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Editorial
Opioid Therapy for Osteoarthritis of the Hip and Knee: Use It or Lose It?
Osteoarthritis (OA) is a painful condition whose prevalence will increase as the population ages globally1. The American College of Rheumatology (ACR) defines OA as a "heterogeneous group of conditions that lead to joint symptoms and signs that are associated with defective integrity of articular cartilage in addition to related changes in the underlying bone at the joint margins."2 Patients, however, seek medical attention due to joint pain and loss of function3. Prevalence rates for hip and knee OA depend on whether the diagnosis is made radiographically or clinically4. The most comprehensive survey, from the Netherlands5, reveals that radiographic prevalence among adults aged 45-54 was 13 per 100 for knees, and 2.5 per 100 hips. For the age group 65-74, this rose to 28 per 100 knees and 10 per 100 hips. There is often discordance between radiographs and reports of joint pain3,6. Ten percent of those with normal radiographs report pain, while only 40-79% of those with advanced radiographic abnormalities report pain3. Importantly, though, pain is a better predictor of disability than radiographic grade7. In the Johnson County Osteoarthritis Project, 35.6% of subjects over age 45 reported moderate/severe knee pain in the last 30 days, with 11.6% reporting mild pain7. The US National Survey of Self-care and Aging in 38 urban and 12 rural areas addressed arthritis disability. Interviews and telephone followup in a random sample aged 65 and older showed 48% had daily arthritis pain, 32.8% were kept from sleeping, and 43.1% reduced their usual daily activities8. A recent update of this project also documented reduced health related quality of life9. A population based, random stratified sampling in northeast Scotland showed that 50% of the population had chronic pain. Over the age of 75, 62% of the sample reported chronic pain10. Arthritis was the principal reason cited, and was noted in 13.7% of males, 17.8% of females, and 28.1% of those over age 75 years. Nearly 16% of this population reported severe, disabling pain on the von Korff pain grading system11. Thus OA of the hip and knee is an important public health problem, and it is relevant to ask what role potent pain medications, i.e., opioids, may have in its management. What are the pain generators in hip and knee OA? These might include the joint capsule, ligaments and insertions, periosteum and subchondral bone, and the synovium3,12. The exact pain source is often unclear in any individual. There are, however, opioid receptors in inflamed OA synovium13. The American Geriatric Society (AGS) emphasizes the impact of chronic pain in older adults14. They report 18% of older Americans take analgesics more often than weekly, with musculoskeletal pain a common cause. The AGS suggests pain consequences are depression, decreased socialization, poor sleep, poor ambulation, and increased health care use. They further state, "for many patients chronic opioid therapy may have fewer life threatening risks than the longterm daily use of NSAID" and "patients should not be overburdened with opiophobia." Osteoarthritis guidelines provide limited guidance on opioid use. The 1995 ACR guidelines for hip OA suggest opioids be avoided for longterm use, but short term use may be helpful, without reference to primary data15. The 1995 ACR knee OA guidelines do not discuss opioids directly16. The 2000 update of the ACR OA guidelines suggests that opioids might be used as a medication of last resort17. The 1998 UK guidelines on degenerative arthritis suggest that if relief is inadequate with 2.4 grams of ibuprofen and 4.0 grams of paracetamol a day, other antiinflammatories or opioids may be considered18. There are many reasons physicians are reluctant to consider opioids19,20. These include: a perception that pain and suffering are an inevitable part of life; a fear of opioid side effects, including addiction; political and social pressures to control illicit drug use; and lack of knowledge about opioid efficacy in OA. Each of these concerns will be examined. Pain and suffering are related, but different, components of the pain experience21. Suffering is a cognitive experience, not merely the perception of pain. It is pain and its associated impact on the psyche. An artificial mind-body split was originally proposed by Descartes to separate science, the study of the physical world, from the psyche, the exclusive domain of the Church, to allow for human scientific experimentation. This 200-year-old dichotomy lingers in the erroneous belief that suffering is a spiritual, not medical event, outside the realm of medical practice. Yet the public clearly views pain management as a medical priority22. A leading bioethicist argues: "to leave a person in avoidable pain and suffering should be regarded as a serious breach of fundamental human rights."23 Tolerance, the need for a higher dose of a drug to achieve the same pharmacologic effect, is not synonymous with addiction24. Tolerance appears related to a modulation in receptor numbers and their binding capacity, in response to chronic drug administration. Tolerance occurs with many drugs, including nitrate therapy25. Dependence is the presence of unwelcome effects upon drug withdrawal, and is also not equivalent to addiction. Withdrawal symptoms for opioids are characterized by increased adrenergic hyperactivity, and include excitability, nervousness, sweating, and diarrhea. Addiction is abnormal drug seeking behavior24. It is characterized by an unwillingness to taper a medication when an alternative treatment is offered; reports of no relief with non-opioid alternatives; a strong preference for short acting forms or bolus medications; obtaining multiple prescriptions from multiple sources; and by the use of street drugs. Addiction is the continued used of a drug in spite of negative personal, economic, or social consequences of the drug's use. Addiction is rare among individuals who truly have pain14,26-28. The Boston Collaborative Drug Study evaluated many types of drug use and side effects in hospitalized patients26. They reviewed over 10,000 prescriptions for opioids. Abnormal drug seeking behavior was found in only 2 cases (0.04%) of hospitalized patients. Ytterberg and colleagues at the University of Minnesota studied patients with rheumatoid arthritis, OA, and other rheumatic problems for addictive behaviors27. OA patients were the largest group of opioid users. The study found 4 of 800 patients (0.2%) had abnormal opioid behavior when followed 3 years through pharmacy records. There were no obvious predictors of drug seeking, but unresolved psychosocial problems were noted as a cautionary factor. OA patients stop opioids when their pain is relieved by other means. In a study of opioid use before and after definitive orthopedic management of hip or knee OA, patients stopped opioids when their pain improved28. While 39% of patients took opioids preoperatively, only 1.9% did postoperatively, with a parallel decline in pain scores from 4.9/6.0 to 1.8/6.0. The American Geriatric Society notes that "those 60 years of age and older account for less than 1% of participants attending methadone maintenance programs."14 While it is certain that some prescription opioids end up on the streets, the exact magnitude of this problem appears to be small29. A recent ecological study showed that even as the number of prescriptions for opioids was rising, the number of opioid related admissions to emergency departments was declining30. Most of these admissions were in younger males, a different demographic profile from the OA patient population. The euphoric experience addicts seek from opioids is not equivalent across all drugs, and is based on different actions on the mu (µ), kappa (k), and sigma (s) receptors. The mu receptor is mostly responsible for opioid analgesic effects, while the sigma receptor is responsible for the hallucinogenic and excitatory effects of opioids. Methadone, as a relatively pure mu receptor agonist, does not give the euphoria of other opioids31. Respiratory depression is a function of blockade of the mu receptor, and occurs early in the use of the drug. Tolerance rapidly develops within days32. Opioids do cause minor changes in neurological function, especially in body sway33. In a controlled study, patients who required regular medications for control of malignant disease were compared to individuals with malignant disease who did not. A detectable difference in body sway was noted. The clinical significance of this slight sway was unclear to the authors. These authors also reported that a 30% increase in any stable dose is sufficient to overcome any tolerance that had developed. Codeine and propoxyphene have been shown to increase the risk of hip fracture in those over age 6534. The risk declines with continued use, but does not return to baseline. However, lower limb arthritis is also a risk factor for falls35. The relative contribution of both disease and drugs to falls in the elderly is not entirely clear. Nausea, vomiting, and diarrhea are common opioid side effects. The randomized trials shown in Table 1 suggest their occurrence in 25% to 66% of subjects, leading to dropout in 10% to 25% of subjects. These nuisance side effects may be managed with slow dose titration. Tolerance frequently develops to these nuisance side effects with continued use36. It is important to note that there is no evidence that longterm opioid use creates any irreversible physical changes in any organ system32.
Efficacy is best evaluated using the randomized clinical trial design. To judge the potential benefits of opioids in the treatment of OA of the hip and knee, primary studies were sought using Internet Grateful Med V2.6.3. A search was conducted from 1996 to March 2000 using the MeSH headings "osteoarthritis and narcotics" without language restriction. The reference lists from the trials and review articles identified were reviewed. Trials were included if they studied hip or knee OA primarily, but excluded if they focused primarily on back OA or back pain. These 15 trials are summarized in Table 1. A variety of opioids have been studied, including codeine, dextropropoxyphene, dihydrocodeine, meptazinol, oxycodone, pentazocine, tilidine-naloxone, and tramadol. All published trials do demonstrate superiority of the opioids compared to placebo36-41. When acetaminophen (paracetamol) is used as a comparator or rescue medication, opioids are superior analgesics40,42. These trials also suggest that opioids are superior to nonsteroidal antiinflammatory drugs (NSAID)38,43, or lead to reduction in NSAID use44. These trials do not suggest important differences in efficacy between opioid comparators45-50. Equipotent doses of opioid therapy are rarely predefined in these trials, limiting the ability to judge true differences between them. In addition, the inconsistent application of outcome measures in these trials precludes metaanalysis. Most of the studies are of short duration, with the longest double blind phase being 6 weeks taking opioids46 and 8 weeks taking tramadol44. The mean duration of all trials combined is 19.4 days (SD 16.2 days, range 1 day to 8 weeks). It is important to note that both the open label portion of the Roth trial36 and the data from the University of Minnesota27 suggest that opioid benefits continue for 1 to 3 years. While the exact role of opioids is best established using patient based utilities comparing risks and benefits of opioid with competing therapies51, the published literature provides some basis for recommendations. There are several categories of OA patients who would seem appropriate for a trial of opioids. This includes those with moderate to severe OA pain, requiring medicinal therapies, where acetaminophen is insufficient, and for whom traditional NSAID or cyclooxygenase-2 (COX-2) specific inhibitors are contraindicated. An opioid trial may also be warranted when traditional NSAID or COX-2 specific inhibitors are not useful, or are insufficient on their own. Opioids are effective in OA hip and knee pain, and have predictable side effects. It would be unwise were physicians to discount an entire class of medications over unfounded fears and incomplete knowledge of their benefits.
PAUL M. PELOSO, MD, MSc, FRCPC,
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