SYMPOSIUM ON PAIN MANAGEMENT

Opioids for chronic noncancer pain

Tailoring therapy to fit the patient and the pain

Hussam Antoin, MD; Ralph D. Beasley, MD

VOL 116 / NO 3 / SEPTEMBER 2004 / POSTGRADUATE MEDICINE

CME learning objectives

• To be able to identify patients with chronic noncancer pain who are good candidates for long-term opioid therapy
• To understand the basic guidelines for starting or maintaining opioid treatment in patients with chronic noncancer pain
• To achieve early identification of patients with abnormal behavior or side effects due to opioid use

The authors disclose no financial interests in this article and no unlabeled uses of any product mentioned.

Preview: Opioids are powerful medications with a history that includes use for pain relief and, at times, addiction. This history of therapy versus drug abuse continues to cloud their prescription today, despite reports of effective treatment for the chronic pain that certain diseases can bring. Here, Drs Antoin and Beasley review the use of opioid agents in medicine, highlight the importance of proper patient selection and education in their use, and convey how opioids can be a viable option today for successful therapy for chronic noncancer pain.
Antoin H, Beasley RD. Opioids for chronic noncancer pain: tailoring therapy to fit the patient and the pain. Postgrad Med 2004;116(3):37-44

The analgesic effect of the poppy plant and its opium has been known for thousands of years (1). Morphine, the most active constituent of opium, was isolated in 1806. Codeine, oxycodone, hydrocodone, and hydromorphone are opioids derived from the morphine structure based on poppy extract. Meperidine, methadone, and fentanyl and its derivatives are synthetic opioids. Each of these newer opioids was developed with the objective of having a nonaddicting opioid. None has achieved that goal, however.

For many years, morphinelike drugs were commonly called narcotics, a term that stems from the Greek word narkosis, which means to deaden or numb (2). Narcosis now refers to a "nonspecific reversible depression of neuronal activity," which can be produced by a number of agents (2). However, it is not really an accurate description of the principal effect of these drugs. To avoid confusion, drugs that act on opioid receptors in a way similar to that of morphine are now called opioids (1).

Through the 1950s, the opioid-related literature was mainly concerned with addiction (3). Such emphasis led to opioid phobia, which resulted in undertreatment of pain, including cancer pain. This trend to undertreat pain has been slowly reversed, beginning in the 1970s. Opioids have become the mainstay treatment of cancer pain, and in fact, they remain a part of the World Health Organization's analgesic ladder for cancer pain, because their useful effects are well established.

Opioids and noncancer pain

In 1986, Portenoy and Foley (4) published an article describing the use of long-term opioid therapy in treatment of chronic noncancer pain in 38 patients. Although the medical literature clearly establishes use of opioids in cancer-related pain, their use in chronic noncancer pain remains controversial. Yet, on average, such pain is more commonly seen by primary care physicians than is cancer-related pain.

In a mail survey in northeast Scotland in 1996, 45% of respondents said they suffered from constant or recurrent pain for longer than 3 months (5). In 2000, a follow-up mail survey of the 1,608 respondents found that 54% had chronic pain (5). Newly developed chronic noncancer pain occurred in about 8% of respondents annually during the 4 years between the two surveys, and the annual rate of recovery from chronic noncancer pain was about 5%. These findings mirror the prevalence of pain in the United States.

Clinical outcome studies

Few double-blind, placebo-controlled studies have been done to evaluate the effect of opioids on chronic noncancer pain; most of such information is available from case series. Rathmell and Jamison (6) summarized the various early reports from before 1996, and Ballantyne and Mao (7) provided a review of the newer studies. Many of these studies supported the usefulness of opioids in chronic noncancer pain, including neuropathic pain, during trials that lasted for weeks to months. To date, no study of opioid use in chronic noncancer pain has extended over years.

Opioid side effects, concerns

Use of opioids for chronic noncancer pain can be associated with long-term side effects, and their use against such pain should be individualized accordingly. Common side effects are sedation, respiratory depression, nausea, vomiting, itching, urinary retention, and constipation. Tolerance usually occurs rapidly for sedation, respiratory depression, nausea, and vomiting, and each of these side effects, respectively, requires more time for tolerance to develop. However, tolerance to constipation usually does not occur, and routine use of stool softeners and stimulants is often required (8).

Other serious problems related to opioid therapy include weight gain (8), myoclonus, adrenal suppression (7,8), immunosuppression (7,8), and hypogonadism (7,9). The long-term effect of opioid use on the respective systems requires more study. Additionally, opioids are known to impair decision making and reaction time. Therefore, it is important to advise patients "that they are responsible for ensuring their own fitness to drive" (8) and to operate hazardous machinery. If doubts arise, the patient may need to be referred for a medical assessment for driving.

Patients need to restrict their activities at the beginning of opioid therapy and during periods of dose adjustment or escalation. Restrictions should be continued for at least 7 days after an initial or new stable dose has been achieved (10). The literature indicates that patients are then generally fit to drive (8,10). Despite this literature, however, most states include driving while taking opioids or other controlled substances as "driving under the influence" and consider it to be illegal. The laws do not differentiate between acute use and long-term use of opioids, and patients need to be made aware of this aspect of their treatment.

For both physicians and patients, one of the most significant concerns about opioid use is fear of addiction. Escalation of opioid dose to achieve the same effect (ie, tolerance) was often considered evidence of addiction. Current definitions of this and other relevant terms (see box at the end of this article) need to be understood by physicians who prescribe opioids for chronic noncancer pain.

Experience with opioid treatment of cancer pain indicated that addiction was a rare problem (3). In a 1980 letter to the New England Journal of Medicine, Porter and Jick (11) reported that of 11,882 patients who took one or more narcotic preparations, only 4 patients showed signs of addiction.

The information cited in this letter led to the belief among physicians that addiction is rare also during long-term opioid treatment of chronic noncancer pain. However, the true incidence of addiction during such therapy is still unknown. Savage (12) used population studies to estimate the risk of addiction at 3% to 16% in the general population. Currently, a 10% incidence of addiction is probably the best estimate to discuss with patients when initiating opioid treatment.

However, the issue can be viewed from another perspective: Rosenblum and associates (13) reported that almost 40% of patients in a methadone maintenance clinic had chronic noncancer pain. Physicians need to be cognizant of this fact when patients present to their office requesting opioid treatment for such pain.

Guidelines for opioid use

Given the lack of randomized controlled studies of long-term opioid therapy for chronic noncancer pain, various guidelines have been developed by expert panels (7,8,14-16). These guidelines form the basis of opioid use in patients with chronic noncancer pain.

Patient selection
Every patient being considered for long-term opioid therapy for chronic noncancer pain should be thoroughly evaluated with detailed history taking, physical examination, and appropriate laboratory studies. This evaluation should include an assessment of previous treatments; long-term opioid therapy should be one of the last options of treatment.

A complete and consistent diagnosis should be developed. There should be no issues of previous addiction or substance abuse, including alcohol abuse. Additionally, patients with personality disorders, those with no response to opioid therapy by 6 months, and patients with insufficient response to opioid therapy in the past may be poor candidates for long-term opioid treatment. Formal psychologic evaluation may be appropriate in some patients.

An informed discussion of the pros and cons of opioid treatment should be undertaken with the patient. Goals should be set, and an opioid agreement between patient and physician should be instituted. (For a sample informed consent and controlled substance agreement for treatment of chronic pain, see the appendix to this article.) The agreement should include the patient's responsibilities as well as his or her agreement to provide random urine samples for monitoring.

Although being pain-free is probably an unreasonable objective, the goals should include pain reduction and improved function. This functional goal varies from one patient to the next. Return to work may be a reasonable goal for some patients, whereas others may set an appropriate goal of being able to do more activities of daily living. Whenever possible, treatment aimed at the specific underlying disease should be continued. Other pain medications, such as nonsteroidal anti-inflammatory drugs that are partially effective, antidepressants, and antiseizure agents, should be continued as indicated.

Trial period
Patients appropriately selected for opioid therapy should proceed to a trial period. This trial should be agreed on by patient and physician and cover 3 to 6 months of drug initiation and dose adjustment. It is best to have one physician manage the patient's care and prescribe the selected opioid therapy.

If a sustained-release opioid preparation is used, it should be administered on a regular, time-contingent basis. Table 1 shows equianalgesic dose ranges for long-acting opioids. Short-acting opioids may be used to adjust the initial dose. However, they usually should not be part of the long-term plan or, at most, should be limited in the final regimen to three or four doses per week for breakthrough pain.

During the trial period, the patient should be carefully evaluated for pain relief and improved functional activity and assessed for adverse effects of opioids, including abnormal behaviors (table 2). Urine drug screening should be included in this evaluation process. Also, it is usually reasonable to set an upper dose limit for the trial. A sensible but arbitrary limit is about 100 mg per day of morphine or its equivalent (3). If there has not been some indication of effectiveness by the time that limit is reached, it may signify that this pain will not respond to opioid use.

Table 2. Abnormal behaviors or warning signs of abuse

Lost or stolen prescriptions Prescription forgery Concurrent illicit drug use Unauthorized dose escalation Excessive consumption of opioids, including "running out of medication" early Visits without appointments Intolerance of multiple opioids Frequent office phone calls Drug diversion or sale of drugs Borrowing drugs from others Multiple prescribers Phone calls after office hours Physical signs of abuse Failure to keep appointments Information from Fanciullo and Cobb (3), Ballantyne and Mao (7), and Katz and Fanciullo (17).

If the goals for pain and function are met with acceptable side effects at a reasonable opioid dose (which may be higher than the initial limit of 100 mg of morphine per day but usually is less than 180 mg daily [7]), then long-term opioid therapy may continue for chronic noncancer pain. If these goals are not met, the trial should be declared a failure and the opioid dose reduced gradually and stopped.

Maintenance period
During the maintenance phase, ongoing patient evaluation for the effectiveness of opioid treatment is required, including assessment of pain relief and functional status, adverse effects, and addictive behavior. Abnormal behaviors (see table 2) must be investigated. Also, plans for management of pain flares should be in place and followed. If these flares cannot be managed by short-term, small increases in opioid dose, hospitalization may be necessary. Return to baseline dose should be rapid after a flare unless changes in the patient's underlying disease have been documented. Continued escalation of opioid dose or drug tolerance should be carefully evaluated and may indicate failure of opioid treatment.

Urine drug screening
The ability to identify patients in whom opioid therapy is problematic remains difficult when evaluated on a clinical basis alone. Moreover, a patient's self-report of abuse is often unreliable (17). Urine tests for drugs of abuse and opioids can be helpful in this situation.

In a study of 122 patients receiving long-term opioid treatment, Katz and Fanciullo (17) found that 22% of patients presented with abnormal behavior issues, while 29% had abnormal positive urine toxicology results. When they combined the percentage of patients with an abnormal behavioral issue or an abnormal positive urine test, or both, the investigators found that 43% of the patients had problems with opioid use. (For various reasons, they omitted from the results those patients whose laboratory reports did not show the prescribed drug in the urine.) Katz and Fanciullo recommend that, in addition to good clinical evaluation, urine drug testing should be one of the monitoring tools in the care of all patients who undergo long-term opioid therapy.

Use of urine for drug screening can present a host of pitfalls, however. Many urine screening tests for "drugs of abuse" include opiates in their report, but they may not detect or differentiate some opioids, such as oxycodone or fentanyl. Even urine tests specifically designed to identify opioids may not detect fentanyl, and they do not test for cocaine, benzodiazepines, and other drugs of abuse.

Usually, the screening test is an enzyme-multiplied immunoassay technique, which lacks specificity. Some laboratories automatically send the sample for confirmatory gas chromatography or mass spectrometry if the screening test is positive; other laboratories do not do this routinely. Thus, it is important to know the policies and limitations of the laboratory used for such tests. For example, we request both a urine screening test and a urine confirmatory test for both "drugs of abuse" and "opiates." Since fentanyl is not a drug routinely included in our laboratory's urine testing for these drugs, we specifically request tests for its detection if the patient is taking fentanyl.

When making clinical decisions on the basis of urine test results, it is necessary to also understand the metabolism of opiates. Codeine is metabolized to morphine, so if a patient is taking Tylenol With Codeine No. 3, both codeine and morphine will show up in the urine. Similarly, a patient taking hydrocodone will test positive for both hydrocodone and its metabolite hydromorphone. The half-life of these drugs and the time from the last dose of the drug also affect urine test results.

Even with the specificity of gas chromatography and mass spectrometry, sources other than drugs can cause false-positive test results. Poppy seeds in various pastries can cause a positive test for morphine. Vicks Vapor Inhaler contains L-methamphetamine, and its use can produce a test result positive for amphetamine; some diet pills, such as chlorobenzorex and fenproperex, are metabolized to amphetamine or methamphetamine and also produce a positive result for amphetamine. Use of dronabinol (Marinol) and consumption of hemp-containing foods, such as Seedy Sweeties, can yield a positive result on tests for marijuana.

False-negative opiate test results do occur and can be difficult to deal with. An opiate may be in the urine but at levels below the laboratory's identification threshold, and thus the result is negative. A patient may be a rapid metabolizer of the drug, and time from the last dose to the collection of the test sample may have allowed the patient to metabolize and eliminate enough of the drug so that the test result is negative (17). The ethics and philosophy of interpretation of the various patient scenarios derived from these results could be, in and of themselves, the subject of another article.

Finally, it should be remembered that unless collected with adherence to strict rules about the chain of custody, a sample has no basis for any legal decision, although the sample may be adequate for clinical decisions.

Conclusion

Whether long-term opioid treatment for chronic noncancer pain is efficacious and safe will continue to be a subject of extensive research. However, with the information now available, physicians should have a much better understanding of the various uses of these drugs. Opioids may be considered one part of an overall rehabilitation program for highly selected patients with chronic noncancer pain.

The goals of opioid therapy should be clearly outlined before therapy is initiated. While relief of pain may be the short-term goal, improvement of function and, if applicable, return to work should be considered desirable goals of long-term opioid therapy. Although the risk of addiction is low in patients with chronic pain who take nonescalating doses of opioids, physicians should remain vigilant when prescribing these medications and should monitor closely the patients taking them.

References

1. A short history of opioids. Available at: http://www.manbit.com/obstetspain/peth2.shtml. Accessed Jun 23, 2004
2. Hensyl WR, ed. Stedman's medical dictionary. 25th ed. Baltimore: Williams & Wilkins, 1990:1924
3. Fanciullo GJ, Cobb JL. The use of opioids for chronic non-cancer pain. Int J Pain Med Palliative Care 2001;1(2):49-55
4. Portenoy RK, Foley KM. Chronic use of opioid analgesics in non-malignant pain: report of 38 cases. Pain 1986;25(2):171-86
5. Elliott AM, Smith BH, Hannaford PC, et al. The course of chronic pain in the community: results of a 4-year follow-up study. Pain 2002;99(1-2):299-307
6. Rathmell JP, Jamison RN. Opioid therapy for chronic noncancer pain. Curr Opin Anaesthesiol 1996;9:436-42
7. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003;349(20):1943-53
8. The Pain Society. Recommendations for the appropriate use of opioids for persistent non-cancer pain. London: The Pain Society, 2004. Available at: http://www.painsociety.org. Accessed Jul 7, 2004
9. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain 2002;3(5):377-84
10. Vainio A, Ollila J, Matikainen E, et al. Driving ability in cancer patients receiving long-term morphine analgesia. Lancet 1995;346(8976):667-70
11. Porter J, Jick H. Addiction rare in patients treated with narcotics. (Letter) N Engl J Med 1980;302(2):123
12. Savage SR. Long-term opioid therapy: assessment of consequences and risks. J Pain Symptom Manage 1996;11(5):274-86
13. Rosenblum A, Joseph H, Fong C, et al. Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA 2003;289(18):2370-8
14. Simpson KH. Opioids for persistent non-cancer pain: recommendations for clinical practice. Br J Anaesth 2004;92(3):326-8
15. Guidelines for outpatient prescription of oral opioids for injured workers with chronic, non-cancer pain. Olympia, Wash: Washington State Department of Labor and Industries, 2000. Available at: http://www.guidelines.gov/summary/summary.aspx?doc_id=2609. Accessed Jun 23, 2004
16. Kalso E, Allan L, Dellemijn PL, et al; 2002 European Federation of Chapters of the International Association for the Study of Pain. Recommendations for using opioids in chronic non-cancer pain. Eur J Pain 2003;7(5):381-6
17. Katz N, Fanciullo GJ. Role of urine toxicology testing in the management of chronic opioid therapy. Clin J Pain 2002;18(4 Suppl):S76-82

Definitions of potential side effects of opioid use Tolerance Loss of analgesic effect to opioid agent, necessitating an escalating dose to provide an equipotent analgesic effect Physical dependence, psychologic dependence Marked, specific physical disturbance when opioid is withdrawn or an antagonist administered. Physical dependence is common in patients who take a stable opioid dose but is not important clinically if the opioid dose is tapered during withdrawal. Psychologic dependence is the compulsion to use the drug because of need for its stimulant or anxiolytic effects. Addiction A cluster of behavioral, cognitive, and psychologic phenomena associated with a strong desire to use the drug, difficulty controlling its use, and use of the drug despite its harmful consequences Pseudoaddiction Behaviors such as drug hoarding, attempts to obtain extra supplies, and requests for an early prescription or increased dose. These behaviors may be mistaken for addiction but in reality are an attempt to obtain better pain relief; they stop when pain is properly managed. Information from Rathmell and Jamison (6) and Savage (12).

Dr Antoin is a fellow in pain medicine and Dr Beasley is assistant professor of anesthesia, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. Correspondence: Ralph D. Beasley, MD, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756. E-mail: ralph.d.beasley@hitchcock.org.

Symposium Index

• THREE COMMON NEURALGIAS: How to manage trigeminal, occipital, and postherpetic pain. By Avi Ashkenazi, MD, Morris Levin, MD
• OPIOIDS FOR CHRONIC NONCANCER PAIN: Tailoring therapy to fit the patient and the pain. By Hussam Antoin, MD, Ralph D. Beasley, MD
• Clinical Commentary. CHANGING THE FACE OF PAIN MANAGEMENT: Mechanism-based treatment most likely to succeed. By Morris Levin, MD

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