fiellin DA, Pantalon MV, Chawarski MC, et al. Counseling plus buprenorphine-naloxone maintenance therapy for opioid dependence. N Engl J Med. 2006;355:365-374.

49. Defulio A, Everly JJ, Leoutsakos JM, et al. Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone in opioid-dependent adults: a randomized controlled trial. Drug Alcohol Depend. 2012;120:48-54.

50. Savage SR. Management of opioid medications in patients with chronic pain and risk of substance misuse. Curr Psychiatry Rep. 2009;11:377-384.

This article was originally published in the Journal of Family Practice. 2012;61:588-597.

The effects of breast cancer on obstetric and gynecologic practices are pervasive. In this article, we touch on three aspects of breast cancer that are particularly relevant to the practicing ObGyn:

• the need to identify women at high risk for breast cancer and select those who would benefit from a discussion of the advantages and risks of chemoprophylaxis, which can reduce the likelihood of breast cancer by 50% or more
• the need for strategies to manage menopausal symptoms in the general population without increasing the risk of breast cancer. The traditional approach to this problem changed dramatically with the Women’s Health Initiative (WHI), which demonstrated an increased risk of breast cancer in women taking conjugated equine estrogen and progestin. The widely publicized initial findings of the estrogen-progestin arm of the WHI sharply contrast the equally relevant, somewhat unexpected, and less publicized results of the estrogen-alone arm, which demonstrated a substantial and statistically significant decrease in the incidence of breast cancer, even after estrogen was discontinued.
• the potential effects of breast cancer treatment on ovarian function in young women. This year, of the approximately 250,000 women who will be diagnosed with invasive breast cancer, more than 50,000 women will be of reproductive age. Most of these young women will require adjuvant chemotherapy; as a result, many will experience the premature onset of menopause. Along with the attendant loss of fertility these women will face, many will also develop distressing and life-altering menopausal symptoms. Management of these women before and after initiation of chemotherapy requires an understanding of both the expected effects of the chemotherapy and knowledge of how to actively manage these women with strategies to either prevent these events or to manage menopausal symptoms.

In women at normal risk for breast cancer, unopposed estrogen lowers the rate of the malignancy and the likelihood of mortality if the cancer occurs—but is not recommended as a prophylactic agent. Tamoxifen and other chemoprophylactic drugs can halve the rate of breast cancer in high-risk women but are not without drawbacks.

A look at the lower rate of breast cancer in the estrogen-alone arm of the WHI

Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.

From 1993 through 1998, the WHI enrolled 10,739 postmenopausal women in the largest prospective trial evaluating the effect of hormone therapy (HT) on various clinical outcomes. The women were randomly allocated to three groups:

• conjugated estrogen with medroxyprogesterone acetate
• conjugated estrogen alone (in women with a prior hysterectomy)
• placebo.

The negative effects of estrogen plus progestin on the risk of breast cancer were the most widely discussed oucomes.¹ Shortly after the findings from this arm of the study were published, the use of HT in the United States declined dramatically and unequivocally.²

In 2012, WHI published the results of the estrogen-alone arm in the British cancer specialty journal Lancet Oncology. As shown in the TABLE below, the incidence of breast cancer was statistically significantly lower (23%) in the estrogen group than in the placebo group. Women who were treated with estrogen alone were also 63% less likely to die of breast cancer, and all-cause mortality was 38% lower; both of these findings were statistically significant. Not only was there a significant reduction in the incidence of invasive breast cancer while the subjects were taking estrogen, but that reduction continued for a median of 4.7 years of follow-up after discontinuation of estrogen.

Breast cancer incidence and mortality in the estrogen-only arm of the WHI, compared with placebo*

The incidence figure is somewhat remarkable (199 in the placebo group versus 151 in the estrogen-alone group) in that it was nearly the exact reverse of the estrogen-progestin arm of the WHI trial (199 in the estrogen/progestin group vs 150 in the placebo group).³

All breast cancer chemoprophylactic agents carry risks as well as benefits

Goss P, Ingle J, Ales-Martinez J, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381–2391.

Cheung A, Tile L, Cardew S, et al. Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomized controlled trial. Lancet Oncol. 2012;13(3):275–284.

Vogel V, Costantino J, Wickerham L, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res. 2010;3(6):696–706.

The number of new cases of breast cancer in the United States last year reached nearly a quarter-million. Clearly, reducing this number remains an important goal.⁴ Chemoprevention—the use of medication to reduce cancer risk—may be offered to women who are at high risk of developing breast cancer.

In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial, tamoxifen (a selective estrogen-receptor modulator) was shown to reduce the risk of invasive breast cancer by 49% in a high-risk population, resulting in the FDA approving tamoxifen as the first drug for breast cancer prevention.⁵ The P-1 trial was followed by the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial, which demonstrated relative equivalence between the two medications as cancer prevention agents in menopausal women.⁶ Serious side effects of these medications limit their use among eligible women, although raloxifene seems to be associated with fewer adverse events. In the update of the STAR trial with an average of 81 months of follow-up, the risk ratio for adverse events (raloxifene:tamoxifen) was 0.75 for thromboembolic events, 0.55 for endometrial cancer, and 0.19 for uterine hyperplasia.

Another drug used for cancer treatment has now entered the prevention scene. In 2011, the NCIC Clinical Trials Group Mammary Prevention.3 trial (NCIC CTG MAP.3) compared exemestane (an aromatase inhibitor) with placebo for menopausal women at high risk for breast cancer, demonstrating a 65% relative reduction in the incidence of invasive breast cancer. This study validated another option for cancer prevention in high-risk women, although its adoption is likely also to be limited by side effects, including vasomotor symptoms, a high rate of arthralgias, and vaginal dryness/dyspareunia. The greatest concern may be the potential effect on bone density. Though the rates of serious adverse events including fracture did not differ in the MAP.3 trial at 35 months of follow-up, women on exemestane had significantly larger losses of bone mineral density, compared with controls.

Managing the reproductive health concerns of young women with breast cancer

Azim H, Kroman N, Paesmans M, et al. Prognostic impact of pregnancy after breast cancer according to estrogen receptor status: a multicenter retrospective study. J Clin Oncol. 2013;31(1):73–79.

Howard-Anderson J, Ganz P, Bower J, Stanton A. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: a systematic review. J Natl Cancer Inst. 2012;104(5):1386–1405.

Of the approximately 230,000 new cases of invasive breast cancer identified in 2011, 50,430 cases involved women less than 50 years of age.⁴ For these women, the diagnosis of cancer raises multifaceted concerns, including the physical changes that accompany breast cancer treatment, concerns about recurrence and mortality, and significant sexual and reproductive consequences of treatment that alters ovarian function. Pregnancy-associated breast cancers (breast cancers diagnosed during pregnancy, lactation, and for 12 months postpartum) represent a small subset of these cancers and occur in about 1 in 3,000 pregnancies. One might anticipate that this rate will increase as women continue to delay childbearing, because pregnancy-associated breast cancers are more common in older women.

In the review article by Howard-Anderson and colleagues, the importance of these reproductive health consequences in young women diagnosed with breast cancer is highlighted. The women who transition to menopause as a result of chemotherapy (reported to range from 33%–73%) experience more symptoms, including hot flashes, night sweats, breast pain, vaginal dryness, and lack of sexual desire. Sixty-one percent of women younger than 40 years at diagnosis reported that they were concerned about menopause, and 30% reported that this concern influenced their treatment decisions. Thirty-nine percent of women in this group had major concerns about treatment-associated infertility, and only half of the women studied felt that their fertility concerns were adequately addressed.

On a positive note, for women who successfully achieve pregnancy after breast cancer, pregnancy outcomes appear to be similar to those of their nonpregnant peers. In the study by Azim and colleagues, women who became pregnant after a breast cancer diagnosis had disease-free survival that was statistically similar to that of matched women who did not have subsequent pregnancies. In addition, this outcome did not differ based on estrogen/progesterone receptor status (ER/PR positive or negative).

We want to hear from you! Tell us what you think.

The effects of breast cancer on obstetric and gynecologic practices are pervasive. In this article, we touch on three aspects of breast cancer that are particularly relevant to the practicing ObGyn:

• the need to identify women at high risk for breast cancer and select those who would benefit from a discussion of the advantages and risks of chemoprophylaxis, which can reduce the likelihood of breast cancer by 50% or more
• the need for strategies to manage menopausal symptoms in the general population without increasing the risk of breast cancer. The traditional approach to this problem changed dramatically with the Women’s Health Initiative (WHI), which demonstrated an increased risk of breast cancer in women taking conjugated equine estrogen and progestin. The widely publicized initial findings of the estrogen-progestin arm of the WHI sharply contrast the equally relevant, somewhat unexpected, and less publicized results of the estrogen-alone arm, which demonstrated a substantial and statistically significant decrease in the incidence of breast cancer, even after estrogen was discontinued.
• the potential effects of breast cancer treatment on ovarian function in young women. This year, of the approximately 250,000 women who will be diagnosed with invasive breast cancer, more than 50,000 women will be of reproductive age. Most of these young women will require adjuvant chemotherapy; as a result, many will experience the premature onset of menopause. Along with the attendant loss of fertility these women will face, many will also develop distressing and life-altering menopausal symptoms. Management of these women before and after initiation of chemotherapy requires an understanding of both the expected effects of the chemotherapy and knowledge of how to actively manage these women with strategies to either prevent these events or to manage menopausal symptoms.

In women at normal risk for breast cancer, unopposed estrogen lowers the rate of the malignancy and the likelihood of mortality if the cancer occurs—but is not recommended as a prophylactic agent. Tamoxifen and other chemoprophylactic drugs can halve the rate of breast cancer in high-risk women but are not without drawbacks.

A look at the lower rate of breast cancer in the estrogen-alone arm of the WHI

Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.

From 1993 through 1998, the WHI enrolled 10,739 postmenopausal women in the largest prospective trial evaluating the effect of hormone therapy (HT) on various clinical outcomes. The women were randomly allocated to three groups:

• conjugated estrogen with medroxyprogesterone acetate
• conjugated estrogen alone (in women with a prior hysterectomy)
• placebo.

The negative effects of estrogen plus progestin on the risk of breast cancer were the most widely discussed oucomes.¹ Shortly after the findings from this arm of the study were published, the use of HT in the United States declined dramatically and unequivocally.²

In 2012, WHI published the results of the estrogen-alone arm in the British cancer specialty journal Lancet Oncology. As shown in the TABLE below, the incidence of breast cancer was statistically significantly lower (23%) in the estrogen group than in the placebo group. Women who were treated with estrogen alone were also 63% less likely to die of breast cancer, and all-cause mortality was 38% lower; both of these findings were statistically significant. Not only was there a significant reduction in the incidence of invasive breast cancer while the subjects were taking estrogen, but that reduction continued for a median of 4.7 years of follow-up after discontinuation of estrogen.

Breast cancer incidence and mortality in the estrogen-only arm of the WHI, compared with placebo*

The incidence figure is somewhat remarkable (199 in the placebo group versus 151 in the estrogen-alone group) in that it was nearly the exact reverse of the estrogen-progestin arm of the WHI trial (199 in the estrogen/progestin group vs 150 in the placebo group).³

All breast cancer chemoprophylactic agents carry risks as well as benefits

Goss P, Ingle J, Ales-Martinez J, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381–2391.

Cheung A, Tile L, Cardew S, et al. Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomized controlled trial. Lancet Oncol. 2012;13(3):275–284.

Vogel V, Costantino J, Wickerham L, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res. 2010;3(6):696–706.

The number of new cases of breast cancer in the United States last year reached nearly a quarter-million. Clearly, reducing this number remains an important goal.⁴ Chemoprevention—the use of medication to reduce cancer risk—may be offered to women who are at high risk of developing breast cancer.

In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial, tamoxifen (a selective estrogen-receptor modulator) was shown to reduce the risk of invasive breast cancer by 49% in a high-risk population, resulting in the FDA approving tamoxifen as the first drug for breast cancer prevention.⁵ The P-1 trial was followed by the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial, which demonstrated relative equivalence between the two medications as cancer prevention agents in menopausal women.⁶ Serious side effects of these medications limit their use among eligible women, although raloxifene seems to be associated with fewer adverse events. In the update of the STAR trial with an average of 81 months of follow-up, the risk ratio for adverse events (raloxifene:tamoxifen) was 0.75 for thromboembolic events, 0.55 for endometrial cancer, and 0.19 for uterine hyperplasia.

Another drug used for cancer treatment has now entered the prevention scene. In 2011, the NCIC Clinical Trials Group Mammary Prevention.3 trial (NCIC CTG MAP.3) compared exemestane (an aromatase inhibitor) with placebo for menopausal women at high risk for breast cancer, demonstrating a 65% relative reduction in the incidence of invasive breast cancer. This study validated another option for cancer prevention in high-risk women, although its adoption is likely also to be limited by side effects, including vasomotor symptoms, a high rate of arthralgias, and vaginal dryness/dyspareunia. The greatest concern may be the potential effect on bone density. Though the rates of serious adverse events including fracture did not differ in the MAP.3 trial at 35 months of follow-up, women on exemestane had significantly larger losses of bone mineral density, compared with controls.

Managing the reproductive health concerns of young women with breast cancer

Azim H, Kroman N, Paesmans M, et al. Prognostic impact of pregnancy after breast cancer according to estrogen receptor status: a multicenter retrospective study. J Clin Oncol. 2013;31(1):73–79.

Howard-Anderson J, Ganz P, Bower J, Stanton A. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: a systematic review. J Natl Cancer Inst. 2012;104(5):1386–1405.

Of the approximately 230,000 new cases of invasive breast cancer identified in 2011, 50,430 cases involved women less than 50 years of age.⁴ For these women, the diagnosis of cancer raises multifaceted concerns, including the physical changes that accompany breast cancer treatment, concerns about recurrence and mortality, and significant sexual and reproductive consequences of treatment that alters ovarian function. Pregnancy-associated breast cancers (breast cancers diagnosed during pregnancy, lactation, and for 12 months postpartum) represent a small subset of these cancers and occur in about 1 in 3,000 pregnancies. One might anticipate that this rate will increase as women continue to delay childbearing, because pregnancy-associated breast cancers are more common in older women.

In the review article by Howard-Anderson and colleagues, the importance of these reproductive health consequences in young women diagnosed with breast cancer is highlighted. The women who transition to menopause as a result of chemotherapy (reported to range from 33%–73%) experience more symptoms, including hot flashes, night sweats, breast pain, vaginal dryness, and lack of sexual desire. Sixty-one percent of women younger than 40 years at diagnosis reported that they were concerned about menopause, and 30% reported that this concern influenced their treatment decisions. Thirty-nine percent of women in this group had major concerns about treatment-associated infertility, and only half of the women studied felt that their fertility concerns were adequately addressed.

On a positive note, for women who successfully achieve pregnancy after breast cancer, pregnancy outcomes appear to be similar to those of their nonpregnant peers. In the study by Azim and colleagues, women who became pregnant after a breast cancer diagnosis had disease-free survival that was statistically similar to that of matched women who did not have subsequent pregnancies. In addition, this outcome did not differ based on estrogen/progesterone receptor status (ER/PR positive or negative).

We want to hear from you! Tell us what you think.

The effects of breast cancer on obstetric and gynecologic practices are pervasive. In this article, we touch on three aspects of breast cancer that are particularly relevant to the practicing ObGyn:

• the need to identify women at high risk for breast cancer and select those who would benefit from a discussion of the advantages and risks of chemoprophylaxis, which can reduce the likelihood of breast cancer by 50% or more
• the need for strategies to manage menopausal symptoms in the general population without increasing the risk of breast cancer. The traditional approach to this problem changed dramatically with the Women’s Health Initiative (WHI), which demonstrated an increased risk of breast cancer in women taking conjugated equine estrogen and progestin. The widely publicized initial findings of the estrogen-progestin arm of the WHI sharply contrast the equally relevant, somewhat unexpected, and less publicized results of the estrogen-alone arm, which demonstrated a substantial and statistically significant decrease in the incidence of breast cancer, even after estrogen was discontinued.
• the potential effects of breast cancer treatment on ovarian function in young women. This year, of the approximately 250,000 women who will be diagnosed with invasive breast cancer, more than 50,000 women will be of reproductive age. Most of these young women will require adjuvant chemotherapy; as a result, many will experience the premature onset of menopause. Along with the attendant loss of fertility these women will face, many will also develop distressing and life-altering menopausal symptoms. Management of these women before and after initiation of chemotherapy requires an understanding of both the expected effects of the chemotherapy and knowledge of how to actively manage these women with strategies to either prevent these events or to manage menopausal symptoms.

In women at normal risk for breast cancer, unopposed estrogen lowers the rate of the malignancy and the likelihood of mortality if the cancer occurs—but is not recommended as a prophylactic agent. Tamoxifen and other chemoprophylactic drugs can halve the rate of breast cancer in high-risk women but are not without drawbacks.

A look at the lower rate of breast cancer in the estrogen-alone arm of the WHI

Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol. 2012;13(5):476–486.

From 1993 through 1998, the WHI enrolled 10,739 postmenopausal women in the largest prospective trial evaluating the effect of hormone therapy (HT) on various clinical outcomes. The women were randomly allocated to three groups:

• conjugated estrogen with medroxyprogesterone acetate
• conjugated estrogen alone (in women with a prior hysterectomy)
• placebo.

The negative effects of estrogen plus progestin on the risk of breast cancer were the most widely discussed oucomes.¹ Shortly after the findings from this arm of the study were published, the use of HT in the United States declined dramatically and unequivocally.²

In 2012, WHI published the results of the estrogen-alone arm in the British cancer specialty journal Lancet Oncology. As shown in the TABLE below, the incidence of breast cancer was statistically significantly lower (23%) in the estrogen group than in the placebo group. Women who were treated with estrogen alone were also 63% less likely to die of breast cancer, and all-cause mortality was 38% lower; both of these findings were statistically significant. Not only was there a significant reduction in the incidence of invasive breast cancer while the subjects were taking estrogen, but that reduction continued for a median of 4.7 years of follow-up after discontinuation of estrogen.

Breast cancer incidence and mortality in the estrogen-only arm of the WHI, compared with placebo*

The incidence figure is somewhat remarkable (199 in the placebo group versus 151 in the estrogen-alone group) in that it was nearly the exact reverse of the estrogen-progestin arm of the WHI trial (199 in the estrogen/progestin group vs 150 in the placebo group).³

All breast cancer chemoprophylactic agents carry risks as well as benefits

Goss P, Ingle J, Ales-Martinez J, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381–2391.

Cheung A, Tile L, Cardew S, et al. Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomized controlled trial. Lancet Oncol. 2012;13(3):275–284.

Vogel V, Costantino J, Wickerham L, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res. 2010;3(6):696–706.

The number of new cases of breast cancer in the United States last year reached nearly a quarter-million. Clearly, reducing this number remains an important goal.⁴ Chemoprevention—the use of medication to reduce cancer risk—may be offered to women who are at high risk of developing breast cancer.

In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial, tamoxifen (a selective estrogen-receptor modulator) was shown to reduce the risk of invasive breast cancer by 49% in a high-risk population, resulting in the FDA approving tamoxifen as the first drug for breast cancer prevention.⁵ The P-1 trial was followed by the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial, which demonstrated relative equivalence between the two medications as cancer prevention agents in menopausal women.⁶ Serious side effects of these medications limit their use among eligible women, although raloxifene seems to be associated with fewer adverse events. In the update of the STAR trial with an average of 81 months of follow-up, the risk ratio for adverse events (raloxifene:tamoxifen) was 0.75 for thromboembolic events, 0.55 for endometrial cancer, and 0.19 for uterine hyperplasia.

Another drug used for cancer treatment has now entered the prevention scene. In 2011, the NCIC Clinical Trials Group Mammary Prevention.3 trial (NCIC CTG MAP.3) compared exemestane (an aromatase inhibitor) with placebo for menopausal women at high risk for breast cancer, demonstrating a 65% relative reduction in the incidence of invasive breast cancer. This study validated another option for cancer prevention in high-risk women, although its adoption is likely also to be limited by side effects, including vasomotor symptoms, a high rate of arthralgias, and vaginal dryness/dyspareunia. The greatest concern may be the potential effect on bone density. Though the rates of serious adverse events including fracture did not differ in the MAP.3 trial at 35 months of follow-up, women on exemestane had significantly larger losses of bone mineral density, compared with controls.

Managing the reproductive health concerns of young women with breast cancer

Azim H, Kroman N, Paesmans M, et al. Prognostic impact of pregnancy after breast cancer according to estrogen receptor status: a multicenter retrospective study. J Clin Oncol. 2013;31(1):73–79.

Howard-Anderson J, Ganz P, Bower J, Stanton A. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: a systematic review. J Natl Cancer Inst. 2012;104(5):1386–1405.

Of the approximately 230,000 new cases of invasive breast cancer identified in 2011, 50,430 cases involved women less than 50 years of age.⁴ For these women, the diagnosis of cancer raises multifaceted concerns, including the physical changes that accompany breast cancer treatment, concerns about recurrence and mortality, and significant sexual and reproductive consequences of treatment that alters ovarian function. Pregnancy-associated breast cancers (breast cancers diagnosed during pregnancy, lactation, and for 12 months postpartum) represent a small subset of these cancers and occur in about 1 in 3,000 pregnancies. One might anticipate that this rate will increase as women continue to delay childbearing, because pregnancy-associated breast cancers are more common in older women.

In the review article by Howard-Anderson and colleagues, the importance of these reproductive health consequences in young women diagnosed with breast cancer is highlighted. The women who transition to menopause as a result of chemotherapy (reported to range from 33%–73%) experience more symptoms, including hot flashes, night sweats, breast pain, vaginal dryness, and lack of sexual desire. Sixty-one percent of women younger than 40 years at diagnosis reported that they were concerned about menopause, and 30% reported that this concern influenced their treatment decisions. Thirty-nine percent of women in this group had major concerns about treatment-associated infertility, and only half of the women studied felt that their fertility concerns were adequately addressed.

On a positive note, for women who successfully achieve pregnancy after breast cancer, pregnancy outcomes appear to be similar to those of their nonpregnant peers. In the study by Azim and colleagues, women who became pregnant after a breast cancer diagnosis had disease-free survival that was statistically similar to that of matched women who did not have subsequent pregnancies. In addition, this outcome did not differ based on estrogen/progesterone receptor status (ER/PR positive or negative).

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SAN ANTONIO – Dietary restrictions prescribed for children with food allergies may lead to growth impairment, according to findings from a review of medical records for 245 food-allergic pediatric patients.

The risk of growth impairment was greatest for children whose dietary restrictions required elimination of more than two foods and/or elimination of cow’s milk, Dr. Brian P. Vickery reported at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

After age 2 years, the food-allergic children had lower mean percentiles for weight (67.5 vs. 72.5) and a lower body mass index (57.6 vs.68.0), than did 4,584 healthy age-matched controls.

Furthermore, the 52 patients with more than two food allergies (and thus more than two food restrictions), compared with 193 patients with one or two food allergies, had significantly lower mean percentiles for height (62.2 vs. 74.8) and weight (55.3 vs. 69.2). The 66 patients with milk allergy, compared with those with other food allergies, had lower mean percentiles for weight (54.5 vs. 70.6) and BMI (48.9 vs. 58.8), according to Dr. Vickery of the University of North Carolina at Chapel Hill.

Milk-allergic children younger than 2 years of age were particularly vulnerable to growth restriction, he said during a press briefing at the meeting.

The food-allergic children in this study, who were aged 1 month to 11 years and who presented to a University of North Carolina outpatient clinic between 2007 and 2011, also were compared with 205 "disease controls," consisting of children with either cystic fibrosis or celiac disease, two conditions that are associated with impaired growth. When children passed their second birthday, the effect of food allergy on growth was very similar to the effect of celiac disease on growth, Dr. Vickery said.

The findings of this study confirm those from a smaller study, conducted more than a decade ago, that also showed that milk allergy and multiple food allergies were associated with growth impairment.

That study is "the most commonly cited previous study to address the growth of food-allergic children in the United States," Dr. Vickery noted.

"The prevalence [of food allergy] has increased over the past 10 years, so we wanted to take another look in a bigger population to kind of reassess the impact of elimination diets on growth," he said.

The current findings demonstrate that a food allergy–associated elimination diet can place children at risk of impaired growth, compared with their healthy peers, regardless of whether they are under age 2 years, or are 2-11 years old, and that after age 2, the effect of food allergy on growth is very similar to that of chronic diseases known to affect growth, he said.

"While awareness of food allergy is increasing along with the prevalence of the disease, it is important to draw attention to the important consequences of elimination diets. We feel that providers should counsel patients and caregivers about the growth-related risks of the elimination diets that are used to treat food allergy, and ensure that families are excluding only the foods that are medically required or otherwise culturally indicated, that nutritional assessment and/or supplementation is provided as needed, and that subspecialty consultation is arranged, especially for children at highest risk," he said.

Dr. Vickery reported having no relevant financial disclosures.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

[email protected]

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

SAN ANTONIO – Dietary restrictions prescribed for children with food allergies may lead to growth impairment, according to findings from a review of medical records for 245 food-allergic pediatric patients.

The risk of growth impairment was greatest for children whose dietary restrictions required elimination of more than two foods and/or elimination of cow’s milk, Dr. Brian P. Vickery reported at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

After age 2 years, the food-allergic children had lower mean percentiles for weight (67.5 vs. 72.5) and a lower body mass index (57.6 vs.68.0), than did 4,584 healthy age-matched controls.

Furthermore, the 52 patients with more than two food allergies (and thus more than two food restrictions), compared with 193 patients with one or two food allergies, had significantly lower mean percentiles for height (62.2 vs. 74.8) and weight (55.3 vs. 69.2). The 66 patients with milk allergy, compared with those with other food allergies, had lower mean percentiles for weight (54.5 vs. 70.6) and BMI (48.9 vs. 58.8), according to Dr. Vickery of the University of North Carolina at Chapel Hill.

Milk-allergic children younger than 2 years of age were particularly vulnerable to growth restriction, he said during a press briefing at the meeting.

The food-allergic children in this study, who were aged 1 month to 11 years and who presented to a University of North Carolina outpatient clinic between 2007 and 2011, also were compared with 205 "disease controls," consisting of children with either cystic fibrosis or celiac disease, two conditions that are associated with impaired growth. When children passed their second birthday, the effect of food allergy on growth was very similar to the effect of celiac disease on growth, Dr. Vickery said.

The findings of this study confirm those from a smaller study, conducted more than a decade ago, that also showed that milk allergy and multiple food allergies were associated with growth impairment.

That study is "the most commonly cited previous study to address the growth of food-allergic children in the United States," Dr. Vickery noted.

"The prevalence [of food allergy] has increased over the past 10 years, so we wanted to take another look in a bigger population to kind of reassess the impact of elimination diets on growth," he said.

The current findings demonstrate that a food allergy–associated elimination diet can place children at risk of impaired growth, compared with their healthy peers, regardless of whether they are under age 2 years, or are 2-11 years old, and that after age 2, the effect of food allergy on growth is very similar to that of chronic diseases known to affect growth, he said.

"While awareness of food allergy is increasing along with the prevalence of the disease, it is important to draw attention to the important consequences of elimination diets. We feel that providers should counsel patients and caregivers about the growth-related risks of the elimination diets that are used to treat food allergy, and ensure that families are excluding only the foods that are medically required or otherwise culturally indicated, that nutritional assessment and/or supplementation is provided as needed, and that subspecialty consultation is arranged, especially for children at highest risk," he said.

Dr. Vickery reported having no relevant financial disclosures.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

[email protected]

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

SAN ANTONIO – Dietary restrictions prescribed for children with food allergies may lead to growth impairment, according to findings from a review of medical records for 245 food-allergic pediatric patients.

The risk of growth impairment was greatest for children whose dietary restrictions required elimination of more than two foods and/or elimination of cow’s milk, Dr. Brian P. Vickery reported at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

After age 2 years, the food-allergic children had lower mean percentiles for weight (67.5 vs. 72.5) and a lower body mass index (57.6 vs.68.0), than did 4,584 healthy age-matched controls.

Furthermore, the 52 patients with more than two food allergies (and thus more than two food restrictions), compared with 193 patients with one or two food allergies, had significantly lower mean percentiles for height (62.2 vs. 74.8) and weight (55.3 vs. 69.2). The 66 patients with milk allergy, compared with those with other food allergies, had lower mean percentiles for weight (54.5 vs. 70.6) and BMI (48.9 vs. 58.8), according to Dr. Vickery of the University of North Carolina at Chapel Hill.

Milk-allergic children younger than 2 years of age were particularly vulnerable to growth restriction, he said during a press briefing at the meeting.

The food-allergic children in this study, who were aged 1 month to 11 years and who presented to a University of North Carolina outpatient clinic between 2007 and 2011, also were compared with 205 "disease controls," consisting of children with either cystic fibrosis or celiac disease, two conditions that are associated with impaired growth. When children passed their second birthday, the effect of food allergy on growth was very similar to the effect of celiac disease on growth, Dr. Vickery said.

The findings of this study confirm those from a smaller study, conducted more than a decade ago, that also showed that milk allergy and multiple food allergies were associated with growth impairment.

That study is "the most commonly cited previous study to address the growth of food-allergic children in the United States," Dr. Vickery noted.

"The prevalence [of food allergy] has increased over the past 10 years, so we wanted to take another look in a bigger population to kind of reassess the impact of elimination diets on growth," he said.

The current findings demonstrate that a food allergy–associated elimination diet can place children at risk of impaired growth, compared with their healthy peers, regardless of whether they are under age 2 years, or are 2-11 years old, and that after age 2, the effect of food allergy on growth is very similar to that of chronic diseases known to affect growth, he said.

"While awareness of food allergy is increasing along with the prevalence of the disease, it is important to draw attention to the important consequences of elimination diets. We feel that providers should counsel patients and caregivers about the growth-related risks of the elimination diets that are used to treat food allergy, and ensure that families are excluding only the foods that are medically required or otherwise culturally indicated, that nutritional assessment and/or supplementation is provided as needed, and that subspecialty consultation is arranged, especially for children at highest risk," he said.

Dr. Vickery reported having no relevant financial disclosures.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

[email protected]