Adjuvants are drugs whose primary indication is not analgesia, but when used in specific pain situations may be effective as analgesics. They include drugs used as antineuropathic medications (antidepressants, anticonvulsants and systemic local anaesthetics) and also steroids, bisphosphonates, ketamine, and clonidine. [1] Non-steroidal anti-inflammatory medications will also be considered here. Adjuvants may be used in situations where the pain is not fully responsive to opioids, as 'step 1' analgesics in the World Health Organization analgesic ladder approach to pain management, and most commonly, in neuropathic pain.

Neuropathic pain is a considerable problem for palliative care patients. [2] However the evidence for most adjuvants for neuropathic pain is limited, and mainly relates to non-malignant chronic conditions like diabetic neuropathy or post-herpetic neuralgia, often from quite small studies. The neuropathic pain of cancer and HIV may have a more complex pathophysiology and clinical context than these conditions. Nonetheless, this evidence may be extrapolated, with care, to palliative care populations.

What is known

• Antidepressants:
  A systematic review [3] supports their role in treatment of neuropathic pain. Both tricyclic antidepressants and the serotonin–noradrenaline reuptake inhibitor, venlafaxine, were effective, with NNTs (number needed to treat) of around 3. Tricyclics were not shown to be effective for treating the neuropathic pain of HIV, and nor is there sufficient evidence to support serotonin-specific reuptake inhibitors (SSRIs) or St John’s Wort for use in neuropathic pain.
   
• Anticonvulsants: 
  A systematic review [4] concluded that the evidence base for most of the anticonvulsants is not strong, apart from a separate a systematic review of gabapentin which showed that it is effective in neuropathic pain. [5] Few of the included studies relate to cancer pain. The evidence for carbamazepine has also been reviewed separately, and supports its role in neuropathic pain, although the numbers are very small. [6] There are no systematic reviews of the newer agent, pregabalin, although a number of randomised controlled trials support its efficacy. Lamotrigine has been shown not to be effective as an adjuvant. [23] 
   
• Systemic local anaesthetics:
  A systematic review [7] suggested that lignocaine and its oral analogues (eg, mexiletine) were as effective as other analgesics in trials where they were compared with carbamazepine, gabapentin, or morphine, although the data were limited. Systemic local anaesthetics appeared to be safe when used in the context of the clinical trials.
   
• Ketamine:
  Its role as an adjuvant has been reviewed [8,24] but the evidence is limited due to very small studies. There is inadequate and contradictory data from controlled trials to demonstrate effectiveness, and its use in palliative care is therefore still controversial.
   
• Bone pain:
  In the management of metastatic bone pain, systematic reviews support the effectiveness of palliative radiotherapy [9] and bisphosphonates. [10] 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 pain management in the treatment of multiple myeloma, [11] advanced prostate cancer with bone metastases, [12] and for prevention of skeletal problems in women with advanced breast cancer and clinically evident bone metastases. [13] A systematic review of studies of calcitonin in bone pain found no evidence to support its use as an adjuvant treatment in bone pain. [14]
   
• Palliative Radiotherapy:
  Single fraction radiotherapy to palliate painful bone metastases is as effective as multiple fractions for controlling pain. [25] Systematic reviews show that more patients who have had single fraction radiotherapy may require retreatment for pain, and there is a non-significant trend to more fractures. [9,15] When there are multifocal painful bone metastases, treatment with radioisotopes such as strontium-89 or samarium-153 can produce sustained analgesia, although they are associated with bone marrow toxicities. [16,17]
   
• NSAIDS:
  An evidence-based report on the management of cancer pain reviewed studies on non-steroidal anti-inflammatory medications, and found that there was evidence that NSAIDS are efficacious, but could not find any differences between different NSAIDS. [18,26] There was also no difference between the efficacy of NSAIDS with and without opioids. Side effects of NSAIDS are potentially significant, including gastric ulceration. The clinical benefit of drugs for gastric protection when treating with NSAIDs is not clear, and it is not known which drugs are most effective in this role. [19]
   
• Antipsychotics:
  There is some emerging evidence that antipsychotics may provide analgesia in both acute and chronic pain, with a number-needed-to-treat of 2.6, although the findings are mixed Extra-pyramidal side-effects were noted in these studies. [27]

What it means in practice

• The role of newer anticonvulsants, (eg gabapentin and pregabalin) in neuropathic pain is evolving. There is evidence to support their efficacy, and evidence-based guidelines now recommend them as one of the first line treatments for neuropathic pain, [20,21] however access to these medications is still limited in Australia. Tricyclics and venlafaxine are alternative recommended first line drugs from the antidepressant class. 
   
• The antidepressant secondary amine tricyclics (nortriptyline, despiramine) have less anticholinergic side effects and are often better tolerated than the frequently used tertiary amines, such as amitriptyline. [21] Antipsychotics, including antypical antipsychotics, have a potential role as adjuvant analgesics, although the evidence is not strong. 
   
• For bone pain due to metastases, radiotherapy is an effective treatment and should be offered first line along with opioid analgesia. Bisphosphonates may be used if the therapeutic response is inadequate, but the analgesic effect is not immediate. There is no role for calcitonin in managing bone pain. 
   
• In considering a radiotherapy fractionation schedule the palliative goals, prognosis, and whether the problem is uncomplicated, should be taken into account. Patients who have had single fraction (hypofractionated) radiotherapy may require re-treatment, but overall, shifting to hypofractionated schedules reduces the burden on patients and the workload of radiotherapy units. [15] 
   
• 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. There is therefore little clinical benefit to be gained from using high dose non-steroidals. [19]

Finding out more
Guidelines

• Pharmacological management of neuropathic pain: Evidence-based recommendations. [21]
• Radiotherapy fractionation for the palliation of uncomplicated painful bone metastases: an evidence-based practice guideline. [22]

Link to prescribing information
NB. Prescribing information may not yet have been updated to include the most recent evidence.

• Online Palliative Medicine Handbook
  Click on “Notes on Prescribing”
  This prescribing information is from the UK - some medications or formulations may not be available in Australia. Diamorphine is not used in Australia.
• Therapeutic Guidelines for Palliative Care
  An Australian source of prescribing information not available directly online through CareSearch, but can be accessed online in most hospitals, or purchased.

Overview articles

• Adjuvant analgesics in cancer pain management.
  Lussier D, Huskey AG, Portenoy RK. Oncologist. 2004;9(5):571-91.

Related CareSearch pages
Assessment tools 
Health service issues in pain management
Opioid Analgesics
Non-pharmacological approaches to pain management

References

1. Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in pain management. Oncologist. 2004;9(5):571-91.
2. Caraceni A, Portenoy RK. An international survey of pain characteristics and syndromes. IASP Task Force on Cancer Pain. International Association for the Study of Pain. Pain. 1999 Sep;82(3):263-74.
3. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Revi. 2007 Oct 17;(4):CD005454.
4. Wiffen P, Collins S, McQuay H, Carroll D, Jadad A, Moore A. Anticonvulsant drugs for acute and chronic pain. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD001133.
5. Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database of Systematic Reviews. 2005 Jul 20;(3):CD005452. 
6. Wiffen PJ, McQuay HJ, Moore RA. Carbamazepine for acute and chronic pain. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD005451. 
7. Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003345.
8. Bell RF, Eccleston C, Kalso E. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2003;(1):CD003351.
9. McQuay HJ, Collins SL, Carroll D, Moore RA. Radiotherapy for the palliation of painful bone metastases. Cochrane Database Syst Rev. 2000;(2):CD001793.  
10. Wong R, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database Syst Rev. 2002;(2):CD002068.
11. Djulbegovic B, Wheatley K, Ross J, Clark O, Bos G, Goldschmidt H, et al. Bisphosphonates in multiple myeloma. Cochrane Database Syst Rev. 2002;(3):CD003188.
12. Yuen KK, Shelley M, Sze WM, Wilt T, Mason MD. Bisphosphonates for advanced prostate cancer. Cochrane Database  Syst Rev. 2006 Oct 18;(4):CD006250.
13. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD003474.
14. Martinez-Zapata MJ, Roque M, Alonso-Coello P, Catala E. Calcitonin for metastatic bone pain. Cochrane Database  Syst Rev. 2006 Jul 19;3:CD003223.
15. Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol. 2007 Apr 10;25(11):1423-36.
16. Finlay IG, Mason MD, Shelley M. Radioisotopes for the palliation of metastatic bone cancer: a systematic review. Lancet Oncol. 2005 Jun;6(6):392-400.
17. Bauman G, Charette M, Reid R, Sathya J. Radiopharmaceuticals for the palliation of painful bone metastases - a systematic review. Radiother Oncol. 2005 Jun;75(3):258-70.
18. Carr DB, Goudas LC, Balk EM, Bloch R, Ioannidis JP, Lau J. Evidence report on the treatment of pain in cancer patients. J Natl Cancer Inst Monogr. 2004;(32):23-31. 
19. Gotzsche PC. NSAIDS. Clin Evid (Online). 2007 Jun 1;2007. pii: 1108.
20. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005 Dec 5;118(3):289-305. Epub 2005 Oct 6. 
21. Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, et al. Pharmacological management of neuropathic pain: evidence-based recommendations. Pain. 2007 Dec 5;132(3):237-51. Epub 2001 Oct 24.
22. Wu JS, Wong RK, Lloyd NS, Johnston M, Bezjak A, Whelan T, et al. Radiotherapy fractionation for the palliation of uncomplicated painful bone metastases - an evidence-based practice guideline. BMC Cancer. 2004 Oct 4;4:71.
23. Wiffen PJ, Rees J. Lamotrigine for acute and chronic pain. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD006044. 
24. Legge J, Ball N, Elliott DP. The potential role of ketamine in hospice analgesia: A literature review. Consult Pharm. 2006 Jan;21(1):51-7.
25. Sze WM, Shelley M, Held I, Mason M. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy. Cochrane Database Syst Rev. 2002;(1):CD004721.
26. McNicol E, Strassels SA, Goudas L, Lau J, Carr DB. NSAIDS or paracetamol, alone or combined with opioids, for cancer pain. Cochrane Database Syst Rev. 2005 Jan 25;(1)CD005180.
27. Seidel S, Aigner M, Ossege M, Pernicka E, Wildner B, Sycha T. Antipsychotics for acute and chronic pain in adults. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD004844.

This page was created on 23 May 2008
Last updated 26 November 2009