A multimodal approach to pain management is considered essential and the use of non-opioid analgesics in the management of pain is well established. The pharmacological management of pain with opioids alone is not always effective, particularly in instances where the pain is neuropathic. Simple analgesics, paracetamol and non-steroidal anti-inflammatory medications (NSAIDS), adjuvant medications (drugs whose primary indication is not analgesia, such as anti-depressants or membrane stabilisers), and bisphosphonates are all considered in this section. As for other analgesics, research on these medications often comes from outside the palliative care setting.
Neuropathic pain is a considerable problem for palliative care patients.  Neuropathic pain may be due directly to the disease process, such as cancer or renal failure, or may be related to treatment of the illness. The management of neuropathic pain can be difficult as it does not often respond to opioids and clinical practice guidelines are available to help guide clinicians. [2-4] Adjuvant analgesics form the principal approach to the pharmacological management of neuropathic pain. The effectiveness of one particular medication over another in this group is not associated with the underlying cause of the neuropathic pain and most treatment approaches produce side effects. 
Mild pain can be effectively treated with paracetamol. Adding paracetamol to some opioids, such as codeine, improves analgesia while adding it to other opioids, such as morphine has limited effect.  There is no high quality evidence for or against its use in cancer pain.  Paracetamol is widely used in older people in aged care facilities and there is a higher use in older people with dementia than the general population. [7,8] A recent systematic review of paracetamol use in children showed inconsistent evidence, yet its use remains high clinically.  This would suggest that there is limited high quality evidence for the use of paracetamol but clinical experience may be guiding practice.
Non-Steroidal Anti-Inflammatory Drugs
NSAIDs are used across several clinical situations to manage pain associated with inflammation, such as with bone pain. A recent systematic review and meta-analysis of NSAIDs in palliative medicine examined the efficacy and safety of these medications.  The studies reviewed were limited to cancer pain, with the authors noting that there was a lack of research of the use of NSAIDS in other life-limiting illnesses. There was moderate quality evidence for the use of NSAIDs to relieve cancer pain but no significant difference between the type of NSAID and no research comparing the route of administration.  There was also moderate evidence that combining NSAIDs with opioids produced improved analgesic efficacy and produced a potential opioid sparing effect.  Side effects of NSAIDs are potentially significant, including gastric ulceration, renal dysfunction and cardiac toxicity. While all NSAIDs, both nonselective and selective, produce GI or cardiovascular toxicity, cox-2 NSAIDs produce fewer GI side effects with similar cardiovascular side effects and are potentially more useful in palliative care.  The clinical benefit of drugs for gastric protection when treating patients with NSAID therapy is supported by clinical practice guidelines.  NSAIDs should be avoided in patients with renal dysfunction or renal failure. 
Medications originally designed for non-analgesic purposes such as the treatment of depression or epilepsy have been shown to be effective in the treatment of neuropathic pain. There is limited evidence for their use in cancer pain alone, without a clear neuropathic component.  There is limited research on these medications in the palliative care setting and in the paediatric population, so evidence is extrapolated from other patient groups.  The role of some adjuvants in multimodal approaches to reduce opioid doses has been examined in acute pain patients but there is limited research and low quality evidence to support their use for this action in palliative care. 
Clinical practice guidelines and strong evidence from systematic reviews support the use of both duloxetine and venlafaxine (serotonin-noradrenaline reuptake inhibitors (SNRIs)), and amitriptyline (tricyclic antidepressant (TCA)), in the management of neuropathic pain. [2,4] SNRIs have high quality evidence for their use and moderate reported tolerability, with a meta-analysis placing the numbers needed to treat at 6.4 with the numbers needed to harm at 11.8.  TCAs have similar high quality evidence for their use, but are better tolerated with numbers needed to harm at 13.4, and lower associated cost.  No one antidepressant was superior in studies relating to neuropathic pain in cancer  in older people  or in children.  In end stage renal disease both duloxetine and venlafaxine are not recommended, however, amitriptyline can be used cautiously. 
There is strong evidence to support the use of pregabalin and gabapentin in the management of neuropathic pain.  Both have similar numbers needed to treat, at 7.7 and 7.2 respectively and both are moderately well tolerated, pregabalin number needed to harm is 13.9 while gabapentin’s number needed to harm is 25.6.  There is inconclusive evidence to support the use of carbamazepine and no evidence to support the use of valproate. [2,16] In end stage renal disease gabapentin and pregabalin are both recommended for use with caution. 
Local anaesthetic lignocaine patches are available in Australia and have moderate quality evidence to support their use and moderate tolerability in post herpetic neuralgia but there is inconsistent evidence to support its use for other types of neuropathic pain. [2,16] A high concentration capsaicin patch is recommended for use as a second line treatment for neuropathic pain but this is not available in Australia. [2,16] There is limited evidence to support the use of capsaicin ointment or cream. 
Alpha 2 Agonist
Alpha-2 agonists are more commonly used for blood pressure management and sedation but they do act as an analgesic in the dorsal horn of the spinal cord.  As a sedative both clonidine and dexmedetomidine have been used in various clinical environments such as procedural pain management [19,20] and have been combined with opioids to improve efficacy. [19,21] These may also be useful in managing autonomic dysfunction and spasticity in children with life limiting illnesses. [20,22]
Ketamine is an NMDA-receptor antagonist which has analgesic properties but also produces sedation, amnesia, and dissociation. The use of ketamine in palliative care has been controversial with a number of primary studies producing varied results. A recent systematic review and a number of clinical practice guidelines state there is low quality evidence for the use of ketamine in adult cancer pain. [3,23] Part of the reason for this is the lack of homogeneity in study design. However, one systematic review established that there was moderate quality evidence to support the use of ketamine in neuropathic pain.  A recent study examining refractory cancer pain showed ketamine provided improved analgesia when given for a short period of time at moderate doses.  The use of ketamine to manage neuropathic pain is also supported in paediatrics, although the quality of evidence is low. [14,21]
In the management of metastatic bone pain, systematic reviews support the effectiveness of bisphosphonates.  Whilst bisphosphonates have no immediate analgesic effect, they are recommended as an adjuvant where the response to radiotherapy and analgesia are inadequate. There is also evidence to support their role in management of pain associated with multiple myeloma, advanced prostate cancer and breast cancer. 
Cannabis / Cannabinoids
There remains limited evidence to support the use of cannabis or cannabinoids in pain management in palliative care. [27,28] Systematic reviews of randomised controlled trials and observational studies have been unable to establish analgesic efficacy, tolerability or safety in cannabis-based medicines when used as analgesics. 
- There is limited evidence to support the use of paracetamol in the palliative care setting. 
- NSAIDs are effective analgesics for musculoskeletal pain in cancer. No differences have been shown between different NSAIDs. Recommended doses produce close to the maximum benefit, whilst side effects increase linearly with dose. 
- Evidence for combining opioids with adjuvants to improve analgesic effectiveness is limited. 
- Adjuvants should be added with the diagnosis of neuropathic pain. Antidepressants and anticonvulsants are recommended as first line pharmacotherapy. [2,16] The choice of a specific adjuvant relates to clinical context and to the specific side-effect profile of the treatment combination and patient characteristics. When treating neuropathic pain reassessment and cessation of ineffective therapy is recommended. 
- Reduced doses of adjuvant medication are recommended for paediatrics,  older people  and end stage renal disease. 
- For bone pain due to metastases bisphosphonates may be used if the therapeutic response is inadequate to other therapies, but their analgesic effect is not immediate. There is no role for calcitonin in managing bone pain.