Commonly prescribed analgesics

Below is a summary of some of the analgesics commonly that can be used. A summary of major contraindications, precautions and potential drug interactions with these analgesic agents is located in Table 2. Clinicians are advised to refer to the Approved Product Information before prescribing.

Paracetamol
It is widely accepted and supported by many treatment guidelines that paracetamol is the oral analgesic of choice for OA pain^10-16.

Recommended doses in adults:

1-2 x 500 mg immediate-release tablets every 4-6 hours; maximum 8 tablets (4 g) per day¹⁷.
1 - 2 x 665 mg modified-release tablets every 6-8 hours maximum 6 tablets (3990 mg) per day¹⁷.

Dosing should be regular (by the clock) rather than as needed^{18, 19}. Patient education is often needed to enhance compliance.
Unless contraindicated, regular paracetamol should be used as an adjunct when other forms of analgesia are employed¹⁴.
Patients should be advised not to take more than 4 g paracetamol per day (including over-the-counter e.g. cold and flu preparations)¹⁷.
Paracetamol is well tolerated and toxicity at therapeutic doses is extremely rare. Most cases of paracetamol-induced hepatotoxicity have resulted from either deliberate self-poisoning or accidental overdoses¹⁴.

NSAIDs

Because of their potential risks, NSAIDs should only be considered after a trial of maximum doses (4g/daily) of “regular” (i.e. around the clock) paracetamo^{10, 11, 17, 18}.
NSAIDs should only be used where potential benefits outweigh potential risks, at the lowest effective dose for the shortest possible duration^{10, 17, 18, 19, 20}.
Both selective and non-selective NSAIDs can be associated with gastrointestinal, renal and cardiovascular toxicit¹⁷.
Rofecoxib was withdrawn in 2004 due to an observed increase in cardiovascular events (including MI and stroke)¹⁷. Lumiracoxib was withdrawn in August 2007 because of serious liver adverse reactions²¹.
No NSAID is risk-free and this should be discussed with the patient¹⁷.
The elderly are more at risk of NSAID-related adverse effects and the need for NSAID therapy should be assessed carefully¹⁷.
NSAIDs should be avoided if possible in patients at high risk of renal and/or cardiovascular risk factors^{11, 18}.
In the presence of gastrointestinal risk factors, NSAIDs with a lower relative risk of serious gastrointestinal complications should be prescribed in patients where NSAID therapy is unavoidable. For example a COX-2 inhibitor (e.g. celecoxib) or a NSAID with a short half life (e.g. ibuprofen) or diclofenac^{11, 17}. Selective COX-2 inhibitors reduce but do not eliminate gastrointestinal toxicity¹⁷. Co-administration of a proton pump inhibitor may be require¹⁷.
Enteric-coated and rectal formulations do not reduce the risk of GI ulceration²².
NSAIDs with a long half life (e.g. piroxicam) have higher rates of serious gastrointestinal complications and should be avoided where possible¹⁶.
NSAIDs with a short half life are recommended for use in the elderly and in patients with renal impairment (e.g. ibuprofen)¹⁷.
There is no benefit in using two or more NSAIDs concurrently and this significantly increases the risk of gastrointestinal toxicity²³ (the exception is low dose aspirin for cardioprotection) ¹⁷.
Topical NSAIDs may provide some benefit in OA with fewer adverse effects than oral NSAIDs²⁴. They are usually absorbed in small amounts, however, topical NSAIDs can still cause gastrointestinal haemorrhage and are generally less effective than oral NSAIDs¹⁷.
Combining another agent such as paracetamol and/or weak opioid like tramadol may enable lower doses of the NSAID, potentially reducing the risk of adverse effects^{14, 25, 26}. Fish oil can also be used as a NSAID-sparing drug, and has the added benefit of reducing cardiovascular risk¹⁷.
Adding a weak opioid (e.g. codeine) or tramadol in conjunction with paracetamol may be used as an alternative to a NSAID¹⁴.
Before prescribing a NSAID, assess for drug interactions including ACE inhibitors or angiotensin-II receptor antagonists, warfarin and diuretics. Please refer to the individual Approved Product Information for complete prescribing information.

Tramadol

Consider adding or substituting with tramadol when the patient is unresponsive to a trial of therapeutic doses of paracetamol and/or a NSAID. i.e. second line use for relief of moderate to severe pain^{11, 27, 28}.
Tramadol is an atypical centrally-acting analgesic with weak action on m-opioid receptors in addition to inhibiting the reuptake of noradrenaline and serotonin¹⁷.
Recommended dose for individuals over the age of 12 years²⁹:

Immediate release capsules 50 mg -100 mg every 4-6 hours up to 400 mg /day (maximum dose 300 mg/day if aged > 75 years)
Tramadol SR 50 mg twice daily (swallowed whole). If required titrate dose up to 400 mg/day (maximum dose 300 mg/day if aged > 75 years), in order to increase tolerability and compliance.
Prolonged release tablets 100mg once daily (swallowed whole). If required titrate dose up to 400mg once daily.

Tramadol is better tolerated and less likely to cause dependence than other opioid analgesics^{13, 29, 30}.
Assess for potential drug interactions (including warfarin and SSRIs) and closely monitor for adverse effects. Please refer to the tramadol Approved Product Information for complete prescribing information²⁹.
The concomitant use of tramadol and MAO inhibitors is contraindicated because of the risk of serotonin syndrome¹⁷.
May induce seizures, particularly in patients with epilepsy or recognised risk of seizure, or when tramadol is prescribed with other drugs that reduce seizure threshold (e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors [SSRIs], some antipsychotics, quinolones)^{17, 29}.
Counsel patients about potential side effects. The most commonly reported include nausea, vomiting, constipation, dizziness and autonomic nervous system effects, headache, asthenia, fatigue, sedation and sweating²⁹.

Combination analgesics

Consider adding or substituting with a weak opioid when a trial of therapeutic doses of paracetamol and/or a NSAID gives insufficient pain control. i.e. second line use for relief of moderate to severe pain^{11, 27, 28}.
Avoid paracetamol/dextropropoxyphene combinations, as they are no more effective to paracetamol alon³¹.
Dextropropoxyphene’s major metabolite is cardiotoxic^{14, 17} and accumulation can cause dependence, dizziness and confusion.
Combinations of codeine 60 mg and paracetamol 1000 mg are more effective for acute pain than paracetamol 1000 mg alone, although the incidence of drowsiness and dizziness is increased³².
There is no evidence that combination analgesics containing lower than 60mg of codeine with paracetamol, aspirin or ibuprofen have any benefits over these non-opioids alone²².
Many fixed dose combinations contain 8mg of codeine and thus two tablets deliver a dose that is less than the effective dose. Another problem associated with codeine is severe constipation at doses above 60mg¹⁷.
Codeine is short-acting and its place in long-term management of chronic pain is limited^{16, 23}. In about 7-10% of Caucasians and 1-2% Asian people codeine is ineffective as they lack the enzyme to metabolise codeine into its active metabolite, morphine¹⁷.
Note, aspirin is a NSAID. Before prescribing a combination analgesic containing aspirin, please review the NSAIDs section above.

Opioids

Strong opioids are recommended third line, for relief of severe pain^{27, 28}.
Opioids should only be commenced after a thorough assessment of the patient, including their psychosocial situation¹⁷. An assessment by a pain clinic or consultation with a pain physician is recommended²⁷.
Although opioids provide short term efficacy in chronic pain, there are no relevant long-term randomised controlled trials¹⁷.
Discuss treatment goals, likelihood of developing physical dependence, tolerance, potential for cognitive impairment and potential side effects with the patient ^{17, 33}.
Injectable opioids or pethidine are not recommended for persistent pain and are best reserved for patients with acute pain conditions ^{17, 27}.
Titrate dose and frequency to effect (i.e. adequate pain control and tolerable side effects). Reassess after 2-3 weeks ²⁷.
Initial dosing is usually with an immediate-release short-acting preparation, which is titrated up until, ideally, it prevents the emergence of pain. When the dose necessary to achieve pain relief is established, a more convenient sustained-release or controlled-release preparation is usually substituted¹⁷. It is important to note that use of opioids in non-cancer patients can be problematic. Dependency may develop with long term use of opioids.
Monitor for adverse events (e.g. constipation, nausea and vomiting, dry mouth sedation) and use appropriate prophylaxis and treatmen¹⁷.