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MAY / JUNE 2013 :: 74(3)
Chronic Pain

This issue focuses on the challenge of managing chronic pain. Commentaries present various treatment options, including opioids, nonopioid medications, surgery, and alternative therapies. Authors also address the problems of opioid misuse and abuse and discuss ways to lessen these risks. Original articles examine health professionals’ communication with adolescents about smoking, as well as children's immunization status as verified by practice records and by the North Carolina Immunization Registry.

INVITED COMMENTARY

Long-Term Opioid Therapy for Chronic Pain: Optimizing Management, Minimizing Risk

Jennifer L. Roux

N C Med J. 2013;74(3):205-208.PDF | TABLE OF CONTENTS



Opioid analgesics are commonly used for the management of chronic noncancer pain. Although they can be beneficial for select patients, opioids are also at the heart of a nationwide epidemic of misuse and diversion.

The use of opioids for the management of chronic pain in the United States has increased dramatically over the past 2 decades. While opioids are widely considered to be the mainstay of therapy for cancer pain, their increasing use for chronic noncancer pain is controversial. This controversy is driven by the lack of high-quality evidence demonstrating the efficacy of long-term opioid therapy and by the myriad of potential adverse effects and risks associated with opioid use. This commentary offers a basic review of opioid medications and their use in chronic pain management, examines the nationwide epidemic of opioid misuse, and discusses strategies that health care providers can use to help curb this widespread problem.

Opioid Analgesics
Opioid medications produce analgesia by binding to opioid receptors throughout the central and peripheral nervous systems. Opioids can be divided into 2 classes based on their duration of action (Table 1).

Short-acting opioids (SAOs) are characterized by more rapid changes in the plasma concentration of the drug; they are thus best suited for treating pain that is acute or intermittent. Some of the most commonly prescribed SAOs are morphine, hydromorphone, oxymorphone, fentanyl, tramadol, tapentadol, buprenorphine, codeine, hydrocodone, and oxycodone. Tramadol, codeine, hydrocodone, and oxycodone are often formulated in combination with a nonopioid analgesic such as acetaminophen or a nonsteroidal anti-inflammatory drug. Because the latter drugs can potentially cause gastrointestinal or hepatic toxicity, their presence in the combination product limits the maximum daily dose of these formulations.

Long-acting opioids (LAOs) include drugs that are inherently long-lasting and formulations that have been pharmacologically modified to release drug into the bloodstream more gradually. LAOs are more appropriate for chronic and/or constant pain, since their analgesic effects can last approximately 8–72 hours. Available LAOs include methadone and the extended-release, sustained-release, or controlled-release formulations of morphine, hydromorphone, oxymorphone, fentanyl, tramadol, tapentadol, buprenorphine, and oxycodone.

Multiple studies comparing SAOs versus LAOs have failed to establish the superiority of one class over the other for management of chronic noncancer pain syndromes [1-3]. Providers should therefore tailor the choice of therapy to the individual patient. Patients with persistent unrelenting pain may benefit more from the consistent analgesia offered by an LAO, with the added potential advantages of less frequent dosing, less medication dispensed, and less preoccupation with medication use. On the other hand, some patients may prefer to use medication only when their pain is severe, rather than perpetually having the drug in their system. In these cases, an SAO may be a more logical choice. In my experience, a patient with constant pain and intermittent episodes of pain triggered by activity—known as breakthrough pain—may do well with combination therapy consisting of an LAO dosed regularly and an SAO taken only when needed.

Positive Outcomes
Manchikanti and colleagues [4] recently conducted a rigorous review of the literature regarding the effectiveness of opioids for the management of chronic noncancer pain. They concluded that short-term opioid therapy (defined as treatment for 3 months or less) may result in a moderate degree of pain relief, but the evidence to support this conclusion is weak. Likewise, there is a paucity of high-quality evidence to support the efficacy of long-term opioid therapy (therapy lasting longer than 3 months), and studies assessing the impact of long-term opioid therapy on quality of life show equivocal results [4].

Despite this dearth of evidence, some of the most influential pain medicine organizations recognize the potential benefits of long-term opioid therapy for select individuals with chronic noncancer pain. In 2009 the American Pain Society and the American Academy of Pain Medicine concluded that long-term opioid therapy “can be an effective therapy for carefully selected and monitored patients with chronic noncancer pain” [5]. In 2012 the American Society of Interventional Pain Physicians stated, “long-term opioid therapy for chronic non-cancer pain should be reserved for select patients with moderate or severe pain that significantly affects function or quality of life” [6]. The latter organization also recommended that opioid therapy be continued only if it leads to improvement in pain and function [6].

Negative Consequences
As with nearly all types of medications, opioids have several possible side effects. Some of the most common side effects include constipation, nausea, somnolence (drowsiness), dizziness, and pruritus (itching). Other side effects include cognitive and psychomotor impairment, myoclonus (muscle twitching), sleep disturbance, and exacerbation of sleep apnea [4]. Opioids can interfere with the production of sexual hormones, namely testosterone, leading to diminished libido, erectile dysfunction, fatigue, depression, decreased muscle mass, and osteoporosis [4]. Also, there is debate about a phenomenon known as opioid-induced hyperalgesia, which is characterized by a paradoxical increase in pain sensitivity in patients who are taking opioids to manage pain. Studies to determine whether opioid-induced hyperalgesia exists and/or how prevalent it might be have come to mixed conclusions [4].

Among the most feared risks of opioids are addiction, respiratory depression, and death. Although these risks are rare, they add further serious consequences to the nationwide problem of opioid misuse and diversion.

Scope of the Opioid Misuse Epidemic
The United States comprises 4.6% of the world’s population but consumes 80% of the global supply of opioids [7]. Between 1997 and 2007, total retail sales of commonly used opioids jumped 149% [7]. Hydrocodone was the most commonly prescribed medication in the United States between 2006 and 2011; during this period, the US population consumed 27.4 million grams per year, compared to 3,237 grams per year in Britain, France, Germany, and Italy combined [4]. Without question, opioids are readily available to the public.

The National Survey on Drug Use and Health is a useful source for analyzing the prevalence of opioid misuse, as this survey furnishes statistical information on the use of illegal drugs, alcohol, and tobacco. In 2011 an estimated 22.5 million Americans aged 12 years or older reported having used illicit drugs in the month prior to being surveyed [8]. This survey found that nonmedical use of psychotherapeutic drugs (a category that includes opioid pain relievers) ranked second only to marijuana use [8]. Nonmedical use is defined as use by anyone other than the person for whom the prescription is written or use by anyone for the experience or feeling the drugs cause.

Among individuals who reported using opioids nonmedically, most had obtained these drugs through a legitimate prescription from a single provider or had acquired them at no cost from a friend or relative [8]; the latter practice is known as diversion. In 81.6% of these reported instances of diversion, the friend or relative had secured the medication through a legitimate prescription from a single provider [8]. These findings suggest that “doctor shopping” may no longer be necessary to acquire opioids for recreational use.

Recreational use of opioids often causes adverse events that require emergency medical attention, and emergency department visits for nonmedical use of opioid pain relievers increased 156% from 2004 to 2010 [9]. From 2003 to 2007, the number of unintentional overdose deaths due to opioid analgesics was greater than the combined total of deaths due to heroin plus deaths due to cocaine [10]. In 2009, unintentional poisoning caused more deaths among individuals aged 25–64 years than did motor vehicle crashes. The vast majority (91%) of unintentional poisoning deaths were caused by drugs, most commonly prescription opioids [11].

What Can Health Care Providers Do?
Having recognized the scope of the problem, the US Food and Drug Administration now has a risk evaluation and mitigation strategy (REMS) for LAOs. This requires all manufacturers of LAOs to provide education for prescribers regarding how to choose which patients should take these opioids and how to manage such patients, as well as education for patients regarding proper handling of opioids [12].

Given the alarming epidemic of opioid misuse, it is incumbent upon health care providers to rigorously screen, carefully select, and comprehensively manage patients who are receiving long-term opioid therapy. Each patient should first undergo a detailed evaluation in an attempt to diagnose the pain complaint. Long-term opioid therapy is rarely a first-line treatment; rather, it is typically considered following the failure of more conservative measures, such as nonopioid medications, physical therapy, behavior modification, and basic interventional pain management procedures [6]. Examples of interventional pain management procedures include epidural steroid injections, joint injections, and various nerve blocks.

Even if conservative measures have failed, some patients are not appropriate candidates for long-term opioid therapy. The strongest predictor of opioid misuse is a personal or family history of alcohol abuse or illicit drug abuse. Other strong predictors for opioid misuse include a history of driving while intoxicated, drug conviction, childhood sexual abuse, lost or stolen prescriptions, or use of supplemental sources to obtain opioids [13]. For providers who desire an objective way of identifying patients who are at high risk for opioid abuse, numerous screening tools are available, including the revised Screener and Opioid Assessment for Patients with Pain (SOAPP), the Opioid Risk Tool, and the Diagnosis, Intractability, Risk, Efficacy (DIRE) risk assessment tool. Unfortunately, no single tool has enough evidence to support universal use [5].

If clinicians are considering long-term opioid therapy, it is important to obtain informed consent from the patient before initiating therapy. This discussion should focus on the potential benefits and risks of opioids, realistic goals, and expectations for treatment. Informed consent can be combined with an opioid treatment agreement, which often contains guidelines for responsible opioid use and grounds for discontinuation of opioid therapy. Evidence to support the use of informed consent and opioid treatment agreements is weak, but such documentation is consistently recommended by many pain medicine organizations [5, 6].

Once long-term opioid therapy has been initiated, clinicians can monitor compliance using one of several instruments, although evidence is lacking with regard to their effects on clinical outcomes. The Pain Medication Questionnaire and the Current Opioid Misuse Measure are patient-administered surveys that screen for potentially aberrant behaviors related to opioid use [14, 15].

Although evidence to support the use of urine drug screening is mixed, such testing is often utilized as part of a comprehensive monitoring approach. This testing may ensure treatment compliance and safer use of opioid medications. The frequency of drug screening should correlate with the provider’s perception of the risk for aberrant medication-related behavior. Providers need to understand how to correctly interpret drug screening results, and these results should not be interpreted in isolation; decisions regarding patient care should be based on the entire clinical picture [5].

Prescription drug monitoring programs represent another element of an inclusive monitoring plan. As of December 2012, 44 states had operational prescription drug monitoring programs and an additional 5 states had passed legislation authorizing such programs, leaving Missouri as the only state without plans for a prescription drug monitoring program [16]. These programs differ in terms of how data are collected, but most programs gather information about the controlled substance prescriptions filled by a patient, the prescriber of each prescription, and the pharmacy that fills each prescription. Once again, the literature contains conflicting evidence about the impact of these programs on opioid use [6].

Throughout the course of a patient’s opioid therapy, the provider should maintain the patient on the lowest effective dose, since higher doses of opioids are associated with higher risks of overdose and/or death [10]. The provider must frequently assess the patient’s degree of analgesia and his or her level of activity. Adverse effects and aberrant medication-related behaviors need to be addressed immediately. Discontinuation of opioids should be considered if the patient is not meeting his or her treatment goals or is exhibiting patterns of irresponsible behavior that may jeopardize his or her safety on opioid medications [6]. Signs of true opioid addiction—characterized by impaired control over medication use, compulsive medication use, continued medication use despite harm, or cravings for the medication—should prompt referral to an addiction specialist [17].

In pain management settings across the United States, long-term opioid therapy will continue to be utilized for the treatment of chronic noncancer pain. For the safety of these patients and the general public, both health care providers and patients must be educated regarding the limitations and potential risks of opioids. Patients need instruction on responsible opioid use, and providers must be attentive and conscientious when considering and managing opioid therapy.


Acknowledgment
Potential conflicts of interest. J.L.R. has no relevant conflicts of interest.

References
1. Argoff CE, Silvershein DI. A comparison of long- and short-acting opioids for the treatment of chronic noncancer pain: tailoring therapy to meet patient needs. Mayo Clin Proc. 2009;84(7):602-612.

2. Rauck RL. What is the case for prescribing long-acting opioids over short-acting opioids for patients with chronic pain? A critical review. Pain Pract. 2009;9(6):468-479.

3. Carson S, Thakurta S, Low A, Smith B, Chou R. Drug Class Review: Long-acting Opioid Analgesics. Final Update 6 Report. Prepared by the Oregon Evidence-based Practice Center for the Drug Effectiveness Review Project. Portland, OR: Oregon Health and Science University; 2010. http://www.ncbi.nlm.nih.gov/books/NBK62335/pdf/TOC.pdf. Accessed March 5, 2013.

4. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part I—Evidence Assessment. Pain Physician. 2012;15(3 suppl):S1-S66.

5. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130.

6. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2—Guidance. Pain Physician. 2012;15(3 suppl):S67-S116.

7. Manchikanti L, Fellows B, Ailinani H, Pampati V. Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. Pain Physician. 2010;13(5):401-435.

8. Substance Abuse and Mental Health Services Administration. Results from the 2011 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-44, HHS Publication No. (SMA) 12-4713. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2012. http://www.samhsa.gov/data/NSDUH/2k11Results/NSDUHresults2011.htm. Accessed March 6, 2013.

9. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. The DAWN Report: Highlights of the 2010 Drug Abuse Warning Network (DAWN) Findings on Drug-Related Emergency Department Visits. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2012. http://www.samhsa.gov/data/2k12/DAWN096/SR096EDHighlights2010.pdf. Accessed March 6, 2013.

10. Centers for Disease Control and Prevention. CDC grand rounds: prescription drug overdoses—a U.S. epidemic. MMWR Morb Mortal Wkly Rep. 2012;61(1):10-13.

11. Centers for Disease Control and Prevention (CDC). Poisoning in the United States: Fact Sheet. CDC Web site. http://www.cdc.gov/HomeandRecreationalSafety/Poisoning/poisoning-factsheet.htm. Updated June 29, 2012. Accessed May 7, 2013.

12. US Food and Drug Administration. Extended-release (ER) and long-acting (LA) opioid analgesics risk evaluation and mitigation strategy (REMS). FDA Web site. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM311290.pdf. Updated August 28, 2012. Accessed February 20, 2013.

13. Turk DC, Swanson KS, Gatchel RJ. Predicting opioid misuse by chronic pain patients: a systematic review and literature synthesis. Clin J Pain. 2008;24(6):497-508.

14. Adams LL, Gatchel RJ, Robinson RC, et al. Development of a self-report screening instrument for assessing potential opioid medication misuse in chronic pain patients. J Pain Symptom Manage. 2004;27(5):440-459.

15. Butler SF, Budman SH, Fernandez KC, et al. Development and validation of the current opioid misuse measure. Pain. 2007;130(1-2):144-156.

16. National Alliance for Model State Drug Laws (NAMSDL). Compilation of State Prescription Monitoring Program Maps. NAMSDL Web site. http://www.namsdl.org/documents/CompilationofPMPMaps01022013.pdf. Accessed March 6, 2013.

17. Savage SR. Assessment for addiction in pain-treatment settings. Clin J Pain. 2002;18(4 suppl):S28-S38.


Jennifer L. Roux, MD attending physician, Carolinas Pain Institute; clinical assistant professor, Department of Anesthesiology, and assistant director, Pain Medicine Fellowship, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Address correspondence to Dr. Jennifer Roux, Carolinas Pain Institute, 145 Kimel Park Dr, Ste 330, Winston-Salem, NC 27106 (jroux@ccrpain.com).