Pharmacological Management – Non-opioid analgesics

Evidence Summary

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. [1] 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. [2]

Simple Analgesics

Paracetamol

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. [5] There is no high quality evidence for or against its use in cancer pain. [6] 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. [9] 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. [5] 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. [5] There was also moderate evidence that combining NSAIDs with opioids produced improved analgesic efficacy and produced a potential opioid sparing effect. [5] 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. [10] The clinical benefit of drugs for gastric protection when treating patients with NSAID therapy is supported by clinical practice guidelines. [11] NSAIDs should be avoided in patients with renal dysfunction or renal failure. [12] 

Adjuvant Medications

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. [13] 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. [14] 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. [15]

Antidepressants

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. [2] 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. [2] No one antidepressant was superior in studies relating to neuropathic pain in cancer [3] in older people [4] or in children. [14] In end stage renal disease both duloxetine and venlafaxine are not recommended, however, amitriptyline can be used cautiously. [12]

Anticonvulsants

There is strong evidence to support the use of pregabalin and gabapentin in the management of neuropathic pain. [2] 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. [2] 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. [12]

Topical Medications

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. [17]

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. [18] 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

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. [24] A recent study examining refractory cancer pain showed ketamine provided improved analgesia when given for a short period of time at moderate doses. [25] The use of ketamine to manage neuropathic pain is also supported in paediatrics, although the quality of evidence is low. [14,21] 

Bisphosphonates

In the management of metastatic bone pain, systematic reviews support the effectiveness of bisphosphonates. [26] 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. [26]

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. [28]

Practice Implications

  • There is limited evidence to support the use of paracetamol in the palliative care setting. [5]
  • 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. [5]
  • Evidence for combining opioids with adjuvants to improve analgesic effectiveness is limited. [15]
  • 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. [15]
  • Reduced doses of adjuvant medication are recommended for paediatrics, [14] older people [16] and end stage renal disease. [12]
  • 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.
  1. 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.
  2. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015 Feb;14(2):162-73. doi: 10.1016/S1474-4422(14)70251-0. Epub 2015 Jan 7.
  3. Fallon M, Giusti R, Aielli F, Hoskin P, Rolke R, Sharma M, et al. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2018 Oct 1;29(Suppl 4):iv166-iv191. doi: 10.1093/annonc/mdy152.
  4. National Institute for Health and Care Excellence (NICE). Neuropathic pain in adults: pharmacological management in non-specialist settings [Internet]. London: NICE; 2019 [updated 2019 Jul; cited 2019 Oct 31]. (Clinical guideline [CG173]).
  5. Schüchen RH, Mücke M, Marinova M, Kravchenko D, Häuser W, Radbruch L, et al. Systematic review and meta-analysis on non-opioid analgesics in palliative medicine. J Cachexia Sarcopenia Muscle. 2018 Dec;9(7):1235-1254. doi: 10.1002/jcsm.12352. Epub 2018 Oct 29.
  6. Wiffen PJ, Derry S, Moore RA, McNicol ED, Bell RF, Carr DB, et al. Oral paracetamol (acetaminophen) for cancer pain. Cochrane Database Syst Rev. 2017 Jul 12;7:CD012637. doi: 10.1002/14651858.CD012637.pub2.
  7. La Frenais FL, Bedder R, Vickerstaff V, Stone P, Sampson EL. Temporal Trends in Analgesic Use in Long-Term Care Facilities: A Systematic Review of International Prescribing. J Am Geriatr Soc. 2018 Feb;66(2):376-382. doi: 10.1111/jgs.15238. Epub 2017 Dec 23.
  8. Bullock L, Bedson J, Jordan JL, Bartlam B, Chew-Graham CA, Campbell P. Pain assessment and pain treatment for community-dwelling people with dementia: A systematic review and narrative synthesis. Int J Geriatr Psychiatry. 2019 Jun;34(6):807-821. doi: 10.1002/gps.5078. Epub 2019 Apr 8.
  9. Radman M, Babic A, Runjic E, Jelicic Kadic A, Jeric M, Moja L, et al. Revisiting established medicines: An overview of systematic reviews about ibuprofen and paracetamol for treating pain in children. Eur J Pain. 2019 Jul;23(6):1071-1082. doi: 10.1002/ejp.1380. Epub 2019 Mar 18.
  10. Wood H, Dickman A, Star A, Boland JW. Updates in palliaiteve care- overview and recent advancements in pharmacological management of cancer pain. Clin Med (Lond). 2018 Feb;18(1):17-22. doi: 10.7861/clinmedicine.18-1-17.
  11. National Institute for Health and Care Excellence (NICE). Gastro-oesphaegeal reflux disease and dyspepsia in adults: investigation and management. London: NICE; 2019 [updated 2019 Oct; cited 2019 Nov 6]. (Clinical guideline [CG184]).
  12. Wilcock A, Charlesworth S, Twycross R, Waddington A, Worthington O, Murtagh FEM, et al. Prescribing Non-Opioid Drugs in End-Stage Kidney Disease. J Pain Symptom Manage. 2017 Nov;54(5):776-787. doi: 10.1016/j.jpainsymman.2017.08.014. Epub 2017 Aug 24.
  13. van den Beuken-van Everdingen MH, de Graeff A, Jongen JL, Dijkstra D, Mostovaya I, Vissers KC, et al. Pharmacological Treatment of Pain in Cancer Patients: The Role of Adjuvant Analgesics, a Systematic Review. Pain Pract. 2017 Mar;17(3):409-419. doi: 10.1111/papr.12459. Epub 2016 May 21.
  14. Anghelescu DL, Tesney JM. Neuropathic Pain in Pediatric Oncology: A Clinical Decision Algorithm. Paediatr Drugs. 2019 Apr;21(2):59-70. doi: 10.1007/s40272-018-00324-4.
  15. Kane CM, Mulvey MR, Wright S, Craigs C, Wright JM, Bennett MI. Opioids combined with antidepressants or antiepileptic drugs for cancer pain: Systematic review and meta-analysis. Palliat Med. 2018 Jan;32(1):276-286. doi: 10.1177/0269216317711826. Epub 2017 Jun 12.
  16. Dosenovic S, Jelicic Kadic A, Miljanovic M, Biocic M, Boric K, Cavar M, et al. Interventions for Neuropathic Pain: An Overview of Systematic Reviews. Anesth Analg. 2017 Aug;125(2):643-652. doi: 10.1213/ANE.0000000000001998.
  17. Derry S, Lloyd R, Moore RA, McQuay HJ. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007393.
  18. Chan AK, Cheung CW, Chong YK. Alpha-2 agonists in acute pain management. Expert Opin Pharmacother. 2010 Dec;11(17):2849-68. doi: 10.1517/14656566.2010.511613. Epub 2010 Aug 13.
  19. Splinter W. Novel Approaches for Treating Pain in Children. Curr Oncol Rep. 2019 Feb 4;21(2):11. doi: 10.1007/s11912-019-0766-6.
  20. Hauer J, Houtrow AJ; SECTION ON HOSPICE AND PALLIATIVE MEDICINE, COUNCIL ON CHILDREN WITH DISABILITIES. Pain Assessment and Treatment in Children With Significant Impairment of the Central Nervous System. Pediatrics. 2017 Jun;139(6). pii: e20171002. doi: 10.1542/peds.2017-1002.
  21. Friedrichsdorf SJ, Kang TI. The management of pain in children with life-limiting illnesses. Pediatr Clin North Am. 2007 Oct;54(5):645-72, x.
  22. Baenziger PH, Moody K. Palliative Care for Children with Central Nervous System Malignancies.  2018 Oct 13;5(4). pii: E85. doi: 10.3390/bioengineering5040085.
  23. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2017 Jun 28;6:CD003351. doi: 10.1002/14651858.CD003351.pub3.
  24. Aiyer R, Mehta N, Gungor S, Gulati A. A Systematic Review of NMDA Receptor Antagonists for Treatment of Neuropathic Pain in Clinical Practice. Clin J Pain. 2018 May;34(5):450-467. doi: 10.1097/AJP.0000000000000547.
  25. Mercadante S, Caruselli A, Casuccio A. The use of ketamine in a palliative-supportive care unit: a retrospective analysis. Ann Palliat Med. 2018 Apr;7(2):205-210. doi: 10.21037/apm.2018.01.01.
  26. Porta-Sales J, Garzón-Rodríguez C, Llorens-Torromé S, Brunelli C, Pigni A, Caraceni A. Evidence on the analgesic role of bisphosphonates and denosumab in the treatment of pain due to bone metastases: A systematic review within the European Association for Palliative Care guidelines project. Palliat Med. 2017 Jan;31(1):5-25. doi: 10.1177/0269216316639793. Epub 2016 Jul 10.
  27. Darkovska-Serafimovska M, Serafimovska T, Arsova-Sarafinovska Z, Stefanoski S, Keskovski Z, Balkanov T. Pharmacotherapeutic considerations for use of cannabinoids to relieve pain in patients with malignant diseases. J Pain Res. 2018 Apr 23;11:837-842. doi: 10.2147/JPR.S160556. eCollection 2018.
  28. Hauser W, Serafimovska T, Arsova-Sarafinovska Z, Stefanoski S, Keskovski Z, Balkanov T. Cannabinoids in Pain Management and Palliative Medicine. Dtsch Arztebl Int, 2017. 114(38): p. 627-634.

Guidelines

Link to Prescribing Information

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

Last updated 06 November 2019