NPC Archive Item: Opioid analgesics associated with an increased risk of adverse events compared with NSAIDs

14th January 2011

An observational study has found that, in older adults with arthritis, use of opioid analgesics was associated with an increased risk of morbidity and mortality, compared with use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) or coxibs. In particular, opioid-users were about 4.5 times more likely to suffer a fracture and almost twice as likely suffer a cardiovascular event or die from any cause, compared with those taking non-selective NSAIDs. However, the study has limitations and residual bias cannot be excluded.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Action
Healthcare professionals should follow NICE guidance on osteoarthritis. All patients with osteoarthritis should be offered education and advice on understanding and managing their condition, muscle strengthening exercises, general aerobic fitness and, if they are overweight or obese, weight loss. If pain relief is required, paracetamol and/or topical NSAIDs should be considered ahead of oral NSAIDs, coxibs or opioids. Regular doses of paracetamol may be necessary. If paracetamol and/or topical NSAIDs are insufficient for pain relief, the addition of an opioid analgesic, NSAID or coxib should be considered.

Where an NSAID, coxib or opioid is required, prescribing should be based on the safety profiles of individual agents and on individual patient risk factors. Analgesics should generally be used at the lowest effective dose and for the shortest period of time necessary to control symptoms. The ideal prescribing choice will vary from patient to patient, depending on individual risk factors (including age), therapeutic response, patient preference, and the patient’s attitude to the risk of adverse events. When prescribing these drugs, consideration should be given to appropriate assessment and/or ongoing monitoring of these risk factors.

What is the background to this?
This study compared the safety of non-selective NSAIDs, coxibs and opioids in elderly patients (85% women, mean age 80 years) with osteoarthritis or rheumatoid arthritis using a large US database. A range of safety-related outcomes were considered including composites of cardiovascular (CV) adverse events, gastro-intestinal (GI) adverse events and fractures; and hospitalisation due to adverse events, death related to adverse events, and all cause mortality.

What does this study claim?
Compared with non-selective NSAIDs, coxibs and opioids were associated with an increased risk of CV adverse events (coxibs; hazard ratio [HR] 1.28, 95% confidence interval[CI] 1.01 to 1.62: opioids; HR 1.77, 95%CI 1.39 to 2.24). The risk of fracture was similar with coxibs and non-selective NSAIDs. However, fracture risk was significantly elevated with opioid use (HR 4.47, 95%CI 3.12 to 6.41).

Compared with non-selective NSAIDs, use of opioids, but not coxibs, was associated with an increased risk of adverse events requiring hospitalisation (HR 1.68, 95%CI 1.37 to 2.07). In addition, use of opioids, but not coxibs, raised the risk of all cause mortality compared with use of non-selective NSAIDs (HR 1.87, 95%CI 1.39 to 2.53).

So what?
Although the study raises concerns about the safety of opioids in particular, it has limitations. A single observational study can only prove association not causation and observational studies are prone to confounding. Unlike in the setting of a randomised controlled trial, in ‘real life’, treatment plans are chosen, changed, or actively not chosen in the light of individual patients’ risk factors, preferences and tolerability or response to other drugs. Thus observed differences in outcomes may well be due to differences among the patients, not only the different treatments. Although propensity matching was used in this study to reduce the likelihood of bias, and the characteristics of the three treatment groups were well matched, some known confounders were not measured (e.g. body mass index, tobacco and alcohol use, and use of aspirin and over-the-counter NSAIDs). An accompanying comment suggests that a significant proportion of patients included in the study are likely to have used an over-the-counter NSAID because physicians routinely recommend anti-inflammatory medication in addition to opioids to achieve therapeutic synergy in the treatment of arthritis. Another accompanying comment points out that the study authors did not distinguish between the type of medication used within a given class (methadone vs codeine, for example), its dose, or its duration, and highlights other possible residual sources of bias, including the possibility that sicker patients preferentially received opioids.

Nevertheless, the study highlights that opioid-use in non-malignant pain is associated with adverse effects, and these drugs should not be initiated without due consideration for the risks they can pose, especially in older patients. For patients with osteoarthritis, healthcare professionals should continue to follow NICE guidance on osteoarthritis. As outlined above, paracetamol and/or topical NSAIDs should be considered ahead of oral NSAIDs, coxibs or opioids, in addition to core treatment (exercise, advice, etc); regular dosing may be required. The risks and benefits of treatment options should be considered on an individual patient basis, taking into account comorbidities and age, and communicated to the patient in ways that can be understood.

Prescribers should continue to follow our previous recommendations given in MeReC Extra 30 when considering the prescribing of NSAIDs:

• Where NSAIDs are required, prescribing should be based on the safety profiles of individual NSAIDs and on individual patient risk factors. All NSAIDs should generally be used at the lowest effective dose and for the shortest period of time necessary to control symptoms.
• The ideal anti-inflammatory prescribing choice will vary from patient to patient, depending on individual risk factors, therapeutic response, patient preference, and the patient’s attitude to the risk of adverse events.
• Low-dose ibuprofen (≤1200mg per day) is an appropriate first choice NSAID in view of its low risk of both GI and CV side effects.
• Low-dose ibuprofen or naproxen 1000mg per day would appear more appropriate than other NSAIDs for patients in whom CV risk is a significant consideration in decision making.
• Consider prescribing a proton pump inhibitor (PPI) with any NSAID to reduce the risk of adverse GI effects, particularly in those who are at high GI risk (includes anybody aged 65 years or older) and long-term NSAID users. PPIs should be prescribed routinely with NSAIDs for people with osteoarthritis or rheumatoid arthritis according to NICE clinical guidelines 59 and 79).
• Although coxibs are associated with a lower risk of GI side effects than traditional NSAIDs, there is still no high-quality evidence to support the use of coxibs alone ahead of traditional NSAIDs co-prescribed with a PPI. Coxibs also have a higher CV risk than ibuprofen ≤1200mg per day or naproxen 1000mg per day.

Study details
Solomon DH, et al. The comparative safety of analgesics in older adults with arthritis. Arch Intern Med. 2010;170:1968–78

Design: Observational study

Patients: 12,840 Medicare beneficiaries in Pennsylvania and New Jersey with osteoarthritis or rheumatoid arthritis who received a first prescription for a non-selective NSAID, coxib or opioid between January 1 st 1999 and December 31 st 2005.  Patients receiving more than one class of analgesic simultaneously, those with cancer, and those under hospice care were excluded. Patients were matched on propensity scores using various confounders e.g. prior CV diagnoses and medication use, osteoporosis and fracture diagnoses etc.

Intervention and comparison: The comparative safety of non-selective NSAIDs, coxibs and opioids was examined. The safety events consisted of all clinically significant unintended health effects related to analgesics. Three composite measures were analysed: any of the specific CV events, any of the specified fractures, and upper or lower GI tract bleeding. In addition, the following were studied: any of these adverse events leading to a hospitalisation, any of these safety events leading to an acute care hospitalization and subsequent death or out-of-hospital cardiac death, and all cause mortality.

Outcomes and results: The baseline characteristics of the 3 propensity score-matched cohorts were similar. Almost 85% of the subjects were women, most were white, and the mean age was 80.0 years. More than 80% in each exposure category had osteoarthritis, but the percentage with rheumatoid arthritis varied from 13.4% of those using coxibs to 9.0% among opioid users.

Table: Safety events among propensity-score matched older adults with arthritis initiating prescription analgesic treatment vs non-selective NSAIDs

* Includes myocardial infarction, stroke, hospitalisations for heart failure, coronary revascularisation, and out-of-hospital cardiac death
^† Includes hip, humerus, pelvis and wrist fractures

Sponsorship: The Agency for Healthcare Research and Quality

More information on analgesics can be found on the pain section of NPC

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