Key messages

• Use paracetamol as ongoing therapy: the modified-release formulation offers convenience
• Use NSAIDs where cardiovascular, renal and gastrointestinal risk is acceptable
• Consider an opioid when non-opioids offer inadequate pain control or NSAIDs are unsuitable
• Tramadol's role in mild–moderate pain is limited by drug interactions and CNS adverse effects.

Use paracetamol as ongoing therapy: modified release offers convenience

Use regular paracetamol at an adequate dose

Paracetamol is effective and has an excellent safety profile and so remains the analgesic of choice, particularly in mild-to-moderate pain.

Around-the-clock pain control depends on taking adequate doses regularly. Ask people who report insufficient pain control with paracetamol about the dose and frequency they have used to date. The recommended dose for immediate-release paracetamol is 500–1000 mg at 4–6 hourly intervals to a maximum of 4 g per day.

Modified-release paracetamol may be useful

Modified-release paracetamol tablets are available on the PBS for osteoarthritis. The modified-release tablets may be more convenient for patients who are reluctant to take 4 doses per day; the recommended dose is 2 x 665 mg tablets every 6–8 hours to a maximum of 6 tablets per day.

Two bioequivalent brands of modified-release paracetamol, Panadol Osteo and Duatrol, are on the PBS for osteoarthritis. Panadol Osteo has a $4.88 premium, which doubles its price for people with concession cards.

Use NSAIDs where cardiovascular, renal and gastrointestinal risk is acceptable

Do the potential benefits of adding an NSAID outweigh the potential harms?

If paracetamol is insufficient to control pain, consider prescribing a non-steroidal anti-inflammatory drug (NSAID). Assess the patient's risk of gastrointestinal, cardiovascular and renal adverse effects — people at high risk should avoid NSAIDs if possible.

For people at low risk of these adverse effects, NSAIDs are valuable analgesics. For those with risk factors for one or more adverse effects, assessing the balance of benefit and harm will be more complex and should involve discussing the risks with the patient and considering alternative analgesics, such as opioids.

Prefer NSAIDs with a low risk of gastrointestinal adverse effects

NSAIDs with a lower risk of gastrointestinal adverse effects are diclofenac and ibuprofen, and the COX-2 selective NSAIDs celecoxib and lumiracoxib. COX-2 selective NSAIDs have equivalent efficacy and a similar range of adverse effects to conventional NSAIDs, so they are not preferred routinely to conventional NSAIDs. Using a COX-2 selective NSAID rather than a conventional NSAID is most justified in those with risk factors for gastrointestinal adverse effects (age ≥ 65 years, history of ulcer, concomitant use of anticoagulants or corticosteroids, presence of serious comorbidity). Alternatively, consider adding a gastroprotective agent (a proton pump inhibitor or misoprostol) to a conventional NSAID. For more information about gastroprotective options, see NPS News 46: Proton pump inhibitors.

A new COX-2 selective NSAID, lumiracoxib, has recently been PBS listed. The NPS RADAR review 'Lumiracoxib (Prexige) for osteoarthritis' details its PBS listing and its place in therapy.

Assess cardiovascular risk before prescribing an NSAID

Use the most caution when prescribing NSAIDs for people at high cardiovascular risk (such as those with established cardiovascular disease, diabetes plus renal impairment, familial hypercholesterolaemia or diagnosed left ventricular hypertrophy) because they will have the largest absolute increase in risk of myocardial infarction or stroke when taking an NSAID.

Since the withdrawal of rofecoxib in 2004, evidence for an increased risk of vascular events with COX-2 selective NSAIDs has continued to emerge.[1–3]

A meta-analysis has estimated that taking a COX-2 selective NSAID is associated with a 42% increase in relative risk of a first serious vascular event compared with placebo, or an extra 3 people having a vascular event per 1000 per year.[4]

Several epidemiological studies have implied an increased risk of vascular events with conventional NSAIDs.[1,2,5–9]

Monitor for renal impairment and symptoms of heart failure in patients
at risk

Avoid or use NSAIDs with caution in people with risk factors for impaired renal function, which include:

• volume depletion
• age > 60 years
• salt-restricted diet
• concomitant use of diuretics, ACE inhibitors, angiotensin II receptor blockers, cyclosporin or aspirin
• glomerular filtration rate ≤ 60 mL/min
• cirrhosis
• congestive heart failure.[10]

NSAIDs also increase the risk of developing or exacerbating symptoms of heart failure. In a recent study, patients aged > 60 years using an NSAID had a 30% increase in the risk of hospital admission for heart failure. In those with established heart failure, the relative risk of hospitalisation was 8.6 (95% confidence interval 5.3 to 13.8) in users of NSAIDs compared with non-users without heart failure.[11]

In patients at risk of these adverse effects who cannot avoid taking an NSAID, assess plasma sodium, potassium and creatinine levels, blood pressure, weight, the presence of oedema and symptoms and signs of heart failure at baseline, 2–4 weeks after initiation and at regular intervals during treatment.[10,12]

Use NSAIDs at the lowest effective dose for the shortest possible duration

Studies suggest that the risk of cardiovascular and gastrointestinal events is associated with dose and duration of NSAID use.[1,3–6,13]

To limit exposure, add an NSAID to ongoing regular paracetamol as intermittent as-needed treatment during exacerbations in pain. Periodically evaluate the need to continue NSAID treatment.

Consider an opioid when non-opioids offer inadequate pain control or NSAIDs are unsuitable

Starting opioids

An opioid is an alternative if an NSAID fails to control pain adequately or is unsuitable because of an unacceptable risk of adverse effects.

Weak opioids have similar efficacy to NSAIDs and offer modest additional analgesic efficacy when added to paracetamol.[14–16] They produce the same range of adverse effects as strong opioids but with lower efficacy.

Choosing a weak opioid: codeine, dextropropoxyphene or tramadol?

Codeine is the most frequently used weak opioid, although about 10% of Caucasian people and 1–2% of Asian people will have little or no response as they cannot metabolise codeine to morphine.[17] Switch non-responders to an alternative opioid. A short half-life and lack of a sustained-release formulation also limit the usefulness of codeine for persistent pain. It may be of greatest use in controlling incident pain or other short-lived mild-to-moderate pain.

Ensure that an adequate dose of codeine is used — trials have demonstrated the efficacy of codeine 60 mg added to paracetamol.[15,16]The lowest effective dose is not established but it is thought that doses below 30 mg are unlikely to be effective.

Maintain effective paracetamol doses when adding codeine. If a combination tablet containing paracetamol and codeine is prescribed, this means two tablets per dose to achieve 1000 mg paracetamol. The resulting codeine dose may be associated with intolerable adverse effects, particularly constipation. Adding codeine as a separate prescription allows more flexible dosing.

Avoid dextropropoxyphene because regular use leads to accumulation of the parent drug (causing dizziness and confusion) and its cardiotoxic metabolite.

Tramadol's role in mild-moderate pain is limited by drug interactions and CNS adverse effects

Tramadol's potential for serious drug interactions and adverse effects precludes its use in some. It may cause serotonin syndrome (particularly when combined with other serotonergic drugs, such as most antidepressants). Seizures have been reported and appear to be most likely in people taking drugs that lower the seizure threshold, or who have a history of seizures.[18–20] Tramadol is often poorly tolerated — up to 20% of patients in trials discontinued treatment due to adverse effects such as nausea, vomiting, dizziness and drowsiness.[21–28]

Use strong opioids for pain not controlled by other analgesics

Strong opioids have a role in persistent pain that is not adequately controlled by weak opioids or NSAIDs. Morphine is usually considered the strong opioid of first choice because of familiarity, cost and the range of formulations available. Other strong opioids include oxycodone, hydromorphone, fentanyl, buprenorphine and methadone. Oral, controlled-release formulations are preferred.

Starting opioids in the community

Changes to the PBS prescribing requirements mean that subsidised opioid analgesics for persistent non-cancer pain can now be started in the community.

If possible, refer patients to a multidisciplinary pain clinic or a pain specialist before prescribing a strong opioid. However, it may be inappropriate to delay prescribing effective pain control until an appointment can be scheduled. Telephone advice from a specialist may be helpful in such cases.

To obtain an authority to continue the opioid for more than 12 months, the prescriber needs to seek review of the patient's pain management by a second doctor (who may be a general practitioner or a specialist) to confirm the clinical need for ongoing opioid analgesics. Consider scheduling a clinic or specialist appointment so this review can be used to fulfil the PBS criteria for ongoing opioid supply.

Addiction and dependence are distinct entities

The fear that patients will become addicted appears to be a major barrier to the use of opioids in persistent pain[29–33], yet this may partly stem from misunderstanding of the meaning of addiction.[30,34] Addiction is defined as compulsive use of drugs for non-medical purposes, in spite of harm to the user. This is distinct from physical dependence, which is adaptation of the body to the presence of an opioid, characterised by the development of withdrawal symptoms when the opioid is stopped. In contrast to addiction, dependence is a predictable and normal physiological response to repeated opioid use.

Being judged to be at high risk of opioid abuse or addiction is not an absolute contraindication to being prescribed opioids for pain relief — all patients have a right to effective pain treatment. However, in patients thought to be at risk of abuse (such as those with a previous history of substance abuse), referral to or advice from a pain clinic or addiction specialist should be sought.

Reviewer:

Associate Professor Milton Cohen, Department of Medicine, St Vincent's Clinical School, Sydney

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